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Pathophysiological Basis of Vulnerability to Drug Abuse: Role of an Interaction Between Stress, Glucocorticoids, and Dopaminergic Neurons
Abstract
Reviews data supporting an individual-centered vision of addiction and discusses the experimental evidence suggesting that stress, glucocorticoids, and dopamine are organized in a pathophysiological chain, giving rise to vulnerability to drug abuse. The development of addiction does not seem to be the simple consequence of the intrinsic effects of drugs of abuse, but rather the result of their interaction with specific individual substrates. Differences in the propensity to develop drug intake can be demonstrated in animals with equal access to drugs under stable laboratory conditions and can be predicted by drug-independent behaviors. An understanding of the part played by individuals and their biological makeup in the etiology of drug abuse is an essential step in the development of new strategies for the treatment of addiction. (PsycINFO Database Record (c) 2006 APA, all rights reserved)
... Stressful events are correlated with craving for most drugs of abuse (Piazza & Le Moal, 1996), and the hypothalamicpituitary-adrenal (HPA) axis response to stress is a critical factor influencing individual vulnerability to drug abuse (Aouizerate et al., 2006;Kreek, 2000;Piazza & Le Moal, 1996;Wemm & Sinha, 2019;Zhou et al., 2013;Zhou & Leri, 2016). During prolonged abstinence from opioids, HPA axis dynamics are altered in ways that are specific among drugs of abuse and relapse vulnerability (Aouizerate et al., 2006;Bunce et al., 2015;Zhou et al., 2013). ...
... Stressful events are correlated with craving for most drugs of abuse (Piazza & Le Moal, 1996), and the hypothalamicpituitary-adrenal (HPA) axis response to stress is a critical factor influencing individual vulnerability to drug abuse (Aouizerate et al., 2006;Kreek, 2000;Piazza & Le Moal, 1996;Wemm & Sinha, 2019;Zhou et al., 2013;Zhou & Leri, 2016). During prolonged abstinence from opioids, HPA axis dynamics are altered in ways that are specific among drugs of abuse and relapse vulnerability (Aouizerate et al., 2006;Bunce et al., 2015;Zhou et al., 2013). ...
... Perspectives: An abnormal response to stress, and the effects of drugs on the HPA axis that mediate its reactivity to stress, have been proposed as a biological basis for substance misuse (Piazza & Le Moal, 1996;Shi et al., 2009;Sinha et al., 2003;Zhou & Leri, 2016). The female HPA axis responds differently than the male HPA axis to acute and chronic stressors and to drugs of abuse, including opioids (Becker et al., 2017;Becker & Koob, 2016;Carroll & Lynch, 2016;Figueira & Ouakinin, 2010;Laviola et al., 2002;Ordaz & Luna, 2012). ...
Hypothalamic-pituitary-adrenal (HPA) axis dynamics are disrupted by opioids and may be involved in substance abuse; this persists during withdrawal and abstinence and is associated with co-morbid sleep disruption leading to vulnerability to relapse. We hypothesized that chronic sleep restriction (SR) alters the HPA axis diurnal rhythm and the sexually dimorphic response to acute stressor during opioid abstinence. We developed a rat model to evaluate the effect of persistent sleep loss during opioid abstinence on HPA axis dynamics in male and female rats. Plasma ACTH and corticosterone were measured diurnally and in response to acute restraint stress in rats Before (control) compared to During subsequent opioid abstinence without or with SR. Abstinence, regardless of sleep state, led to an increase in plasma ACTH and corticosterone in the morning in males. There was a tendency for higher PM plasma ACTH during abstinence in SR males (P = 0.076). ACTH and corticosterone responses to restraint were reduced in male SR rats whereas there was a failure to achieve the post-restraint nadir in female SR rats. There was no effect of the treatments or interventions on adrenal weight normalized to body weight. SR resulted in a dramatic increase in hypothalamic PVN AVP mRNA and plasma copeptin in male but not female rats. This corresponded to the attenuation of the HPA axis stress response in SR males during opioid abstinence. We have identified a potentially unique, sexually dimorphic role for magnocellular vasopressin in the control of the HPA axis during opioid abstinence and sleep restriction.
... In the context of more basic investigations, a multitude of animal studies [59][60][61] and some human studies [62] suggest that acute stress manipulation, possible through an increase of brain levels of glucocorticoids and catecholamines [63], quickly activates mesocorticolimbic dopaminergic neurons [59,60,62,64] which in turn potentiates cue-triggering wanting, attentional orienting toward salient events and learning from behavioral reinforcements [61,65]. ...
... In the context of more basic investigations, a multitude of animal studies [59][60][61] and some human studies [62] suggest that acute stress manipulation, possible through an increase of brain levels of glucocorticoids and catecholamines [63], quickly activates mesocorticolimbic dopaminergic neurons [59,60,62,64] which in turn potentiates cue-triggering wanting, attentional orienting toward salient events and learning from behavioral reinforcements [61,65]. ...
Perseverative cognition (PC) is a transdiagnostic risk factor that characterizes both hypo-motivational (e.g., depression) and hyper-motivational (e.g., addiction) disorders; however, it has been almost exclusively studied within the context of the negative valence systems. The present study aimed to fill this gap by combining laboratory-based, computational and ecological assessments. Healthy individuals performed the Probabilistic Reward Task (PRT) before and after the induction of PC or a waiting period. Computational modeling was applied to dissociate the effects of PC on reward sensitivity and learning rate. Afterwards, participants underwent a one-week ecological momentary assessment of daily PC occurrence, as well as anticipatory and consummatory reward-related behavior. Induction of PC led to increased response bias on the PRT compared to waiting, likely due to an increase in learning rate but not in reward sensitivity, as suggested by computational modeling. In daily-life, PC increased the discrepancy between expected and obtained rewards (i.e., prediction error). Current converging experimental and ecological evidence suggests that PC is associated with abnormalities in the functionality of positive valence systems. Given the role of PC in the prediction, maintenance, and recurrence of psychopathology, it would be clinically valuable to extend research on this topic beyond the negative valence systems.
... In the context of more basic investigations, a multitude of animal studies [59][60][61] and some human studies [62] suggest that acute stress manipulation, possible through an increase of brain levels of glucocorticoids and catecholamines [63], quickly activates mesocorticolimbic dopaminergic neurons [59,60,62,64] which in turn potentiates cue-triggering wanting, attentional orienting toward salient events and learning from behavioral reinforcements [61,65]. ...
... In the context of more basic investigations, a multitude of animal studies [59][60][61] and some human studies [62] suggest that acute stress manipulation, possible through an increase of brain levels of glucocorticoids and catecholamines [63], quickly activates mesocorticolimbic dopaminergic neurons [59,60,62,64] which in turn potentiates cue-triggering wanting, attentional orienting toward salient events and learning from behavioral reinforcements [61,65]. ...
Perseverative cognition (PC) is a transdiagnostic risk factor that characterizes both hypo- motivational (e.g., depression) and hyper-motivational (e.g., addiction) disorders; however, it has been almost exclusively studied within the context of the negative valence systems. The present study aimed to fill this gap by combining laboratory-based, computational and ecological assessments. Healthy individuals performed the Probabilistic Reward Task (PRT) before and after the induction of PC or a waiting period. Computational modeling was applied to dissociate the effects of PC on reward sensitivity and learning rate. Afterwards, participants underwent a one-week ecological momentary assessment of daily PC occurrence, as well as anticipatory and consummatory reward- related behavior. Induction of PC led to increased response bias on the PRT compared to waiting, likely due to an increase in learning rate but not in reward sensitivity, as suggested by computational modeling. In daily-life, PC increased the discrepancy between expected and obtained rewards (i.e., prediction error). Current converging experimental and ecological evidence suggests that PC is associated with abnormalities in the functionality of positive valence systems. Given the role of PC in the prediction, maintenance, and recurrence of psychopathology, it would be clinically valuable to extend research on this topic beyond the negative valence systems.
... have been associated with substance use and the risk of substance use disorders (Piazza & Le Moal, 1996;Sinha, 2008). Conceptual models have proposed distinct, sex-related pathways linking altered stress reactivity with risk for substance use and disorders (Chaplin et al., 2018). ...
Background
Alcohol use disorder (AUD) and stress influence overlapping neural circuits in the brain. The literature is mixed regarding the presence of sex differences in the neural response to acute stressors, and this issue has not been examined in individuals with AUD. We validated a stress functional magnetic resonance imaging (fMRI) paradigm in individuals with AUD and tested for sex differences.
Methods
Twenty‐five treatment‐seeking individuals with AUD (15M/10F) were recruited to participate in the neuroimaging study linked to a clinical trial of ibudilast (NCT03594435). To assess social‐evaluative stress, participants completed the Montreal Imaging Stress Task (MIST). Whole brain and amygdala region‐of‐interest analyses were conducted. Subjective ratings of anxiety and distress were collected. Repeated measures ANCOVAs were performed to evaluate the effect of stress on anxiety and distress and to evaluate sex differences.
Results
There were trend‐level effects of stress on anxiety ratings and amygdala activation (p's = 0.06). There was a significant effect of stress in the bilateral thalamus, ventral tegmental area, and paracingulate (Z's > 4.09, p's < 0.03). There was a trend‐level effect of sex on subjective ratings of stress (p's = 0.07). Females had higher amygdala activation in response to stress (p = 0.02). Females also had greater activation than males in the precuneus, posterior cingulate cortex, and right inferior frontal gyrus during acute stress (Z's > 3.56, p's < 0.03).
Conclusions
This study provides an initial validation of the MIST in a sample of individuals with AUD. It also provides preliminary evidence of sex differences in the response to social‐evaluative stress, which is important, given the relevance of stress and negative emotionality as motivators for alcohol use in females.
... The multifactorial etiology of drug addiction may be precipitated by the complex interaction between various genetic, environmental, and psychosocial factors (Kreek et al., 2005;Malone et al., 2022;Piazza and Le Moal, 1996). Environmental enrichment is a model achieved by housing animals in large chambers with social partners and access to novel objects. ...
... Similar to insufficient fetal iron loading, prenatal stress impairs learning [55], increases anxiety and depressive behaviors [56] (reviewed in [10]), and affects dopaminergic and hippocampal development [57,58]. Exposure to stress during prenatal development is linked to cortical thinning and reduced cognitive functioning in offspring [59]. ...
This review presents evidence from animal and human studies demonstrating the possible connection and significant impact of poor iron status and psychological distress on neurocognitive development during pregnancy and the neonatal period, with implications for long-term cognition. Stress and iron deficiency are independently prevalent and thus are frequently comorbid. While iron deficiency and early-life stress independently contribute to long-term neurodevelopmental alterations, their combined effects remain underexplored. Psychological stress responses may engage similar pathways as infectious stress, which alters fundamental iron metabolism processes and cause functional tissue-level iron deficiency. Psychological stress, analogous to but to a lesser degree than infectious stress, activates the hypothalamic–pituitary–adrenocortical (HPA) axis and increases proinflammatory cytokines. Chronic or severe stress is associated with dysregulated HPA axis functioning and a proinflammatory state. This dysregulation may disrupt iron absorption and utilization, likely mediated by the IL-6 activation of hepcidin, a molecule that impedes iron absorption and redistributes total body iron. This narrative review highlights suggestive studies investigating the relationship between psychological stress and iron status and outlines hypothesized mechanistic pathways connecting psychological stress exposure and iron metabolism. We examine findings regarding the overlapping impacts of early stress exposure to iron deficiency and children’s neurocognitive development. We propose that studying the influence of psychological stress on iron metabolism is crucial for comprehending neurocognitive development in children exposed to prenatal and early postnatal stressors and for children at risk of early iron insufficiency. We recommend future directions for dual-exposure studies exploring iron as a potential mediating pathway between early stress and offspring neurodevelopment, offering opportunities for targeted interventions.
... Maternal experience of stressful events during developmental periods in the pregnancy has long been considered a risk factor for psychiatric disorders, including substance abuse, as well as disorders associated with anxiety (Piazza & Le Moal, 1996;Sinha, 2008). In the present work, we examined the potential of agmatine as a therapeutic agent F I G U R E 3 Anxiety-like behavior in the elevated plus maze: (a) closed arm and (b) open arm duration. ...
Prenatal stress (PS) results from a maternal experience of stressful events during pregnancy, which has been associated with an increased risk of behavioral disorders including substance abuse and anxiety in the offspring. PS is known to result in heightened dopamine release in the ventral tegmental area (VTA), in part through the effects of corticotropin‐releasing hormone, which directly excites dopaminergic cells. It has recently been suggested that agmatine plays a role in modulating anxiety‐like behaviors. In this study, we investigated whether agmatine could reduce negative cognitive outcomes in male mice prenatally exposed to psychological/physical stress, and whether this could be associated with molecular changes in VTA. Agmatine (37.5 mg/kg) was administrated 30 min prior to PS induction in pregnant Swiss mice. Male offspring were evaluated in a series of behavioral and molecular assays. Findings demonstrated that agmatine reduced the impairment in locomotor activity induced by both psychological and physical PS. Agmatine also decreased heightened conditioned place preference to morphine seen in PS offspring. Moreover, agmatine ameliorated the anxiety‐like behavior and drug‐seeking behavior induced by PS in the male offspring. Molecular effects were seen in VTA as the enhanced brain‐derived neurotrophic factor (BDNF) induced by PS in the VTA was reduced by agmatine. Behavioral tests indicate that agmatine exerts a protective effect on PS‐induced impairments in male offspring, which could be due in part to agmatine‐associated molecular alterations in the VTA. Taken together, our data suggest that prenatal treatment with agmatine exerts protective effect against negative consequences of PS on the development of affective circuits in the offspring.
... The individual differences in both the degree of sign-tracking and the development of impulse control deficits suggests the possibility of additional risk factors at play. Both sign-tracking 49 and impulse control disorders 47 are influenced by stressful early environments. Our finding that STs have lower income households, increased difficulty for affording basic needs, and less social support suggests probable environmental impacts on individual differences in sign-tracking tendencies and the underlying neurobiological mechanisms. ...
Externalizing behaviors in childhood often predict impulse control disorders in adulthood; however, the underlying bio-behavioral risk factors are incompletely understood. In animals, the propensity to sign-track, or the degree to which incentive motivational value is attributed to reward cues, is associated with externalizing-type behaviors and deficits in executive control. Using a Pavlovian conditioned approach paradigm, we quantified sign-tracking in 40 healthy 9–12-year-olds. We also measured parent-reported externalizing behaviors and anticipatory neural activations to outcome-predicting cues using the monetary incentive delay fMRI task. Sign-tracking was associated with attentional and inhibitory control deficits and the degree of amygdala, but not cortical, activation during reward anticipation. These findings support the hypothesis that youth with a propensity to sign-track are prone to externalizing tendencies, with an over-reliance on subcortical cue-reactive brain systems. This research highlights sign-tracking as a promising experimental approach delineating the behavioral and neural circuitry of individuals at risk for externalizing disorders.
... Humans form associations between illicit drugs and aspects of the drug-taking environment (de Wit 2009), and they report an increase in liking for that drug-paired environment (Napier et al. 2013). These initial drug-environment associations may play a role in perpetuating that desire for drug reward and perhaps even drug addiction (Piazza and Le Moal 1996). A commonly used rodent model of drug-environment associations is conditioned place preference (CPP). ...
Rationale and objectives
Drug-seeking behavior occurs more readily in some individuals than others. This phenomenon is considered in studies of drug self-administration in which high drug-seeking/taking individuals can be identified. In contrast, studies of conditioned place preference (CPP) often involve a random sample of drug-naïve rodents that includes phenotypes not considered relevant to addiction. The main objective of the current studies was to determine if a priori identification of different conditioning phenotypes could improve the validity and sensitivity of CPP expression as a preclinical test for vulnerability to addiction.
Methods and results
Analysis of cocaine place conditioning data from 443 Swiss-Webster mice revealed a trimodal distribution with peaks corresponding to means of k = 3 clusters. The cluster means occurred at high, low, or negative preference scores, the latter suggesting a phenotype acquiring conditioned place aversion (CPA). The same clusters were identified in mice conditioned with methamphetamine, MDPV, or amphetamine, and these clusters remained stable and reliable during three additional expression tests spaced at 24 h. A meta-analysis of effect sizes obtained from CPP literature revealed a positively skewed distribution affected by sample size, consistent with the existence of a CPA phenotype within the populations tested. A dopamine receptor antagonist, flupentixol, blocked cocaine CPP expression in a group containing all phenotypes, but sensitivity improved markedly when CPA phenotypes were excluded from the dataset.
Conclusions
These studies suggest that taking phenotype into consideration when designing place conditioning studies will improve their application as a preclinical tool in addiction biology and drug discovery.
... The maladaptive persistence of responding has been extensively demonstrated in animal models of both drugs and sucroseseeking (see review (Venniro et al. 2020), confirming that energy-dense palatable foods and drugs of abuse can impact similarly the reward brain circuits (Small et al. 2001;Volkow and Morales 2015;Volkow et al. 2012). The vulnerability to addiction and relapse results from the complex interaction between rewarding stimulus exposure, biological factors (genetics, epigenetics, synaptic and neuronal plasticity) and environmental factors (socioeconomic conditions, family and peer relationship, stress, exposure to alternative reinforcers) (Kreek et al. 2005;Piazza and Le Moal 1996;Volkow and Boyle 2018). Indeed, it is well known that the conditioning spatial context (Cx) plays an important role in addiction, promoting reward taking and relapse (Crombag et al. 2008;Crombag and Shaham 2002;Khoo et al. 2017). ...
Rationale
Several single or combined therapeutic approaches have been developed to treat addiction, however with partial efficacy in preventing relapse. Recently, the living environment has been suggested as a critical intervening factor determining the treatment outcomes. Despite accumulating evidence confirming a role of living conditions in the vulnerability to addictive behaviours, their impact on single or integrative therapeutic strategies preventing relapse is yet to be identified.
Objectives
Here, we explore the possible interaction between brief Environmental Enrichment (EE) exposure and acute fluoxetine administration in inhibiting sucrose-seeking behaviours, and whether this effect could be affected by living environment.
Methods
Social and isolated adult male C57BL/6 mice were trained to sucrose self-administration associated to a specific conditioning context (CxA), followed by a 7-day extinction in a different context (CxB). Afterwards, mice were exposed for 22 h to EE and then injected with fluoxetine (10 mg/kg, i.p.) 1 h before a CxA-induced sucrose-seeking test.
Results
Brief EE exposure and acute fluoxetine administration alone inhibited context-induced sucrose-seeking in both housing conditions; however, they exhibited additive properties only in social condition.
Conclusions
Our data show that social environment may influence the EE/fluoxetine interaction in inhibiting relapse to sucrose. These findings suggest that setting up proper living conditions to boost the efficacy of therapeutic approaches may represent a fundamental strategy to treat addiction disorders.
... La vulnérabilité à l'addiction à une drogue résulte d'interactions complexes entre la drogue, les facteurs génétiques et l'environnement (Piazza and Le Moal, 1996). Ainsi, les facteurs négatifs de stress, les relations entre pairs, la pauvreté et les difficultés, ou les facteurs d'expériences positives, augmentent ou diminuent respectivement les risques d'engager dans des comportements addictifs (Koob, 2008;Sinha, 2001) (Fig. 2). ...
Les produits du tabac sont hautement addictifs et leur abus est un problème majeur de santé publique. Chez les humains, cette addiction met en jeu une expérience consommatoire orale avec des composantes sensorielles gustatives et olfactives. De nos jours, le rôle de ces composantes est amplifié avec l’utilisation accrue des produits du tabac non-brûlé, mais aussi les cigarettes électroniques, où la nicotine est associée à des additifs incluant flaveurs et sucres. L’impact des additifs sur le comportement de consommation du tabac doit donc être évalué. Dans ce travail de recherche, notre intérêt se porte sur la nicotine orale et l’interaction bidirectionnelle avec les flaveurs associées. Nous questionnons notamment les propriétés de renforcement secondaire, les effets des arômes sur la palatabilité de la nicotine et son encodage affectif. Dans un premier chapitre, nous avons investigué les propriétés irritantes de la nicotine dans un modèle d’auto-administration orale de nicotine diluée dans de la saccharine chez des souris génétiquement modifiées (knockout) pour le thermorécepteur TRPV1 (Transient receptor potential vanilloid 1), impliqué dans l’échauffement lié au tabagisme et qui a la particularité d’être sensibilisé par la nicotine. Nous mettons en évidence que l’absence de ce récepteur promeut la consommation de nicotine par diminution de son aversion orale. Il n’a cependant pas un rôle spécifique dans les mécanismes de motivation et de rechute. Il a été montré que les stimuli sensoriels non-pharmacologiques deviennent plus salients quand ils sont associés à la nicotine. Ainsi, nous étudions dans un deuxième chapitre, le renforcement secondaire putatif des stimuli oraux par la nicotine. Nous mettons en évidence la nécessité d’association orale de la nicotine à des additifs masquant son goût amer, afin de permettre sa consommation volontaire et la modélisation des différents stades du processus addictif. Ce processus se montre sensible aux stimuli dans la consommation et la rechute, mais insensible aux challenges pharmacologiques malgré l’absorption de nicotine mesurée par la présence de cotinine plasmatique. Les solutions de nicotine à fortes concentrations révèlent des propriétés aversives et réduisent la consommation volontaire. Bien que nous ne montrions pas le renforcement des propriétés incitatives de la vanille par la nicotine, de façon surprenante nous montrons que l’arôme seul peut renforcer le comportement d’auto-administration. Enfin, du fait de l’importance des effets sensoriels oraux dans la consommation de nicotine, nous avons étudié ses propriétés de palatabilité. Les tests de réactivité gustative montrent bien l’aversion gustative pour la nicotine seule et l’amélioration de la palatabilité par l’ajout d’additif aromatique. Ce changement de la palatabilité ne s’est néanmoins pas traduit par des changements du codage neuronal mesuré par le marquage de la protéine c-Fos dans les structures contribuant à l’expression de la valence positive ou négative, notamment le noyau accumbens, le cortex insulaire gustatif, le noyau basolatéral de l’amygdale, l’habenula et la noyau paraventriculaire du thalamus. En revanche, la nicotine, aromatisée ou non, a augmenté l’activation neuronale dans toutes ces structures. L’ensemble de ces résultats met en lumière cette problématique d’association de la nicotine aux additifs pouvant moduler sa perception sensorielle et promouvoir par la suite sa consommation. L’attractivité des nouveaux produits du tabac et leur potentiel d’abus est une question authentique et un problème de santé publique dont l’étude et la régulation sont urgentes.
... Personal problems due to substance abuse include family [38], relational [39] and psychological [40] problems, and the loss of friendships and even jobs [41]. Moreover, these effects are quite frequent and independent of the type of drug used [42,43]. The CRAFFT Screening Test is a short and widely used clinical assessment tool designed to screen for substance-related risks and problems. ...
Background and objectives: Drug abuse has become a major worldwide health concern among all age groups. The present study analyses substance misuse and its social and personal consequences using a population-based internet survey in Spain. Materials and Methods: Screening for drug abuse (of alcohol, marijuana/hashish and psychostimulants) and its related risks and problems was performed using the Car, Relax, Alone, Forget, Friends, Trouble (CRAFFT) score. Socio-demographic factors, depressive, anxiety and stress symptoms as well as health habits were also evaluated. We used Linear regression methods to compare each variable’s individual contribution so as to determine which one best explains the results. Results: In this population-based study, 1224 people completed and returned the online survey. Of all participants, 57% reported consuming at least one substance based on the CRAFFT scale. While increasing age reduces the probability of personal and social consequences of consumption, people who smoke receive up to three times more (OR = 3.370) recommendations from family and friends to reduce their consumption. As for the type of substance, the consumption of marijuana increases the risk of forgetting (OR = 2.33) and the consumption of other psychostimulant substances almost triples the risk of consuming alone (OR = 2.965). Combining substances can increase the rate of driving a vehicle after consumption by 3.4 times. Conclusions: Although age, smoking and the type of substances used increase the risk of suffering from social and personal consequences of the use or abuse of substances, future studies are needed to determine the influence of new variables as a potential tool for treating and minimizing the adverse consequences of drug abuse.
... Displacement of the lever with enough force to register a response is considered a sign-tracking behavior (SIGN-CR), while goal-tracking (GOAL-CR) is measured through head entry into the location of food delivery. Neurological differences between subjects who primarily sign-track (sign-trackers) and those who primarily goal-track (goaltrackers) have been noted, with alterations in corticosterone release (Piazza & Le Moal, 1996), alterations in dopamine activity in nucleus accumbens (Piazza et al., 1989), and cue-induced activity in subcortical areas (Tomie et al., 2008) being characteristic of sign-tracking. Sign-and goal-tracking have been found to produce different patterns of activation in nucleus accumbens (Gillis & Morrison, 2019). ...
Sign- and goal-tracking are behaviors seen in many species when a conditioned stimulus and it's corresponding unconditioned stimulus are presented at separate locations, and have been the focus of studies on appetitive conditioned and drug dependence. The neurochemical basis of sign-tracking is of interest for both studies of basic conditioning and addiction. In this work, I examined the role of norepinephrine by employing two noradrenergic drugs used for attention-deficit hyperactivity disorder (ADHD)-(a) atomoxetine, a norepinephrine reuptake blocker, and (b) guanfacine, an α2A-adrenergic receptor agonist. Sprague-Dawley rats were trained using a standard Pavlovian conditioning procedure with a retractable lever as conditioned stimulus and sucrose pellets as unconditioned stimulus. It was found that while atomoxetine reduced both sign- (both doses) and goal-tracking (only at the higher dose), guanfacine did not have any effect on either behavior. While norepinephrine reuptake blocking may be an effective strategy for reducing sign-tracking, manipulation of the α2A-adrenergic receptor appears less viable. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
... Negative affect seems to challenge regulation by making rewards and temptations more salient. This is thought to happen, in part, as a result of an increase in glucocorticoid stress hormones that are released during times of distress; increases in these hormones result in the brain's reward system becoming particularly sensitive, thereby making stimuli (e.g., food, cigarettes, drugs) more tempting (Piazza & Le Moal, 1996). ...
Extensive research shows that negative emotions and stress can prompt eating behavior that is in excess of physiological nutritional needs. Additionally, research indicates that women are more likely than men to cope with negative emotions and stress by overeating. There is a dearth of Human-Computer Interaction (HCI) research related to Health Information Technology (HIT) interventions that address overeating in context of negative emotions and stress. As a result, there is little guidance for HCI design and evaluation in this area. The study uses a convergent mixed methods design to understand how HIT can support overweight/obese women curb emotion- and stressed-related eating (ESRE), with the ultimate goal of sustained weight management. In the interview study strand, cross sectional semi-structured interviews (N = 22) explore ESRE behavior in overweight/obese women (BMI ≥ 25). The survey study strand, consisting of a questionnaire (N = 430) administered to overweight/obese women, comprises data about user characteristics, stress, ESRE, and coping, and digital access and skills. The thesis found that that overweight/obese women who engage in ESRE encountered stressors that spanned from daily hassles, persistent challenges, and life-changing losses; they also experience stressors related to serving as caretakers and social support providers. They used food as a coping response to the stress they encounter, and tend to associate food with social support. Furthermore, some have characteristics that make them particularly vulnerable to ESRE behavior. This thesis suggests that HIT should assist users before their coping eating response is triggered. Additionally, HIT should support women in becoming aware of their tendencies to associate food with social support. The thesis also found that overweight/obese women who engage in ESRE need to be supported in both the acute and chronic dimensions of their ESRE behavior. Their acute needs include instrumental support for eating awareness in- the- moment as they are making food choices that could be ESRE, as well as in the form of a just-in-time distraction intervention to prevent them from engaging in ESRE. Their chronic needs include support for holistic goals and motivation to address their ESRE, emotional support for encouragement in weight loss efforts, and informational support for appraisal to understand ESRE and change thought patterns for lasting behavior change. This thesis suggests that HIT needs to allowi for more self-experimentation and tailoring opportunities. Finally, the thesis found that stress and self-blame contribute to ESRE behavior, and that the relative influence stress and self-blame had on ESRE differs by racial groups. This thesis suggests that HIT avoid content and design choices that may incite feelings of self-blame. The thesis’ contribution is that it fills a gap in the literature by using an interpretivist approach to understand the ESRE experiences of overweight/obese women, which permits insight into previously-undescribed aspects of the experience. Additionally, the thesis relates the lived experience of ESRE to HIT design, and highlights ESRE behavior in context of socioeconomic factors. It also makes the contribution of applying the concept of self-blame to a sample of overweight/obese women who are largely not diagnosed with an eating disorder. Finally, it explores how self-blame could be taken into account in the design of HIT for weight management.
... Les données issues des modèles animaux soulignent le rôle d'une dysrégulation de l'axe hypothalamo-hypophysocorticosurrénalien (ou axe HPA), comme facteur de vulnérabilité pour la consommation et la dépendance. L'activation de l'axe du stress (par exemple l'activation du Corticotropin Releasing Factor qui stimule la secrétion de l'ACTH puis du cortisol) augmente la neurotransmission dopaminergique dans les régions mésolimbiques [20]. Le stress peut induire, en particulier chez des sujets vulnérables, des modifications du système de récompense à l'origine d'une plus grande sensibilité aux effets renforçateurs des drogues. ...
Comme pour l’ensemble des addictions, la dépendance aux opiacés résulte de l’interaction entre de nombreux déterminants : des facteurs liés à la substance, des facteurs de vulnérabilité individuelle et des facteurs environnementaux. Parmi les troubles psychiatriques associés ou comorbides à la dépendance aux opiacés, les troubles de l’humeur et les troubles anxieux sont les plus fréquents. Les études de co- occurrence qui ont examiné la séquence d’apparition des différentes pathologies montrent que les troubles anxieux et en particulier les troubles phobiques précèdent le plus souvent les conduites addictives. Les troubles de l’humeur sont plus souvent secondaires à l’addiction tout en représentant aussi un facteur de vulnérabilité pour l’usage et la dépendance.
... Imaging studies have shown that alcohol, illicit, and licit drugs activate the mesolimbic DA pathways (Breiter et al., 1997;Drevets et al., 2001;Volkow et al., 1999). Chronic stress, itself, has been seen to increase the release of glucocorticoids and DA in these pathways (Piazza & Le Moal, 1996). Further, increases in cortisol as a result of stress have been associated with increases in DA in the ventral striatum (Oswald et al., 2005). ...
Bisexual women report elevated alcohol and drug use compared to other sexual minority women. This review summarized extant research on mechanisms (i.e., coping processes with minority stress and victimization, disclosure of sexual identity, connectedness to lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ +) community, religiosity, and normative perceptions) that may influence alcohol and other drug use among bisexual women. Specifically, bisexual women experience unique sexual discrimination (i.e., binegativity) and are at heightened risk for other forms of victimization and other stressful life events. Given this heightened experience with stress, bisexual women may use alcohol as a maladaptive coping mechanism. Further, disclosure of one's sexual identity may produce opportunities for connecting with the LGBTQ + community, but such openness may increase exposure to discrimination and stigmatization among bisexual women. Findings on religiosity have been mixed, but there is some support that bisexual women may use substances in response to internal conflict between their religious beliefs and sexual identity. Lastly, we found that normative perceptions of other bisexual women's drinking behaviors are strongly tied to their own levels of alcohol use. From a therapeutic perspective, we suggest that practitioners recognize the unique experience of minority stress and teach strategies that lessen internalized stigma and promote healthy psychosocial adjustment among their bisexual clients. Clinicians may also help their clients find sources of support, which may protect them against the use of alcohol and drugs to manage minority-induced stress. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
... Stressful life events are known to worsen health outcomes, especially in domains closely related to stress, such as substance use and mental health. Stressful life events increase substance use in the short term and substance dependence in the long term; stressful life events also increase post-traumatic stress disorder (PTSD), depression, generalized anxiety disorder (GAD), intermittent explosive disorder (IED), and panic disorder (PD) in the long term ( Aseltine and Gore, 2000 ;Bruns and Geist, 1984 ;Kessler et al., 1995 ;Paykel et al., 1969 ;Piazza and Le Moal, 1998 ;Piazza and Le Moal, 1996 ). The Foreign Employment Promotion Board (FEPB) has reported many Nepalese migrant workers have committed suicide in destination countries ( Shrestha, 2016 ). ...
Purpose
This study investigates long-term consequences of individual migration experience on later life health, specifically self-rated health and functional difficulty.
Design/methodology/approach
The study uses multiple community-, household-, and individual-level data sets from the Chitwan Valley Family Study (CVFS) in Nepal. The CVFS selected a systematic probability sample of 151 neighborhoods in Western Chitwan and collected information on all households and individuals residing in the selected sample neighborhoods. This study uses data from multiple surveys featuring detailed migration histories of 1,373 older adults, and information on their health outcomes, households, and communities.
Findings
Results of the multi-level multivariate analysis show a negative association between number of years of migration experience and self-rated health, and a positive association between migration and functional difficulty. These findings suggest a negative relationship between migration experience and later life health.
Research limitations/implications
Although we collected health outcome measures after the measurement of explanatory and control measures—a unique strength of this study—we were unable to control for baseline health outcomes. Also, due to the lack of time-varying measures of household socioeconomic status in the survey, this investigation was unable to control for measures associated with the economic prosperity hypothesis. Future research is necessary to develop panel data with appropriately timed measures.
Practical implications
The findings provide important insights that may help shape individual's and their family's migration decisions.
Originality/value
This research provides important insight to individuals lured by potential short-term economic prospects in destination places, as well as to scholars and policy makers from migrant-sending settings that are grappling with skyrocketing medical expenses, rapid population aging, and old age security services.
... Two subgroups were distinguished in the same batch of rats: those responding to stress by greater locomotor activity (HR: High Responder) and those responding by lower activity (LR: Low Responder). HRs consumed larger amounts of drugs, had higher dopaminergic activity, and secreted more corticosterone in response to stress (58). In addition, the stimulation of glucocorticoid receptors on dopaminoceptive neurons in the nucleus accumbens contributes to increased motivation for cocaine, probably by increasing dopamine release (59). ...
Psychotherapeutic consultations of drug addict's patients in a Care, Support and Prevention Center in Addictology led us to propose several hypotheses on the genesis of addiction and its articulation with currently available neurobiological data. This care center dispenses both pharmacological maintenance medications for heroin dependence, such as methadone or buprenorphine, and psychological support. Our first hypothesis posits that the addictive process is driven by the narcissistic vulnerability of these patients, its neurobiological foundations being mainly mediated by the activation of endogenous opioid systems. Drug use/abuse could be a way to make arise the “True Self,” therefore overcoming the defensive system's set up to protect oneself from early traumas. The neurobiological impact of traumas is also developed and articulated with psychodynamic concepts, particularly those of Winnicott. Additionally, functions of addiction such as defensive, anti-depressant roles and emotional regulation are discussed in relationship with their currently known neuroscientific bases. Although the experience in the psychodynamic clinic is at a level of complexity much higher than what is currently accessible to the neurosciences, most of the research in this domain stays in line with our psychological understanding of the addictive process. Finally, we outline some critically sensitive points regarding the therapeutic support.
... These effects are mediated via direct stimulation of PVN neurons in the hypothalamus, leading to the subsequent release of CRH and ACTH (Lee, Selvage, Hansen, & Rivier, 2004;Rivier, 2014; Fig. 3). Glucocorticoids have been heavily implicated in reward and addiction (Piazza & Le Moal, 1996). Thus, by stimulating glucocorticoid release, alcohol itself acts as an acute stressor and may play a role in the reinforcement as well as in the motivation for alcohol consumption (Goeders, 2004;Sinha, 2001;Stephens & Wand, 2012;Uhart & Wand, 2009). ...
Chronic exposure to stress throughout lifespan alters brain structure and function, inducing a maladaptive response to environmental stimuli, that can contribute to the development of a pathological phenotype. Studies have shown that hypothalamic-pituitary-adrenal (HPA) axis dysfunction is associated with various neuropsychiatric disorders, including major depressive, alcohol use and post-traumatic stress disorders. Downstream actors of the HPA axis, glucocorticoids are critical mediators of the stress response and exert their function through specific receptors, i.e., the glucocorticoid receptor (GR), highly expressed in stress/reward-integrative pathways. GRs are ligand-activated transcription factors that recruit epigenetic actors to regulate gene expression via DNA methylation, altering chromatin structure and thus shaping the response to stress. The dynamic interplay between stress response and epigenetic modifiers suggest DNA methylation plays a key role in the development of stress surfeit disorders.
... Together, these studies confirm the importance of cell-type specific GR signaling in motivational and social reward behaviors (Douma and de Kloet, 2019). The cellular specificity could explain the differential modulation of GR activity in different areas of the mesolimbic and corticolimbic networks during reward-directed behaviors (Deroche et al., 1995;Gourley et al., 2012;Piazza and Le Moal, 1996;Swanson et al., 2013). The knockdown of GR in the forebrain reduces anxiety-like and active-coping behaviors, and it increases HPA axis activity and impairs the glucocorticoid negative feedback (Boyle et al., 2005;Boyle et al., 2006;Jeanneteau et al., 2012;Laryea et al., 2013). ...
The diversity of actions of the glucocorticoid stress hormones among individuals and within organs, tissues and cells is shaped by age, gender, genetics, metabolism, and the quantity of exposure. However, such factors cannot explain the heterogeneity of responses in the brain within cells of the same lineage, or similar tissue environment, or in the same individual. Here, we argue that the stress response is continuously updated by synchronized neural activity on large-scale brain networks. This occurs at the molecular, cellular and behavioral levels by crosstalk communication between activity-dependent and glucocorticoid signaling pathways, which updates the diversity of responses based on prior experience. Such a Bayesian process determines adaptation to the demands of the body and external world. We propose a framework for understanding how the diversity of glucocorticoid actions throughout brain networks is essential for supporting optimal health, while its disruption may contribute to the pathophysiology of stress-related disorders, such as major depression, and resistance to therapeutic treatments.
Keywords: Allostery; Bayesian brain; epigenetic; plasticity; stress-related disorders; synapse.
... Events that induce a stress response usually produce one or more conditioned or unconditioned emotional reactions, such as fear, anxiety, anger, excitement, pleasure and sadness. In so much as these reactions depend on the specific features of the situation, an appraisal of the event, available coping resources, and the prior emotional state of the individual; exposure to acute behavioral stress facilitates self administration of amphetamines (Piazza et al., 1990;Piazza & Le Moal 1996), morphine (Shaham & Stewart 1994) and cocaine (Miczek & Mutschler, 1996). ...
... The dopaminergic system plays an important role in emotional responses to stress (Hirano, Miyata, Onodera, & Kamei, 2007;Segovia, Del Arco, de Blas, Garrido, & Mora, 2008). There is evidence showing that exposure to glucocorticoids in pre and postnatal periods affects the development of the dopaminergic system and suggesting that the increase of sensitivity to drugs of abuse could be related to interactions between prenatal stress, glucocorticoids and dopaminergic neurons (Piazza & Le Moal, 1996;Rentesi et al., 2013). Dopaminergic receptors (DR) are widely distributed in brain regions. ...
Previous researches showed that maternal deprivation (MD) leads to memory deficits that persist until adulthood. The hippocampus, an important brain structure involved in memory processes, receives dopaminergic afferents from other brain areas that modulate memory. Here we demonstrated that MD results in object recognition memory deficits that are reverted by intra-hippocampal stimulation of D1-dopaminergic receptor and peripheral administration of a dopamine precursor. The D1-dopaminergic receptor and peripheral administration of a dopamine precursor also promoted memory persistence in control rats.
Background:
The bed nucleus of the stria terminalis (BNST) is a structure with a peculiar neurochemical composition involved in modulating anxietylike behavior and fear.
Aim:
The present study investigated the effects on the BNST neurochemical composition and neuronal structure in critical moments of the postnatal period in gestational protein-restricted male rats' offspring.
Methods:
Dams were maintained during the pregnancy on isocaloric rodent laboratory chow with standard protein content [NP, 17%] or low protein content [LP, 6%]. BNST from male NP and age-matched LP offspring was studied using the isotropic fractionator method, Neuronal 3D reconstruction, dendritic-tree analysis, blotting analysis, and high-performance liquid chromatography.
Results:
Serum corticosterone levels were higher in male LP offspring than NP rats in 14-day-old offspring, without any difference in 7-day-old progeny. The BNST total cell number and anterodorsal BNST division volume in LP progeny were significantly reduced on the 14th postnatal day compared with NP offspring. The BNST HPLC analysis from 7 days-old LP revealed increased norepinephrine levels compared to NP progeny. The BNST blot analysis from 7-day-old LP revealed reduced levels of GR and BDNF associated with enhanced CRF1 expression compared to NP offspring. 14-day-old LP offspring showed reduced expression of MR and 5HT1A associated with decreased DOPAC and DOPA turnover levels relative to NP rats. In Conclusion, the BNST cellular and neurochemical changes may represent adaptation during development in response to elevated fetal exposure to maternal corticosteroid levels. In this way, gestational malnutrition alters the BNST content and structure and contributes to already-known behavioral changes.
The effects of ketoconazole, an inhibitor of corticosterone synthesis, were examined during food satiation and food restriction in male and female rats to determine whether increases in heroin self-administration prompted by food restriction were due to a stress response. Females self-administered more heroin infusions than males under both feeding conditions. Food restriction increased heroin infusions by an average of 96% for both females and males. Ketoconazole suppressed the increase due to food restriction in females but not in males. Corticosterone reversed the effect of ketoconazole in a group of 8 females, suggesting an interaction between feeding conditions, sex, and the stress response in rats.
The development of drug-reinforced behavior is a transition process characterized by a relatively rapid shift from little or no drug-maintained responding to high, stable levels of responding. Animal studies of drug self-administration focus on how rapidly this process takes place or what percentage of animals acquire drug self-administration. It is essential to have animal models of acquisition because the process is difficult to study with drug-naive humans. Animal studies reveal a wide range of factors that can either accelerate or decrease acquisition of drug self-administration, such as environmental conditions (e.g., feeding conditions, palatable dietary substances, stress), pharmacological variables (e.g., drug dose, drug history, pretreatment drugs), and individual differences (e.g., reactivity level, age, sex, dietary preferences, genetics). This article discusses the methods used to study acquisition of drug-reinforced behavior in laboratory animals and the variables that have been reported to accelerate or prevent the acquisition of drug-reinforced behavior. An understanding of the conditions that can enhance acquisition in animals may help predict vulnerability to drug use in humans and lead to successful methods for prevention of drug abuse.
Predictions concerning mediating processes for the effects of C. R. Cloninger's (1987a) constructs were tested; criterion variables were substance use level and substance use problems. Participants were 1,225 adolescents (M age: 15.5 years). Structural modeling indicated indirect effects for novelty seeking, harm avoidance, and task reward dependence, mediated through self-control; harm avoidance also had an inverse direct path to substance use level, and social reward dependence had a positive direct path to coping motives for substance use. Good self-control had inverse paths to life events and deviant peer affiliations; poor self-control had positive paths to life events and coping motives; and risk taking had positive paths to coping motives and peer affiliations. Coping motives had a path to level and a direct path to problems; peer affiliations had a path only to substance use level.
The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical-activity-dependent pathways. Here, we implicate in this process a nuclear receptor transcription factor, retinoid X receptor alpha (RXRα), which we initially identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that although its own expression remains unaltered after cocaine exposure, RXRα controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types. Behaviorally, bidirectional viral and pharmacological manipulation of RXRα regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXRα in promoting drug addiction and paves the way for future studies of rexinoid signaling in psychiatric disease states.
No decorrer da contemporaneidade diversos tipos de vícios estão sendo estudados pelos especialistas, dentre estes os provocados pelas substâncias psicoativas. Nessa perspectiva, o objetivo principal desta obra é analisar o comportamento e a genética dos usuários de substâncias psicoativas. Para essa pesquisa seja realizada de maneira consistente, optou-se por desenvolver uma revisão bibliográfica fundamentada na literatura atual, isto é, em artigos, livros e dissertações que foram escritas no decorrer dos últimos 20 anos. Após a realização da pesquisa a partir das fontes mencionadas anteriormente, foi possível concluir que existe uma relação constante entre as substâncias psicoativas, vícios e genética do comportamento. Além disso, tornou-se possível estabelecer um entendimento sobre a genética e os vícios.
This theoretical article revives a classical bridging construct, canalization, to describe a new model of a general factor of psychopathology. To achieve this, we have distinguished between two types of plasticity, an early one that we call 'TEMP' for 'Temperature or Entropy Mediated Plasticity', and another, we call 'canalization', which is close to Hebbian plasticity. These two forms of plasticity can be most easily distinguished by their relationship to 'precision' or inverse variance; TEMP relates to increased model variance or decreased precision, whereas the opposite is true for canalization. TEMP also subsumes increased learning rate, (Ising) temperature and entropy. Dictionary definitions of 'plasticity' describe it as the property of being easily shaped or molded; TEMP is the better match for this. Importantly, we propose that 'pathological' phenotypes develop via mechanisms of canalization or increased model precision, as a defensive response to adversity and associated distress or dysphoria. Our model states that canalization entrenches in psychopathology, narrowing the phenotypic state-space as the agent develops expertise in their pathology. We suggest that TEMP - combined with gently guiding psychological support - can counter canalization. We address questions of whether and when canalization is adaptive versus maladaptive, furnish our model with references to basic and human neuroscience, and offer concrete experiments and measures to test its main hypotheses and implications.
Sex/gender effects have been demonstrated for multiple aspects of addiction, with one of the most commonly cited examples being the "telescoping effect" where women meet criteria and/or seek treatment of substance use disorder (SUD) after fewer years of drug use as compared with men. This phenomenon has been reported for multiple drug classes including opioids, psychostimulants, alcohol, and cannabis, as well as nonpharmacological addictions, such as gambling. However, there are some inconsistent reports that show either no difference between men and women or opposite effects and a faster course to addiction in men than women. Thus, the goals of this review are to evaluate evidence for and against the telescoping effect in women and to determine the conditions/populations for which the telescoping effect is most relevant. We also discuss evidence from preclinical studies, which strongly support the validity of the telescoping effect and show that female animals develop addiction-like features (e.g., compulsive drug use, an enhanced motivation for the drug, and enhanced drug-craving/vulnerability to relapse) more readily than male animals. We also discuss biologic factors that may contribute to the telescoping effect, such as ovarian hormones, and its neurobiological basis focusing on the mesolimbic dopamine reward pathway and the corticomesolimbic glutamatergic pathway considering the critical roles these pathways play in the rewarding/reinforcing effects of addictive drugs and SUD. We conclude with future research directions, including intervention strategies to prevent the development of SUD in women. SIGNIFICANCE STATEMENT: One of the most widely cited gender/sex differences in substance use disorder (SUD) is the "telescoping effect," which reflects an accelerated course in women versus men for the development and/or seeking treatment for SUD. This review evaluates evidence for and against a telescoping effect drawing upon data from both clinical and preclinical studies. We also discuss the contribution of biological factors and underlying neurobiological mechanisms and highlight potential targets to prevent the development of SUD in women.
Cue-based associative learning (i.e., Pavlovian conditioning) is a foundational component of behavior in almost all forms of animal life and may provide insight into individual differences in addiction liability. Cues can take on incentive-motivational properties (i.e., incentive salience) through Pavlovian learning. Extensive testing with non-human animals (primarily rats) has demonstrated significant variation among individuals in the behaviors this type of learning evokes. So-named “sign-trackers” and “goal-trackers” have been examined in many studies of non-human animals, but this work in humans is still a nascent area of research. In the present proof-of-concept study, we used a Pavlovian conditioned approach task to investigate human sign- and goal-tracking in emerging adults. Conditioned behaviors that developed over the course of the task were directed toward the reward-cue and toward the reward location. Participants’ eye-gaze and behavior during the task were submitted to a latent profile analysis, which revealed three groups defined as sign-trackers (n = 10), goal-trackers (n = 4), and intermediate responders (n = 36). Impulsivity was a significant predictor of the sign-tracking group relative to the goal-tracking group. The present study provides preliminary evidence that a simple procedure can produce learned Pavlovian conditioned approach behavior in humans. Though further investigation is required, findings provide a promising step toward the long-term goal of translating important insights gleaned from basic research into treatment strategies that can be applied to clinical populations.
Tourette syndrome (TS) is now recognized as a common neurodevelopmental disorder affecting children and adults. It has gained increasingly public awareness and scientific interest worldwide. Knowledge of its clinical presentation and available treatment approaches has increased dramatically over the last two decades. Tourette Syndrome offers a unique, comprehensive, and up-to-date overview of TS. The volume highlights the latest findings regarding clinical presentation, underlying genetic, epigenetic, immunological, and neurobiological causal mechanisms, and state-of-the-art therapies. Importantly, in this digital world of ours and given the ongoing pandemic, this volume also provides a detailed review of the latest available multifaceted and multidisciplinary treatment options including psychoeducational and cognitive-behavioral interventions, many of which can now be accessed online. More than 50 leading scientists and expert clinicians from across the globe authored the chapters. Readers can also access videotaped presentations recorded by several of these scholars. Fortunately, several of these presentations include individuals with TS and related conditions who have graciously volunteered to discuss their life’s journey. This volume is a useful source for a wide audience of scholars and clinicians, all of whom will have access to what is known so far on TS and related conditions within their area of expertise. It provides readers an opportunity to expand and update their knowledge base in other areas of science and advocacy. Families and health professionals will also have access to updates from a broad range of advocacy associations and organizations all around the world that are dedicated to improving lives of individuals with TS.
Maternal sleep-deprivation (MSD) has been shown to induce stress, hyperactivity, and risk taking behavior in the offspring; howbeit, it is not yet clear whether it may also affect vulnerability to psychostimulant abuse in the offspring. We aimed to determine whether MSD affects extinction and reinstatement of methamphetamine (METH) reward memory in the offspring and also to evaluate the possible role of dopamine D1-like and D2-like receptors in these processes. Thirty-day-old male offspring born to control and sleep-deprived dams (during the third week of pregnancy) were trained to acquire METH-induced place preference (2 mg/kg., i.p.). METH reward memory was then reinstated following an 8-day period of extinction. The offspring received SCH 23390 (0.03 or 0.1 mg/kg, i.p.) or sulpiride (20 or 60 mg/kg, i.p.) as antagonists of dopamine D1-like and D2-like receptors, respectively, either immediately after each daily extinction session or prior to the reinstatement session. MSD postponed METH extinction and facilitated METH reinstatement in the offspring. SCH 23390 facilitated METH extinction and decreased reinstatement of the extinguished METH preference. Sulpiride in the offspring from sleep-deprived dams facilitated METH extinction, but it did not affect reinstatement of the extinguished METH place preference. It seems that MSD may enhance vulnerability to METH abuse in the offspring. Furthermore, both dopamine D1-like and D2-like receptors may mediate METH extinction in the offspring born to the sleep-deprived dams; however, only the dopamine D1 receptor may play an important role in reinstating the extinguished METH reward memory in the offspring.
Addiction, also known as severe substance use disorder, is characterised by compulsive drug-seeking and intake in the face of mounting adverse and negative consequences. Despite the prevalence of illicit drug use within society only a small subset of individuals lose control over their intake after protracted drug use. Several antecedent behavioural endophenotypes and perturbations in underlying reward-related circuitry have been linked with increased vulnerability of the development of addiction. To what extent these behavioural and neural markers pre-exist or are induced by drug exposure is still yet to be fully addressed. In this thesis, behavioural testing for risk endophenotypes was combined with a self-administration model of compulsive cocaine seeking and translationally relevant magnetic resonance imaging to investigate the behavioural and neurobiological underpinnings of vulnerability to compulsive cocaine seeking in rats. A behavioural screening procedure was employed and the underlying relationships between several risk endophenotypes was assessed. Attribution of incentive salience was unrelated to impulsivity yet was positively associated with novelty place preference and locomotor reactivity. ‘Stickiness’ – the tendency to repeat the same choice regardless of reward outcome – on a reversal learning procedure was positively associated with motor impulsivity. A concurrent punishment- drug-seeking procedure was next implemented to assess vulnerability to compulsive cocaine seeking. Of the behavioural risk endophenotytpes assessed, impulsivity along with stickiness significantly predicted compulsive cocaine seeking. In the final chapter, impulsivity and compulsivity were shown to predict lower grey matter volume in the infralimbic cortex and ventral striatum. Functionally, compulsivity and stickiness were predicted by decreased connectivity between the prelimbic cortex and the anterior cingulate cortex with the posterior dorsomedial striatum. In summary, this thesis supports previous work implicating impulsivity as a vulnerability marker for substance dependence in humans, and as a marker for compulsive cocaine use in rodents. These findings extend earlier reports to show that impulsivity, alongside stickiness, predicts future compulsive cocaine seeking. Furthermore, this thesis shows overlapping abnormalities in cortico-striatal networks in future compulsive animals and convergent structural deficits in the infralimbic cortex and ventral striatum of high compulsive and impulsive rats. These findings expand our understanding of vulnerability to drug-seeking by showing that pre-existing deficits in circuits contributing to impulse control and flexible, goal-directed behaviour may be precursors for the emergence of compulsive cocaine seeking.
The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical activity-dependent pathways. Here we implicate in this process a novel nuclear receptor transcription factor, Retinoid X Receptor Alpha (RXRα), which we identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that, while its own expression remains unaltered after cocaine exposure, RXRα controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types. Behaviorally, bidirectional viral and pharmacological manipulation of RXRα regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXRα in promoting drug addiction, and paves the way for future studies of rexinoid signaling in psychiatric disease states.
Sensitization of dopaminergic activity has been suggested as an underlying mechanism in the psychotic symptoms of schizophrenia. Adolescent stress and chronic abuse of methamphetamine (Meth) are well-known risk factors for psychosis and schizophrenia; however it remains unknown how these factors compare in terms of dopaminergic behavioural sensitization in adulthood. In addition, while Brain-Derived Neurotrophic Factor (BDNF) has been implicated in dopaminergic activity and schizophrenia, its role in behavioural sensitization remains unclear. In this study we therefore compared the effect of chronic adolescent treatment with the stress hormone, corticosterone (Cort), or with Meth, on drug-induced locomotor hyperactivity and disruption of prepulse inhibition in adulthood in BDNF heterozygous mice and their wild-type controls, as well as on dopamine receptor gene expression. Between 6 and 9 weeks of age, the animals either received Cort in the drinking water or were treated with an escalating Meth dose protocol. In adulthood, Cort-pretreated mice showed significantly reduced Meth-induced locomotor hyperactivity compared to vehicle-pretreated mice. In contrast, Meth hyperlocomotion was significantly enhanced in animals pretreated with the drug in adolescence. There were no effects of either pretreatment on prepulse inhibition. BDNF Het mice showed greater Meth-induced hyperlocomotion and lower prepulse inhibition than WT mice. There were no effects of either pretreatment on D1 or D2 gene expression in either the dorsal or ventral striatum, while D3 mRNA was shown to be reduced in male mice only irrespective of genotype. These results suggest that in adolescence, chronically elevated glucocorticoid levels, a component of chronic stress, do not cause dopaminergic sensitization adulthood, in contrast to the effect of chronic Meth treatment in the same age period. BDNF does not appear to be involved in the effects of chronic Cort or chronic Meth.
Early life stress (ELS) is a well-established risk factor for many psychiatric and medical disorders, including substance use disorders (SUDs). The relationship between ELS and SUDs is complex and there are likely multiple pathways from ELS to adverse substance use outcomes. The association between ELS and substance use emerges in adolescence. Adolescence is a critical period in development during which substance exposure markedly increases risk for SUDs. Therefore, this review focuses on the literature supporting the hypothesis that ELS increases risk for the development of SUDs through its influence on adolescent substance use. We discuss studies substantiating the role of ELS in adolescent substance use and explore how internalizing and externalizing psychopathology may be antecedents of substance use in adolescence. We examine clinical work suggesting ELS sculpts the Hypothalamic-Pituitary-Adrenal (HPA) Axis and developing brain—particularly subcortical brain regions that underlie stress response, mesocorticolimbic brain systems associated with reward sensitivity, and prefrontal regions that underlie executive control—in a way that increases risk for adolescent substance use and SUDs. We further explore how substance use during adolescence alters structure and function of these same systems, and how brain changes following ELS and adolescent substance use may independently, additively, or interactively contribute to risk for addiction. We conclude by discussing how the current literature can inform interventions aimed at reducing risk for SUDs in individuals with a history of ELS.
The central noradrenergic system innervates almost all regions of the brain and, as such, is well positioned to modulate many neural circuits implicated in behaviors and physiology underlying substance use disorders. Ample pharmacological evidence demonstrates that α1, α2, and β adrenergic receptors may serve as therapeutic targets to reduce drug –seeking behavior and drug withdrawal symptoms. Further, norepinephrine is a key modulator of the stress response, and stress has been heavily implicated in reinstatement of drug taking. In this review, we discuss recent advances in our understanding of noradrenergic circuitry and noradrenergic receptor signaling in the context of opioid, alcohol, and psychostimulant use disorders.
Objectives:
Individuals with a cocaine use disorder (CUD) are more likely to present anxiety, which in turn negatively impacts substance use outcomes. Some evidence suggests that cannabidiol (CBD) presents anxiolytic properties and could be a treatment for substance use disorders. This study explores CBD's effect on stress biomarker (cortisol) and anxiety symptoms in people with CUD.
Methods:
Exploratory analyses were conducted using data from a randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy to treat CUD. We randomized 78 individuals with CUD into receiving a daily oral dose up to 800 mg CBD (n = 40) or placebo (n = 38). The trial was divided into 2 phases: an inpatient detoxification lasting 10 days and an outpatient follow-up lasting 12 weeks. Anxiety symptoms and stress response were assessed using a visual analog scale, the Beck Anxiety Inventory, and cortisol levels at multiple time points throughout the study. We also measured anxiety after a stressful and a cocaine-cue scenarios. We used generalized estimating equations models and multiple linear regression to assess CBD's effects on anxiety and cortisol levels.
Results:
Both treatment groups had similar mean anxiety scores according to the Beck Anxiety Inventory (P = 0.27) and the visual analog scale (P = 0.18). CBD did not decrease anxiety after a stressful (P = 0.14) and a cocaine (P = 0.885) scenarios compared with placebo. No statistically significant group difference was found in cortisol levels (P = 0.76).
Conclusions:
We found no evidence for 800 mg of CBD to be more efficacious than placebo for modulating anxiety symptoms and cortisol levels in individuals with CUD.
Psychiatric disorders represent a significant burden in our societies. Despite the convincing evidence pointing at gene and gene-environment interaction contributions, the role of genetics in the aetiology of psychiatric disease is still poorly understood. Forward genetic screens in animal models have helped elucidate causal links. Here we discuss the application of mutagenesis-based forward genetic approaches in common animal model species: two invertebrates, nematodes (Caenorhabditis elegans) and fruit flies (Drosophila sp.); and two vertebrates, zebrafish (Danio rerio) and mice (Mus musculus), in relation to psychiatric disease. We also discuss the use of large scale genomic studies in human populations. Despite the advances using data from human populations, animal models coupled with next-generation sequencing strategies are still needed. Although with its own limitations, zebrafish possess characteristics that make them especially well-suited to forward genetic studies exploring the aetiology of psychiatric disorders.
Emerging evidence suggests that early-life experiences and exposure to environmental factors are strong determinants of behavior. One of the most studied and well-characterized environmental factors is stress. Exposure to stress and its primary agent cortisol is a strong risk factor for many behavioral disorders. Studies show that stress and cortisol can influence gene function through epigenetic mechanisms, which can lead to persistent changes in behavior.
In this chapter, we will explain how stress and our perception of the stressor activate our hypothalamic–pituitary–adrenal (HPA) axis and how exposure to chronic stress influences behaviors such as mood and addiction to drugs. Specifically, we will cover how chronic stress epigenetically alters the HPA axis itself and genes that are critical for brain function, especially those that regulate the activity of neurotransmitters. Together, evidence suggests that stress exposure affects multiple neurotransmitter systems, and behavioral disorders likely arise from a combination of deficiencies in these systems.
Objective
Research has demonstrated that hypothalamic-pituitary-adrenal (HPA) axis function and sleep patterns are dysregulated in patients diagnosed with opioid use disorder (OUD). It is unclear whether and/or when cortisol and sleep might re-regulate over time, and, whether re-regulation is associated with abstinence following discharge from residential treatment. The current study evaluated changes in sleep and basal cortisol levels in prescription OUD patients in residential treatment, and the association between these measures and treatment outcome following discharge.
Method
As part of a larger study, 55 participants with prescription OUD provided two days of salivary cortisol samples and 12 consecutive nights of sleep actigraphy between days 19 to 30 of residential treatment (Time Point 1; TP1). Thirteen of the original 55 participants remained in residence and repeated the measures between days 60 to 72 (Time Point 2; TP2). Thirty-seven healthy controls (HC) provided baseline measures (TP1) of salivary cortisol and sleep. Treatment outcome data, abstinence vs relapse, were established at 120 days following discharge.
Results
Prescription OUD patients had higher cortisol levels and lower total sleep time (TST) than HC at TP1. At TP2, TST and cortisol levels no longer differed from HCs in the subgroup of patients who remained abstinent following discharge after TP2. Individuals whose cortisol and TST did not change from TP1 to TP2 were more likely to relapse following discharge from residential treatment.
Conclusion
Re-regulation of TST and cortisol levels while in residential treatment was associated with better treatment outcome following discharge for prescription OUD patients.
Consuming addictive drugs is often initially pleasurable, but escalating drug intake eventually recruits physiological anti-reward systems called opponent processes that cause tolerance and withdrawal symptoms. Opponent processes are fundamental for the addiction process, but their physiological basis is not fully characterized. Here, we propose an opponent processes mechanism centered on the endocrine stress-response, the HPA axis. We focus on alcohol addiction, where the HPA axis is activated and secretes β-endorphin, causing euphoria and analgesia. Using a mathematical model, we show that slow changes in HPA glands act as an opponent process for β-endorphin secretion. The model explains hormone dynamics in alcohol addiction, and experiments on alcohol preference in rodents. The opponent process is based on fold-change detection (FCD) where β-endorphin responses are relative rather than absolute; FCD confers vulnerability to addiction but has adaptive roles for learning. Our model suggests gland-mass changes as potential targets for intervention in addiction.
Background
Like other forms of psychopathology, vulnerability to opioid addiction is subject to wide individual differences. Animal behavioral models are valuable in advancing our understanding of mechanisms underlying vulnerability to the disorder’s development and amenability to treatment.
Methods
This review provides an overview of preclinical work on behavioral predictors of opioid addiction vulnerability as measured using the intravenous (i.v.) self-administration (SA) model in rats. We also highlight several new approaches to studying individual differences in opioid addiction vulnerability in preclinical models that could have greater sensitivity and lead to more clinically relevant findings.
Results and Conclusions
Evidence for the relationship between various behavioral traits and opioid SA in the preclinical literature is limited. With the possible exceptions of sensitivity to opioid agonist/withdrawal effects and stress reactivity, predictors of individual differences in SA of other drugs of abuse (e.g. sensation-seeking, impulsivity) do not predict vulnerability to opioid SA in rats. Refinement of SA measures and the use of multivariate designs and statistics could help identify predictors of opioid SA and lead to more clinically relevant studies on opioid addiction vulnerability.
The catecholamine-containing brainstem nuclei locus coeruleus (LC) and ventral tegmental area (VTA) are critically involved in stress responses. Alterations of catecholamine systems during chronic stress may contribute to neurodegeneration, including cognitive decline. Stress-related catecholamine alterations, while contributing to anxiety and depression, might accelerate neuronal degeneration by increasing the formation of toxic dopamine and norepinephrine by-products. These, in turn, may impair proteostasis within a variety of cortical and subcortical areas. In particular, the molecular events governing neurotransmission, neuroplasticity, and proteostasis within LC and VTA affect a variety of brain areas. Therefore, we focus on alterations of autophagy machinery in these nuclei as a relevant trigger in this chain of events. In fact, these catecholamine-containing areas are mostly prone to autophagy-dependent neurodegeneration. Thus, we propose a dynamic hypothesis according to which stress-induced autophagy alterations within the LC-VTA network foster a cascade towards early neurodegeneration within these nuclei.
This chapter focuses on the effects of cocaine on the neuroendocrine system. Cocaine's interactions with prolactin, and with hypothalamicpituitarygonadal (HPG) axis and hypothalamicpituitaryadrenal (HPA) axis are poorly understood. Yet, cocaine-related changes in these hormones have broad implications for normal reproductive function and immune function as well as behavior. In addition, there is emerging evidence that cocaine's perturbation of anterior pituitary, gonadal, and adrenal hormones may be related to its reinforcing properties. It also focuses on the interactions between cocaine, hormones, and behavior. Illustrative studies of the role of gender in modulating cocaine's neuroendocrine and behavioral effects are described. It emphasizes findings from preclinical studies, in part, because of the relatively limited number of clinical studies.
The high rate of relapse to drug abuse is one of the main problems in the treatment of addiction. Stress plays an essential role in relapsing to drug abuse. The present study investigates the role of D1- and D2-like dopamine receptors in the dentate gyrus (DG) of the hippocampus on the reinstatement of morphine (5 mg/kg)-induced conditioned place preference (CPP) both by food deprivation stress (FDS) and a sub-threshold dose of morphine (0.5 mg/kg, s.c.). All the animals in this study experienced pre-test, conditioning, post-test (expression), extinction, and reinstatement phases. The CPP scores of the pre-test and post-test were compared between the groups, and a significant difference between the CPP scores of the pre- and post-test was the criterion for the induction of CPP. Extinction continued for each animal until the calculated score for two consecutive days became the same as the pre-test score. The animals received different doses of SCH-23390 or Sulpiride (0.25, 1 and 4 μg/0.5 μl vehicle), as D1- and D2-like dopamine receptor antagonists, into the DG. After the administration of the antagonists, the animals were deprived of food for 24 h. Then, on the reinstatement day, they received a sub-threshold dose of morphine and afterwards, the conditioning scores were measured. The results demonstrated that the effective doses 50% of SCH-23390 and Sulpiride on the reinstatement induced by FDS and morphine was 1.37 and 2.28 (μg/0.5 μl vehicle per side), respectively. The results also showed that both antagonists can lead to a decrease in morphine reinstatement, and this effect was in a dose-dependent manner. In conclusion, these results indicate that D1- and D2-like dopamine receptors in the DG may be a potential target for preventing relapse to drugs in stressful life conditions.
The effects of repeated systemic or intra-nucleus accumbens cocaine administration on locomotor activity were examined for environmental dependence. Repeated IP administration of cocaine (15 mg/kg) for 5 days in the context of a given environment increased the locomotor response to a subsequent IP cocaine challenge in that environment. However, there were no differences in the locomotor response to a subsequent IP cocaine challenge in the test chamber in subjects which had received prior repeated IP administration of cocaine in the home-cage. In a second experiment, cocaine (100 g/side) was infused into the nucleus accumbens (NACC) daily for 5 days. This repeated administration produced increases in locomotor activity to subsequent intra-NACC cocaine infusions that were environmentally independent. In contrast to the effects of repeated IP cocaine administration, subjects which received administration of vehicle, acute cocaine, or repeated cocaine in the NACC did not differ following an IP cocaine challenge. The results from these experiments indicate that increases in the response to IP cocaine following repeated IP administration are in part environmentally dependent. Moreover, repeated intra-NACC cocaine infusions increase the responsiveness of the NACC to subsequent intra-NACC cocaine. However, local activation of the NACC alone does not appear to be adequate to produce sensitization to systemically administered cocaine.
Heightened activity level has been implicated in the liability for substance abuse, but no prior research has directly examined motor activity in a sample of prepubertal boys at high-risk for substance abuse. The magnitude of behavioral activity of 10-12 year-old sons of substance abusing fathers (SA +) (n = 42) and controls (SA -) (n = 60) was assessed using a microprocessor-based activity monitor during tasks that demanded significant concentration, effort, and constraint on motor activity, and when no such demands were present. Psychiatric status, measures of temperament traits, and measures of internalizing and externalizing behaviors were also obtained on the boys. Although the groups did not differ during the lower demand task, SA + boys showed significantly greater motor activity than SA - boys during the tasks that required concerted effort, attention, and behavioral suppression. Multiple regression analysis indicated that under the low-demand condition, the presence of an anxiety disorder in the boy was the only significant predictor of activity level. However, under the conditions that demanded effort, concerted attention and behavioral suppression, SA + group membership, and having low rhythmicity (as a temperament trait) predicted heightened activity. Statistically controlling for rhythmicity, the SA + boys were estimated to have about 24% higher activity than control boys. The results suggest that heightened motor activity may be associated with susceptibility to substance abuse.
Five experiments investigated in rats the effects of increasing or decreasing plasma corticosterone levels on schedule-induced polydipsia and dopamine efflux in the nucleus accumbens. The results indicate that the acquisition of schedule-induced polydipsia could be decreased by adrenalectomy, blockade of corticosterone synthesis, or administration of corticosterone. Performance of established schedule-induced polydipsia was also decreased by adrenalectomy. The effects of corticosterone administration on established schedule-induced polydipsia depended on the level of performance. High levels of drinking were enhanced by a high dose of corticosterone, whereas low rates of drinking were increased by a low dose. Similar injections of corticosterone also significantly increased dopamine efflux. The relative involvement of pituitary-adrenal activity and dopamine neurotransmission in the nucleus accumbens in the acquisition and performance of SIP is discussed and related to contemporary hypotheses of schedule-induced behavior.
It is commonly thought that mu-receptors play an important role in the reinforcing effects of opioids. In the present study, inbred strains widely divergent in CNS opiate receptor densities were used to investigate the influence of genetic variation in receptor concentration on opioid-reinforced behavior. In particular, the CXBK/ByJ mice were used as an investigative tool because of their significantly lower number of CNS mu opioid receptors. The behavioral pharmacology of opioids in the mu-deficient CXBK/ByJ mice was compared to other commonly used inbred mouse strains, C57BL/6J and BALB/cJ, and the opiate receptor rich CXBH/ByJ mice. Operant opioid reinforced behavior, opioid-induced locomotor stimulation, analgesia and respiratory depression were investigated in all four inbred strains. To assess the acquisition and maintenance of opioid reinforced behavior, oral self-administration of the potent benzimidazole opioid, etonitazene, was determined using an operant fixed-ratio schedule of reinforcement (FR 8). Acquisition of etonitazene-reinforced behavior was established in all four strains including the mu-deficient CXBK/ByJ mice. However, there were significant genetic differences in the amount of drug intake during the maintenance of opioid-reinforced behavior and extinction behavior following vehicle substitution. For example, drug intake was significantly greater in the BK versus BH mice during the maintenance phase and an extinction burst was seen in the BH but not the BK mice following vehicle substitution. Thus, mu-receptor density may not account for individual variability in the acquisition of opioid-reinforced behavior under these conditions. Sensitivity to etonitazene-induced respiratory depression, stimulation of locomotor activity and analgesia were unrelated to drug intake during self-administration sessions across these four inbred strains.(ABSTRACT TRUNCATED AT 250 WORDS)
Progress has been made over the last 10 years in determining the neural mechanisms of sensitization induced by amphetamine-like psychostimulants, opioids and stressors. Changes in dopamine transmission in axon terminal fields such as the nucleus accumbens appear to underlie the expression of sensitization, but the actions of drugs and stressors in the somatodendritic regions of the A10/A9 dopamine neurons seem critical for the initiation of sensitization. Manipulations that increase somatodendritic dopamine release and permit the stimulation of D1 dopamine receptors in this region induce changes in the dopamine system that lead to the development of long-term sensitization. However, it is not known exactly how the changes in the A10/A9 region are encoded to permit augmented dopamine transmission in the terminal field. One possibility is that the dopamine neurons of sensitized animals have become increasingly sensitive to excitatory pharmacological and environmental stimuli or desensitized to inhibitory regulation. Alternatively, changes in cellular activity or protein synthesis may result in a change in the presynaptic regulation of axon terminal dopamine release.
Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, experiments began. Experiment 1 examined the effect of isolation rearing upon the locomotor response to a novel environment, and the locomotor stimulant effect of an injection of cocaine (10 mg/kg). Isolation reared animals were more active in a novel environment, and were more responsive to the locomotor stimulant action of cocaine. In succeeding experiments, the effects of isolation rearing on the reinforcing efficacy of intravenous cocaine were assessed. Animals were never primed with noncontinugent infusions of cocaine at any time during these experiments. In experiment 2, the effect of isolation rearing upon the acquisition of the intravenous self-administration of cocaine was examined. Two levers were present in the operant chambers. Depression of one lever resulted in the intravenous delivery of a 1.5 mg/kg infusion of cocaine, responses on the second, control lever were recorded but had no programmed consequences. Isolation reared animals acquired a selective response on the drug lever at a slower rate than socially reared controls. In experiment 3, a full cocaine dose-response function was examined. Isolation rearing shifted the cocaine dose-response function to the right. In addition, isolation rearing impaired the selectivity of the response on the drug lever at lower doses of cocaine. In experiment 4, the effect of isolation rearing upon the response to a conditioned reinforcer associated previously with cocaine delivery was observed. In the absence of cocaine, the contingent presentation of the conditioned reinforcer enhanced selectively the rate of response by socially reared controls. However, isolation reared animals were unresponsive to this manipulation. These data are discussed with reference to dysfunctional cortico-limbic-striatal systems, and their interactions with the mesoaccumbens dopamine projection.
Food restriction has been shown to enchance the behavioral sensitivity to addictive drugs. The biological factors involved in this effect are largely unknown. Since food restriction, among other factors, increases corticosterone secretion, the role of this hormone in the effects of food restriction on the response to psychostimulants and opioids was investigated. The effects of food restriction on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal axis; (ii) animals in which food restriction-induced corticosterone secretion was suppressed by adrenalectomy, but which received exogenous corticosterone from a subcutaneous implant, which slowly releases corticosterone, producing a stable plasma level within the normal physiological range over a period of 20 days. It was found that food restriction enhanced sensitivity to the psychomotor effects of amphetamine (1 mg/kg i.p.) and morphine (1 mg/kg i.p.) in animals with an intact hypothalamo-pituitary-adrenal axis, but not in animals in which endogenous corticosterone secretion was eliminated. These results suggest that corticosterone secretion may be one of the mechanisms by which food restriction amplifies the behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.
The effects of neurotoxic lesions to the medial prefrontal cortex on both the acquisition and maintenance of intravenous cocaine self-administration were examined. In one experiment, acquisition of intravenous cocaine self-administration (0.25, 0.5 or 1.0 mg/kg/infusion) was measured in separate groups of rats 14 days following either a sham or 6-hydroxydopamine lesion to the medial prefrontal cortex. For sham rats, the 1.0 and 0.5 mg/kg dose supported reliable self-administration as indicated by discriminative responding. These rats reliably chose a lever that resulted in the delivery of these doses of cocaine over an inactive lever. Reinforced response rates were reduced when 0.25 mg/kg was the available dose and there was a loss of discriminative responding for some of the rats suggesting that it was close to threshold for self-administration. For rats that sustained a 70% depletion of dopamine in the medial prefrontal cortex, the dose-response curve was an inverse function across the entire dose range tested. In contrast to the data from the control rats, lesioned rats had a high rate of reinforced responses and demonstrated good discrimination for all doses including 0.25 mg/kg/infusion, suggesting a supersensitive response to the initial reward effect of cocaine. Another group of rats was first screened for reliable cocaine self-administration (0.5 mg/kg/infusion) and then subjected to either the prefrontal cortical 6-hydroxydopamine or sham lesion. Dose-response curves for cocaine self-administration were compared 14 days following the infusions. The lesioned rats responded reliably for low doses of cocaine that were unable to maintain responding in sham rats. These data support the hypothesis that the medial prefrontal cortex plays an important role in cocaine self-administration.
Repeated exposures to stressful situations has been shown to increase individual reactivity to psychostimulants, although the biological factors involved in such stress-induced changes are still poorly understood. In this study, we investigated the role of corticosterone in the effects of stress on the response to psychostimulants. We found that repeated corticosterone administration (both 1.5 mg/kg, intraperitoneally and 50 μg/ml in drinking water, once per day for 15 days) increased the locomotor response to amphetamine (1.15 mg/kg, i.p.). At the doses used in these experiments, corticosterone administration induced similar increases in plasma levels of the hormone to those induced by stress. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress increases the behavioral responses to amphetamine. Since an enhanced reactivity to psychostimulants has been found to be an index of a propensity for drug self-administration and a model of certain psychopathological conditions, these findings point to a role for glucocorticoids in such abnormal states.
Individual vulnerability to the reinforcing effects of drugs appear to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with higher locomotor responses to novelty (High Responders, HR) tend to acquire amphetamine SA, while animals with the lower responses (Low Responders, LR) do not. In this study, we examined whether activity of dopaminergic (DA) and serotoninergic (5-HT) systems differed between HR and LR animals. These transmitter systems are thought to be involved in the reinforcing effects of psychostimulants. Animals from both groups were sacrificed under basal conditions and after exposure for 30 or 120 min to a novel environment, and the DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT, and 5-hydroxyindolacetic acid (5-HIAA) contents were determined in the prefrontal cortex, nucleus accumbens and striatum. The HR rats displayed a specific neurochemical pattern: a higher DOPAC/DA ratio in the nucleus accumbens and striatum and a lower one in the prefrontal cortex. Furthermore, HR animals had lower overall 5-HT and 5-HIAA levels, corresponding to the mean of these compounds for the three structures studied over the three environmental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
AbstractIt has been suggested that drug abuse belongs to a larger class of addictive behaviors, including smoking, eating or gambling, which are mediated by common processes. Since laboratory animals can be induced to develop drug self-administration as well as indulge in compulsive eating or drinking, the present experiments were designed to find out if the same animals were susceptible to both behaviors. Only certain rats develop amphetamine intravenous self-administration (SA), and this susceptibility can be predicted from their enhanced locomotor response in a novel environment. Furthermore, excessive, non-regulatory drinking, referred to as schedule-induced polydipsia (SIP), in response to the periodic delivery of small amounts of food is only observed in certain rats. Since the propensity to SA has been shown to be influenced by experimental factors and testing for SIP was found to modify behavioral and biological parameters related to the propensity for drug-seeking, we also investigated whether experience of SIP influenced the subsequent development of SA. In Expt. 1, the rats that developed SA also acquired SIP, and had a higher locomotor response to novelty. The results of Expt. 2 showed that testing for SIP influenced the predisposition to develop amphetamine SA. When animals were tested for SIP first, the polydipsic rats subsequently failed to acquire SA, and had a reduced locomotor response to novelty. These changes seemed to be specific to the experience of SIP, as individual differences in the locomotor response to novelty were unchanged when animals were housed in standard laboratory conditions over a period of one month between the two tests. First and foremost, the results indicate that the predisposition to develop amphetamine SA is related to other behaviors with compulsive features, such as SIP. Secondly, these results demonstrate the powerful influence of a specific experience that is thought to have a coping function, in reducing or altering vulnerability to addiction.
The fluid intake of male Wistar rats with simultaneous access to water and 6% ethanol was determined between 0900 and 1500 h. In high-preferring males (normally covering > 60% of their daily fluid consumption in the form of ethanol), two injections with the corticosterone synthesis inhibitor metyrapone (50 mg/kg) at 0900 h and 1200 h for 4 consecutive days significantly reduced ethanol preference such that they preferred water over alcohol. Treatment with corticosterone (0.6 mg/kg) 2 h before each metyrapone injection partially cancelled this effect of the synthesis inhibitor. By contrast, there was no significant effect of metyrapone treatment on the drinking of ethanol in low-preferring rats (normally covering < 30% of their daily fluid consumption in the form of ethanol). These results suggest that the adrenal secretion of corticosterone directly or indirectly modulates the intake of alcohol in high-preferring rats.
Involvement of stress in the etiology of drug dependence has received little attention. In the present study a number of behavioural manipulations were applied and examined for an effect on intravenous cocainee self-administration in drug-naive rats with no prior training in leverpress responding. Self-administration rate was measured during five consecutive daily sessions. Stress reduction by handling rats daily for two weeks prior to testing for self-administration did not affect cocaine self-administration. Acute physical stress was induced either by a hot plate or by repeated footshocks, and emotional stress was induced by forcing rats to witness another rat being subjected to repeated footshocks. These stressors were applied immediately prior to each cocaine self-administration session. Emotional but not physical stress enhanced the rate of cocaine self-administration. It is concluded that emotional distress may increase the rewarding effects of cocaine and may render an individual more susceptible to development of drug dependence.
It is suggested that drug addiction is more likely to develop in individuals who are particularly sensitive to the reinforcing effects of drugs. Animal studies of intravenous drug self-administration (SA) have shown that rats display a large range of individual differences in the propensity to develop drug-seeking. Predisposed animals are characterized by a higher locomotor reactivity to both novelty and psychostimulants. In this report, we show that prenatal stress (restraint of the mother during the last week of pregnancy) may contribute to an individual's vulnerability to develop amphetamine self-administration. The adult offspring of stressed mothers exhibited: (i) a higher locomotor response to novelty and to an injection of amphetamine (0.3 mg/kg, i.v.); (ii) a higher level of amphetamine self-administration. The data indicate that individual predisposition to drug-seeking in the adult may be induced by prenatal events.
Individual vulnerability to the reinforcing effects of drugs appears to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with high locomotor responses to novelty (high responders, HR) acquire amphetamine SA, while animals with low responses (low responders, LR) do not. In this study we examined by microdialysis whether stress-induced extracellular dopamine (DA) concentrations in the nucleus accumbens differed between these two groups of animals. This neurotransmitter was studied because it is thought to be involved in the reinforcing effects of psychostimulants. Furthermore, previous studies have shown that HR animals have a higher basal DOPAC/DA ratio in the nucleus accumbens and higher extracellular concentrations of dopamine in this structure in response to cocaine. The stress procedure used in this experiment consisted of a 10 min tail-pinch. HR animals displayed a higher and longer stress-induced changes in DA concentrations than the LR group. Regression analysis showed that stress-induced changes in DA levels accounted for 75% of the variance observed in the locomotor response to a novel environment. Since higher DA activity in the nucleus accumbens has been reported in animals in which the propensity to psychostimulant SA is induced by brain lesions or life events, this biochemical modification may be one neurobiological substrate of the predisposition to acquire psychostimulant self-administration.
Recent studies have shown that large genetic differences exist in the extent to which animals will work to obtain drugs abused by humans. These findings suggest that there may be human populations with elevated risk for developing drug addictions. Frank George and Steven Goldberg describe the behavioral genetic and self-administration methods used in these studies of addiction processes, review the findings obtained in genetic studies of drug addiction, and present hypotheses that can be explored in the attempt to better understand and prevent drug addiction.
This paper presents a biopsychological theory of drug addiction, the ‘Incentive-Sensitization Theory’. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether ‘wanting’ drugs (drug craving) is attributable to ‘liking’ drugs (to the subjective pleasurable effects of drugs)? The theory posits the following.
Short-term social isolation has been shown to increase individual reactivity to addictive drugs, although the biological factors involved in this effect are largely unknown. In this study, we investigated the influence of corticosterone secretion on the effects of social isolation on the response to opioids. The effects of social isolation on morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy. The animals in the latter group were implanted with subcutaneous corticosterone pellets (50 mg), which slowly release corticosterone, producing stable plasma levels within the physiological range. Social isolation increased the locomotor response to morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which corticosterone secretion was blocked. These results suggest that corticosterone secretion is required for the expression of the enhanced locomotor response to opioids induced by isolation. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings suggest a role for glucocorticoids in the vulnerability to the reinforcing effects of opioids.
Previous experiments have shown that subjects which exhibit a high locomotor response to novelty (HR) also show a greater locomotor response to psychomotor stimulants than subjects which have a low locomotor response to a novel environment (LR). The current experiments were designed to examine in more detail the behavioral differences between HR and LR rats in non-drug paradigms. In the first experiment HR rats acquired schedule-induced polydipsia (SIP) more readily than LR rats. Panel pressing to gain access to the food pellets, however, was greater in LR rats compared to HR rats, especially after stable levels of SIP had been attained. In the second experiment one group of rats were fed daily after a 30-min period in photocell-cages (food conditioning; FC) while a control group was fed in the home-cage (non-conditioned; NC). FC subjects developed heightened locomotor activity in anticipation of feeding in the initial 30 min in the test-cage compared to NC rats. This anticipatory locomotor activity developed more rapidly and to a greater level in HR rats than in LR rats. The concentrations of dopamine, dihydroxyphenylacetic acid, homovanillic acid, serotonin, 5-hydroxyindoleactic acid, and norepinephrine were determined at the completion of behavioral testing in both the food conditioned and non-conditioned rats. The food conditioned experiment showed that variations in both the dopaminergic and serotoninergic systems may underlie individual differences in behavioral responsiveness. However, no clear pattern of neurochemical differences emerged. The current set of experiments have demonstrated differences between HR and LR rats in non-drug related paradigms and that HR rats appear to show a greater motivational excitement induced by periodic food delivery than LR rats.
The excretion of 4-hydroxy-3-methoxyphenylglycol (HMPG), 4-hydroxy-3-methoxymandelic acid (VMA), metadrenaline (MA), normetadrenaline (NMA) and homovanillic acid (HVA) has been measured in the urine of adrenalectomized rats. Urinary HMPG was significantly increased compared with the controls, presumably reflecting an increased production of noradrenaline. HVA output was similarly increased although to a lesser extent. Treatment with hydrocortisone (10 mg per kg) for 7 days abolished these increases. A small amount of urinary MA was still detectable in four out of six adrenaiectomized rats, providing further evidence for extra-adrenal production of adrenaline. VMA and NMA excretion were not significantly altered by adrenalectomy.After adrenalectomy, changes in the subcellular distribution of monoamine oxidase (MAO) are complex and vary from tissue to tissue. Total activity in heart, brain and vas deferens of adrenalectomized rats was significantly increased, a reflection of increased mitochondrial activity. An increase in microsomal MAO was observed only in the vas deferens. The heart was the only tissue examined to show an increase in the supernatant fraction. In the duodenum mitochondrial MAO activity was significantly increased, but this rise was offset by a significant decrease in enzyme in the supernatant fraction.
Rats given continuous access to etonitazene hydrochloride in their drinking water (5 micrograms per milliliter) more than
doubled their drug intake while deprived of food. Another group of rats with implanted jugular catheters self-administered
etonitazene (10 micrograms per kilogram) intravenously on a continuous reinforcement schedule, and the number of infusions
increased significantly on days when they were deprived of food. These results suggest that feeding condition may be a powerful
determinant of drug-reinforced behavior.
To determine the effect of housing conditions on morphine self-administration, rats isolated in standard laboratory cages and rats living socially in a large open box (8.8 m2) were given morphine in solution (0.5 mg/ml) as their only source of fluid for 57 days. They were then exposed to a series of 3-day cycles previously shown by Nichols et al. (1956) to increase self-administration of morphine in caged rats. On morphine/water choice days late in the period of forced consumption, between the Nichols cycles, and during a subsequent period of abstinence, the isolated rats drank significantly more morphine solution than the social rats, and the females drank significantly more morphine solution than the males. During the four choice days in the Nichols Cycle Period the isolated rats increased their consumption, but the socially housed animals decreased theirs.
The effect of local application of morphine (5 microgram) into the ventral tegmental area (VTA) or substantia nigra, pars compacta (SNc) on spontaneous activity was studied in the rat. Morphine in the VTA but not SNc produced an enhancement of locomotor activity which became progressively augmented with repeated injections. This effect could be blocked by systemic injections of naloxone or haloperidol. It is suggested that stimulation of opiate receptors in the vicinity of dopamine cell bodies can increase the activity of ascending mesencephalic dopamine neurones.
Selective large scale destruction of mesolimbic dopamine-containing terminals is produced by bilateral injection of 8 mug of 6-hydroxydopamine (6OHDA) into the nucleus accumbens septi (NAS) of rats pretreated with pargyline and desipramine (DMI). The DMI prevents the destruction of the noradrenergic innervation of the forebrain normally produced by the NAS 6OHDA lesion, without affecting the destruction of dopamine-containing neurons. The locomotor stimulation produced by the psychostimulants d-amphetamine (1.5 mg/kg) and cocaine (20 mg/kg) is blocked in rats with selective destruction of the mesolimbic dopamine system. In contrast the locomotor stimulation produced by the directly acting dopamine agonist apomorphine (1.0 mg/kg) is enhanced, which may indicate supersensitivity of the denervated dopamine receptors. These results lend further support to the view that psychostimulant-induced locomotr stimulation in rats results from effects on mesolimbic dopamine neurons. In addition, the protection by DMI of noradrenergic neurons from the toxic effects of 6OHDA is evidence that 6OHDA, as used here, destroys catecholamine neurons mainly by an uptake-dependent specific mechanism.
The effects of adrenalectomy (ADX) and dexamethasone (DEX) treatment on brain dopamine (DA) receptors of ovariectomized (OVX) rats were investigated by autoradiography using binding of the D1 and D2 antagonists ligands [3H]SCH 23390 and [3H]spiperone, respectively. Fourteen days after ADX, D1 receptors decreased in the middle striatum (M.CPu) and in the dorsal area of the posterior striatum (P.CPu). A more pronounced decrease was observed in the substantia nigra (SN) and no significant changes occurred in the anterior striatum (A.CPu), globus pallidus (GP) and accumbens (Acb). D2 receptors decreased in the M.CPu and dorsal area of the P.CPu and remained unchanged in the A.CPu as compared to OVX rats. Twenty-eight days after ADX, D1 and D2 receptors decreased in the A.CPu (D2), in the M.CPu (D2) and substantially in the SN (D1). DEX treatment (14 days, 0.5 mg/kg, b.i.d., IM, starting 14 days after ADX) reversed these effects in the A.CPu (D2), M.CPu (D2) and SN (D1) when compared to ADX+OVX rats. DEX also increased the density of D1 receptors in Acb, A.CPu and M.CPu when compared to OVX rats. Striatal homogenates of rats treated chronically with ACTH and corticosterone had an increased density of D1 receptors while these treatments alone left these receptors unchanged, thus suggesting either a minor role or no role of the changes in ACTH levels following glucocorticoids manipulations. Our results suggest that the adrenals play a role in the modulation of DA receptors activity in the rat brain.
The rat adrenal hormone corticosterone can cross the blood-brain barrier and bind to two intracellular receptor populations in the brain--the mineralocorticoid and glucocorticoid receptors. Recent studies have revealed that the corticosteroid hormones are able to restore changes in neuronal membrane properties induced by current or neurotransmitters, probably through a genomic action. In general, mineralocorticoid receptors mediate steroid actions that enhance cellular excitability, whereas activated glucocorticoid receptors can suppress temporarily raised neuronal activity. The steroid-mediated control of excitability and the implications for information processing in the brain are reviewed in this article.
Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer morphine could be identified. Extracellular levels of dopamine and its metabolites were measured bilaterally in the mesocorticolimbic and nigrostriatal systems of naive rats that were subsequently trained to self-administer morphine intravenously. There were several significant relationships between dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels and rates of morphine self-administration during both acquisition and asymptotic phases of testing. DOPAC and HVA levels in the striatum were inversely correlated with self-administration rates during the asymptotic phase whereas hemispheric asymmetries in striatal metabolite levels were inversely correlated with self-administration during the acquisition phase. DOPAC and HVA levels in in the right but not in the left side of the medial prefrontal cortex were positively correlated with self-administration rates during the acquisition phase; right/left asymmetries in cortical metabolite levels were also correlated with acquisition rates. There were no significant relationships between neurochemical indices and rates of bar-pressing for water. These results suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the organization and activity of brain dopamine systems. Furthermore, different mechanisms appear to be responsible for the initiation and maintenance of morphine intake: DA release in the nucleus accumbens appears to be a critical component of both mechanisms; DA release in the striatum appears to modulate maintenance and, in relationship to striatal lateralization, modulate initiation; DA release in the right but not in the left medial prefrontal cortex appears to be an important predictor of initiation.
This series of experiments compared isolation-reared and socially reared rats for their locomotor activity, behavioural stereotypy, and monoamine function both postmortem and in vivo using intracerebral dialysis. In Experiment 1, isolates showed an altered time course of locomotor activity following d-amphetamine sulphate (AMPH) administration (0.5, 2.0, 3.0, or 5.0 mg/kg, SC). Isolation-reared rats also showed increased sensitivity to the sedative effects of a low dose of apomorphine hydrochloride (0.1 mg/kg) but did not differ from social controls following higher doses of the drug (0.5, 1.5, or 3.0 mg/kg, SC). Isolates showed a decrease in the intensity of apomorphine-induced stereotyped behaviours but no change in stereotypy induced by AMPH. In Experiment 2, isolates had higher postmortem dopamine (DA) concentrations and an altered asymmetry in DA function in the medial prefrontal cortex (PFC) but not in the nucleus accumbens (NAC) or caudate putamen (CPu). Isolated rats also had a lower 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the NAC (but not in the PFC or CPu) compared to controls. Experiment 3 used intracerebral dialysis to examine monoamine function in vivo following isolation rearing. Isolates showed greater increases in extracellular DA and greater decreases in DOPAC in response to 2 mg/kg AMPH SC in both the NAC and CPu. There were no apparent differences in the perfusate concentrations of either dopamine (DA), dihydroxyphenylacetic acid (DOPAC), or homovanillic acid (HVA) prior to drug administration. However, consistent with the results of Experiment 2, isolates had a reduced basal perfusate concentration of 5-HIAA from the NAC but not from the CPu. Experiment 4 measured postsynaptic DA function in CPu tissue slices following isolation. Isolation rearing did not affect cAMP accumulation in response to stimulation of D1 DA receptors by DA (0, 2.7, 9, or 30 microM). In addition, isolation rearing did not affect the coupling between D1 and D2 receptors, as measured by the increase in cAMP accumulation with 1 microM 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepin (SK&F 38393) and its reduction by 10 microM quinperole hydrochloride (LY 171555). These results are discussed in terms of the possible relationship between these neurochemical findings and the behavioural disturbances following isolation rearing of rats.
Groups of rats with 6-hydroxydopamine (6-OHDA) lesions of either the medial prefrontal cortex (PFC), nucleus accumbens (NAC), or caudate putamen (CPu) were given daily tests for locomotor activity in photocell cages while food deprived. Two separate groups of NAC-lesioned rats were prepared with either large [NACT (90% NAC dopamine depletion)] or partial [NACP (67% NAC dopamine depletion)] lesions. NACT rats were spontaneously hypoactive whereas NACP rats were hyperactive compared with sham-operated controls. PFC-lesioned rats were also hyperactive compared to their respective controls. Spontaneous locomotor activity in CPu-lesioned rats did not differ from shams. When daily food supplements were paired with the photocell cages, all subjects developed a conditioned locomotor response. During the first few days of conditioning, the response to this conditioning procedure was markedly greater in the NACP group whereas the response in the NACT group was unaffected initially and actually enhanced during the latter days of testing. The locomotor response to the conditioning procedure was unaffected in either the PFC- or CPu-lesioned groups. Both the NACT and NACP lesions attenuated the locomotor response to 1.5 mg/kg d-amphetamine sulphate IP, and the NACT group showed a supersensitive response to 0.1 mg/kg apomorphine HCl SC. PFC or CPu 6-OHDA lesions did not alter the response to either drug. These results differentiate the role of PFC, NAC, and CPu dopamine in spontaneous, conditioned, and drug-induced locomotor activity and further implicate dopaminergic mechanisms of the NAC in the magnitude of the behavioural response to incentive stimuli.
Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated stress on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.
The current experiment examined the role of nucleus accumbens (NACC) dopamine in individual differences. Subjects were divided into high responders (HR) and low responders (LR) based on their locomotor response to a novel environment. HR rats were subjects which had a locomotor response to novelty in the upper third of the population screened and LR rats in the bottom third of the population. A new method of microdialysis was then used that allowed determination of the extracellular dopamine concentration. This was accomplished by adding various dopamine concentrations (0.0, 5.0 and 20.0 nM) to the perfusate. The concentration of dopamine in the dialysate was subsequently determined. The difference in the dialysate and perfusate dopamine was regressed on the perfusate dopamine. The regression yielded the in vivo recovery and the extracellular concentration. HR rats exhibit a 250% higher basal dopamine concentration (6.45 +/- 1.01 nM, n = 6) than LR rats (2.58 +/- 0.16 nM, n = 7). The in vivo microdialysis recovery was used to estimate the extracellular dopamine following cocaine challenge (15 mg/kg) in the two groups. Following i.p. cocaine administration, HR rats had both a greater locomotor response and increase in absolute dopamine concentration compared to LR rats. The maximum dopamine concentration in the HR group was 23 +/- 2.9 nM, while that in the LR group was only 8.6 +/- 1.1 nM. The maximum in the LR group is comparable to the basal level in the HR group. However, there were no difference in percent change in dopamine following cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Rats were screened for locomotor activity in a novel environment and divided into high (HR) or low (LR) responders based on whether their locomotor score for the first hour was above or below the median. In the first experiment, HR and LR rats were compared for their locomotor response following repeated administration of either 0.0, 0.5, 1.0, or 1.5 mg/kg d-amphetamine sulfate (AMPH). Injections of either 0.5 or 1.0 mg/kg AMPH produced higher locomotor activity in HR rats than in LR rats. Furthermore, there was a correlation between the locomotor response to novelty and the response to either 0.5 or 1.0 mg/kg AMPH. In addition, whereas both groups of rats developed the same degree of sensitization to 0.5 mg/kg AMPH, only the HR rats developed pronounced sensitization to repeated administration of 1.0 mg/kg AMPH. When both HR and LR were considered, there was a significant correlation between response to novelty and the extent of sensitization to the locomotor-stimulating properties of 1.0 mg/kg AMPH. There were no differences in locomotor activity or sensitization between HR and LR rats following the highest dose of AMPH (1.5 mg/kg). In a separate experiment, HR and LR rats were compared for locomotor activity following a series of intracranial infusions of AMPH. There were no overall differences in locomotor activity between the HR and LR groups following AMPH infusions into either the nucleus accumbens (NACC) or the anterior dorsal striatum (ADS). However, the locomotor activity scores in the novel environment significantly correlated with the locomotor response to 3.0 micrograms AMPH infused into either the NACC or ADS.(ABSTRACT TRUNCATED AT 250 WORDS)
Previous studies have shown that chronic morphine increases levels of the G-protein subunits Gia and Goa, adenylate cyclase, cyclic AMP-dependent protein kinase, and certain phosphoproteins in the rat locus coeruleus, but not in several other brain regions studied, and that chronic morphine decreases levels of Gia and increases levels of adenylate cyclase in dorsal root ganglion/spinal cord (DRG-SC) co-cultures. These findings led us to survey the effects of chronic morphine on the G-protein/cyclic AMP system in a large number of brain regions to determine how widespread such regulation might be. We found that while most regions showed no regulation in response to chronic morphine, nucleus accumbens (NAc) and amygdala did show increases in adenylate cyclase and cyclic AMP-dependent protein kinase activity, and thalamus showed an increase in cyclic AMP-dependent protein kinase activity only. An increase in cyclic AMP-dependent protein kinase activity was also observed in DRG-SC co-cultures. Morphine regulation of G-proteins was variable, with decreased levels of Gia seen in the NAc, increased levels of Gia and Goa in amygdala, and no change in thalamus or the other brain regions studied. Interestingly, chronic treatment of rats with cocaine, but not with several non-abused drugs, produced similar changes compared to morphine in G-proteins, adenylate cyclase, and cyclic AMP-dependent protein kinase in the NAc, but not in the other brain regions studied. These results indicate that regulation of the G-protein/cyclic AMP system represents a mechanism by which a number of opiate-sensitive neurons adapt to chronic morphine and thereby develop aspects of opiate tolerance and/or dependence. The findings that chronic morphine and cocaine produce similar adaptations in the NAc, a brain region important for the reinforcing actions of many types of abused substances, suggest further that common mechanisms may underlie psychological aspects of drug addiction mediated by this brain region.
The present study was carried out to investigate the role of corticosteroids in the dexamphetamine-induced sensitization of the mesolimbic, noradrenergic system. The experimental design of adrenalectomy and hormone replacement was chosen for exploration of this question. The dexamphetamine-induced sensitization of mesolimbic, alpha 1 adrenergic receptors in the ventral striatum was studied by administering intra-accumbens injections of the alpha 1 agonist, phenylephrine (10 micrograms), given 24 h after a priming injection of intra-accumbens administered dexamphetamine (10 micrograms), which itself elicits an increase in locomotor activity. In this paradigm phenylephrine produces an increase in locomotor activity, an effect which does not occur in rats which are not sensitized by dexamphetamine. Adrenalectomy produced a slight, but significant, attenuation of the response to the priming injections of dexamphetamine. Replacement treatments (500 micrograms/kg per drug) with corticosterone or deoxycorticosterone, agents which preferentially bind with mineralocorticoid receptors, did not affect the dexamphetamine response, whereas replacement treatment with dexamethasone, which preferentially binds with glucocorticoid receptors, strongly potentiated this response. In view of the fact that the adrenalectomy-induced fall in corticosteroids can produce an up-regulation of glucocorticoid receptors, but not mineralocorticoid receptors, these data led to the conclusion that glucocorticoid receptors which are present in the cell bodies of noradrenergic, serotonergic and dopaminergic neurons are critical for the dexamphetamine response in drug-naive rats. The phenylephrine response was also strongly enhanced in adrenalectomized rats treated with dexamethasone. Since the magnitude of the dexamphetamine response is known to determine the magnitude of the phenylephrine response, the role of glucocorticoid receptors in the dexamphetamine-induced sensitization of the phenylephrine response remains to be established. Conversely, adrenalectomy nearly completely abolished the dexamphetamine-induced sensitization of the phenylephrine response. The latter response was reinstated by replacement treatment with corticosterone or deoxycorticosterone. These data show that mineralocorticoid receptors, which are present among others in the ventral striatum, are critical for the dexamphetamine-induced sensitization of mesolimbic, alpha 1 adrenergic receptors in the ventral striatum. The present study opens the perspective that secretion of corticosteroids in response to stressful stimuli--be it pharmacological or environmental--is the key to the question of why dexamphetamine and environmental challenges are interchangeable in the development of sensitization of mesolimbic, alpha 1 adrenergic receptors.
Progress has been made over the last 10 years in determining the neural mechanisms of sensitization induced by amphetamine-like psychostimulants, opioids and stressors. Changes in dopamine transmission in axon terminal fields such as the nucleus accumbens appear to underlie the expression of sensitization, but the actions of drugs and stressors in the somatodendritic regions of the A10/A9 dopamine neurons seem critical for the initiation of sensitization. Manipulations that increase somatodendritic dopamine release and permit the stimulation of D1 dopamine receptors in this region induce changes in the dopamine system that lead to the development of long-term sensitization. However, it is not known exactly how the changes in the A10/A9 region are encoded to permit augmented dopamine transmission in the terminal field. One possibility is that the dopamine neurons of sensitized animals have become increasingly sensitive to excitatory pharmacological and environmental stimuli or desensitized to inhibitory regulation. Alternatively, changes in cellular activity or protein synthesis may result in a change in the presynaptic regulation of axon terminal dopamine release.
We studied cyclic AMP-dependent protein phosphorylation in the mesolimbic and nigrostriatal dopamine systems of two genetically inbred rat strains, Lewis (LEW) and Fischer (F344) rats. These strains represent genetically divergent populations of rats that have been used to study possible genetic factors involved in a variety of biological processes. We found striking differences in levels of tyrosine hydroxylase, and several other phosphoproteins, in the mesolimbic, but not the nigrostriatal, dopamine system between the two rat strains. Interestingly, in Sprague-Dawley rats, these same phosphoproteins are altered by chronic morphine and chronic cocaine specifically in the mesolimbic dopamine system, generally thought to be a brain reward pathway that mediates some of the reinforcing actions of many drugs of abuse. As LEW and F344 rats have been reported to show different levels of preference for several types of drugs of abuse, the results are consistent with the possibility that these phosphoproteins may mediate aspects of drug reinforcement and contribute to individual differences in vulnerability to drug addiction.
Rats were placed in one of two novel test environments for behavioral observation. In one, exploratory behavior (assessed by hole pokes) and locomotion were assessed during a 10-min test session. In the other, the chewing of varied objects on the cage floor was rated over a 20-min session. Within 2-18 days, animals were anesthetized and microdialysis probes were implanted into the nucleus accumbens for measurement of basal and d-amphetamine-stimulated levels of dopamine (DA). These measures were then correlated with the individual behavioral rating collected earlier from the drug-free animals. We found a significant correlation between duration of exploratory behavior and amphetamine-induced DA release. Locomotor activity did not correlated with either basal or amphetamine-stimulated DA release. Duration of chewing episodes correlated with basal levels of DA, as well as with amphetamine-induced DA release. Our studies indicate that differences in the dopaminergic responsivity of the nucleus accumbens (or other circuitry influencing nucleus accumbens DA function) may contribute to individual differences in certain behaviors displayed by the animals when placed in a novel environment.
Several reports in the literature suggested that environmental influences which are reflected in the social housing conditions of the rat may play a role in the expression of individual differences in drug self-administration. The present experiments were performed in order to further examine the effects of early housing manipulations, as reflected by grouped or isolation housing, on cocaine-induced behavioral responding. The first study examined the effects of this manipulation on the locomotor stimulant properties of cocaine. The results suggested that grouped housing produced a significantly greater increase in cocaine-induced locomotion than was observed in animals housed in isolation. Experiment 2 examined the effects of housing manipulations on the self-administration of cocaine under a continuous reinforcement schedule. Differences in the rate of cocaine self-administration were only observed at the lowest dose tested. Responding at all other doses was equivalent, including the optimal dose for both groups, suggesting that the housing manipulations failed to affect the reinforcing efficacy of cocaine. The present investigation suggests that, while the early housing manipulation produced a differential sensitivity in rats to the stimulant properties of cocaine, the same manipulation failed to alter the sensitivity of rats to the reinforcing properties of cocaine as assessed through self-administration.
Individual vulnerability to the reinforcing properties of drugs appears to be an essential characteristic predisposing humans to addiction. In animals, a greater behavioral reactivity to a mild stress, such as exposure to a novel environment, is an index of the vulnerability to acquire amphetamine self-administration. Biological responses to stress as well as behavioral reactivity may predict such a vulnerability. In the present study, rats with a longer duration of corticosterone secretion after exposure to novelty showed facilitation of acquisition of amphetamine self-administration. Furthermore, corticosterone administration in nonpredisposed individuals increased the reinforcing value of the drug and facilitated the acquisition of amphetamine self-administration. These results indicate that the stress-related activity of the hypothalamic-pituitary-adrenal axis may play a role in the pathogenesis of psychostimulant addiction.
Microdialysis was employed to assess extracellular dopamine from medial prefrontal cortex, nucleus accumbens, nucleus caudatus, and acetylcholine from the hippocampus of conscious rats during and after 120 min restraint stress. Restraint stress rapidly stimulated the release and the metabolism of dopamine in the medial prefrontal cortex and in the nucleus accumbens, and acetylcholine release in the hippocampus. Fifty-sixty min later, although rats were still restrained, dopamine and acetylcholine release gradually returned to basal levels. When the animals were freed a considerable increase in the release of both neurotransmitters was observed. No changes in the striatum were observed throughout the experiments. The time-course of plasma corticosterone did not parallel that of dopamine and acetylcholine release, increasing during the whole stress procedure, and decreasing when the animals were released. Adrenalectomized rats responded to stress and liberation in much the same way as intact rats. The administration of exogenous corticosterone (0.5-1.5 mg/kg s.c.) did not change the release of dopamine from the prefrontal cortex and nucleus accumbens, and of acetylcholine from the hippocampus, while the dose of 3.0 mg/kg which stimulated them, raised plasma corticosterone to very high concentrations which had never been attained during stress. Moreover, RU 38486, an antagonist of brain glucocorticoid receptors, did not antagonize the stress-induced increase of neurotransmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)
Mild footshock stress results in the metabolic activation of the prefrontal cortical dopamine (DA) innervation, but does not augment DA utilization in mesolimbic areas (such as the nucleus accumbens septi, NAS) or the striatum. However, increases in either the intensity or duration of footshock stress increase DA utilization in the subcortical sites. DA afferents to the prefrontal cortex (PFC) hold corticofugal projection neurons under tonic inhibition. Previous data suggest that removal of these corticofugal glutamatergic neurons from tonic DA inhibition results in a transsynaptic alteration in the NAS, such that the DA innervation of the NAS is rendered hyperresponsive to certain perturbations. We therefore examined the effects of stress on subcortical DA systems in rats previously subjected to 6-hydroxydopamine lesions of the PFC DA innervation. Mild footshock stress resulted in an increase in concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the PFC, but not NAS or striatum, of sham-lesioned animals. Footshock resulted in a significant increase in the concentration of DOPAC in the nucleus accumbens of animals sustaining PFC lesions two weeks previously. The PFC lesion did not result in a stress-induced increase in DA release in the striatum. These results suggest that disruption of the PFC DA innervation results in an enhanced responsiveness of the mesolimbic DA innervation to stress. These data may help explain the stress-elicited exacerbation of the psychotic process in schizophrenia.
Individual differences related to taste, determined by prior two-bottle tests of quinine and saccharin selection against water, were found to be related to the initial selection of 15% ethanol solution during the first week of access by 60 randomly bred male rats. The 36 rats that drank the least alcohol during the first week (mean +/- SE: 0.49 +/- 0.06 g/kg/day), however, greatly increased their intake during the second and third weeks, to the level of the 24 initially high alcohol drinkers (4.07 +/- 0.39 g/kg/day during 1st week), and the influence of gustatory factors was no longer apparent. Subsequently, the initially low rats drank less alcohol when saccharin was the alternative fluid. The results can be interpreted as showing that initially low rats, that only drank rather large amounts of alcohol after prolonged exposure, resemble Cloninger's Type 1 alcoholics not only in this temporal pattern but also in being high in novelty seeking, and low in harm avoidance and reward dependence, and that the initially high rats that spontaneously drank rather large amounts even in the first week show the opposite characteristics and resemble Type 2 alcoholics. Although these rats are not themselves models for alcoholism, the results nevertheless suggest it might be possible to develop two separate animal models for the two types of alcoholism.
The stimulatory effects of low alcohol doses are of great interest because of their role in human drinking and their possible relation to reinforcement from alcohol. The preferred animal model for studying them is the mouse. The effects of various doses of ethanol on locomotor activity were now studied in both group-housed mice and in mice socially isolated for 36-44 weeks. The housing situation was found to have a strong influence: a large stimulatory effect was observed in isolated mice but little effect was seen in group-housed animals. The results suggest that socially isolated mice are more sensitive to the stimulatory effect of ethanol on locomotor activity.
Individual vulnerability to drug addiction may be an important factor in the prognosis of this pathological behavior in man. However, experimental investigations have largely neglected the psychobiological substrate of predisposition to addiction. In this study, we show using a self-administration (SA) acquisition paradigm that previous repeated exposure to a stressful experience (tail-pinch) or to amphetamine, increase the locomotor response to this drug (behavioral sensitization) and enhance vulnerability to acquire amphetamine SA. These results show that vulnerability to develop amphetamine SA may be influenced by stressful experiences, and that previous contact with the drug may enhance a predisposition to amphetamine-taking behavior. As tail-pinch and amphetamine sensitization affect both the dopamine (DA) neural system and the propensity to self-administer amphetamine (behavior also modulated by DA activity), stress may influence SA via an action on the DA system.
Studies of the influence of housing conditions on ethanol self-administration have been inconsistent, with findings that isolation housing increases, decreases or produces no effects on ethanol intake. One possible explanation for these discrepant findings is that the effects of housing are dependent on the age at which the manipulation is performed. In the present experiment rats were housed from weaning or from age 65 days in either an isolated or grouped condition. After 12 weeks, they were tested for the voluntary oral self-administration of ethanol. Although all rats consumed comparable quantities of ethanol when lower concentrations were available, the rats isolated from weaning consumed significantly greater amounts of more concentrated ethanol than their group-housed counterparts. In contrast, there was no difference in ethanol consumption between isolated and grouped rats when they were differentially housed at maturity. These data suggest that an important determinant of ethanol intake in rats is related to environmental factors and that the influence of these factors is age-dependent.
The effects of apomorphine (0.05 mg/kg, i.p.) and cholecystokinin-8 (sulphated; CCK-8) were analyzed on the levels of dopamine and its metabolites using intrastriatal microdialysis in the adrenalectomized rat with or without corticosterone replacement treatment (5 mg/kg, twice daily for 7 days, last dose given 2 h before killing). Adrenalectomy did not affect the basal release of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA). However, the apomorphine-induced decrease in dopamine release was attenuated following adrenalectomy. Furthermore, there was an enhancement of the apomorphine-induced decrease in DOPAC levels without any modulation of the apomorphine-induced effects on HVA levels. In contrast, the CCK-8-induced increase in dopamine levels was potentiated following adrenalectomy. This potentiation was fully counteracted by replacement treatment with corticosterone. These results indicate that corticosterone may be involved in the regulation of dopamine release, perhaps through glucocorticoid receptors in nigral dopamine cells controlling inter alia the synthesis of G-proteins involved in the regulation of dopamine autoreceptors and CCK-8 receptors located on dopamine nerve terminals or of the receptor proteins themselves.
Twenty male Sprague-Dawley rats were injected intraperitoneally with either 20 micrograms of dexamethasone or an equivalent volume of saline. The rats were then sacrificed at either one or four hours after the injections and their brains analyzed for monoamine and metabolite content using High Performance Liquid Chromatography with Electrochemical Detection. Significant effects were seen in dopaminergic and serotonergic systems, but these effects varied depending on the area of rat brain studied. Significant increases in dopamine (DA) levels were seen in the hypothalamus and nucleus accumbens of the dexamethasone treated rats when compared with saline treated rats. There was no significant effect of dexamethasone on DA levels in frontal or striatal brain areas. In the dexamethasone treated rats a significant increase in serotonin (5-HT) was observed in the hypothalamus; a significant decrease in 5-HT was observed in the frontal cortex. Biological and clinical implications of these findings are discussed.