Content uploaded by Cody A Siciliano
Author content
All content in this area was uploaded by Cody A Siciliano on Jul 04, 2016
Content may be subject to copyright.
A preview of the PDF is not available
Brief Intermittent Cocaine Self-Administration and Abstinence Sensitizes Cocaine Effects on the Dopamine Transporter and Increases Drug Seeking
Abstract and Figures
Although traditional sensitization paradigms, which result in an augmentation of cocaine-induced locomotor behavior and dopamine (DA) overflow following repeated experimenter-delivered cocaine injections, are often used as a model to study drug addiction, similar effects have been difficult to demonstrate following cocaine self-administration. We have recently shown that intermittent access (IntA) to cocaine can result in increased cocaine potency at the DA transporter (DAT); however, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Therefore, we determined a time course of IntA-induced sensitization by examining the effects of I or 3 days of IntA, as well as a 7-day abstinence period on DA function, cocaine potency, and reinforcement. Here we show that cocaine potency is increased following as little as 3 days of IntA and further augmented following an abstinence period. In addition, IntA plus abstinence produced greater evoked DA release in the presence of cocaine as compared with all other groups, demonstrating that following abstinence, both cocaine's ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, are enhanced. Finally, we found that IntA-induced sensitization of the DA system resulted in an increased reinforcing efficacy of cocaine, an effect that was augmented after the 7-day abstinence period. These results suggest that sensitization of the DA system may have an important role in the early stages of drug abuse and may drive the increased drug seeking and taking that characterize the transition to uncontrolled drug use. Human data suggest that intermittency, sensitization, and periods of abstinence have an integral role in the process of addiction, highlighting the importance of utilizing pre-clinical models that integrate these phenomena, and suggesting that IntA paradigms may serve as novel models of human addiction.
Figures - uploaded by Cody A Siciliano
Author content
All figure content in this area was uploaded by Cody A Siciliano
Content may be subject to copyright.
... p = .000; Lever x Day: F (1,42) = 215.71, p = .000). ...
... p = .000; Reinforcer: F (1,42) = 121.47, p = .000; ...
... p = .000; Lever x Reinforcer: F (1,42) = 167.56, p = .000). ...
Reward uncertainty can sensitize reward pathways, promoting increased reward-seeking and -taking behaviours. This is relevant to human conditions such as pathological gambling, eating disorders and drug addiction. In the context of addiction, preclinical self-administration procedures have been developed to model the intermittency of human drug use. These intermittent-access (IntA) procedures involve intermittent but predictable access to drug during self-administration sessions. However, human drug use typically involves intermittent and unpredictable drug access. We introduce a new procedure modeling unpredictable, intermittent access (UIntA) to a reinforcer, and we compare it to procedures that provide predictable reinforcer availability; continuous (ContA) or intermittent (IntA) access. Female rats self-administered water or liquid sucrose in daily hour-long sessions. IntA and ContA rats had access to a fixed volume of water or sucrose (0.1ml), under a fixed ratio 3 schedule of reinforcement. IntA rats had predictable 5-min reinforcer ON and 25-min reinforcer OFF periods. ContA rats had 60min of reinforcer access during each session. For UIntA rats, variation in the length of ON and OFF periods (1, 5 or 9min/period), response requirement (variable ratio 3 schedule of reinforcement), reinforcer probability (50%) and quantity (0, 0.1 or 0.2ml) introduced reward uncertainty. Following 14 daily self-administration sessions, UIntA rats showed the highest levels of both responding for water or sucrose under progressive ratio and extinction conditions, and cue-induced reinstatement of sucrose seeking. Thus, unpredictable, intermittent reward access promotes increased reward pursuit. This has implications for modeling addiction and other disorders of increased reward seeking.
... A clearer result was observed during re-acquisition and quinine-punished drinking tests, as IntA-trained rats immediately returned to their previous binge-like pattern of responding and demonstrated the greatest persistence of the groups in the face of quinineadulteration of their alcohol solution. The increased binge-like drinking and increased resistance to quinine punishment observed in the IntA group are consistent with previous studies with drugs from other classes, demonstrating that IntA self-administration can produce more "addictionlike" behavior compared to continuous-access self-administration (Calipari et al., 2013;Calipari et al., 2015;Kawa, Allain, et al., 2019;Kawa, Valenta, et al., 2019). ...
... It is clear from these data that length of self-administration access and total consumption are not the only factors that influence the expression of addiction-like behavior. This novel finding in terms of operant self-administration of orally consumed alcohol reinforcement is in agreement with results reported for selfadministration of intravenous cocaine infusions (Calipari et al., 2014;Calipari et al., 2013;Calipari et al., 2015). ...
The study of Alcohol Use Disorders (AUD) in preclinical models is hampered by difficulty in training rodents to voluntarily consume high levels of alcohol. The intermittency of alcohol access/exposure is well known to modulate alcohol consumption (e.g., alcohol deprivation effect, intermittent-access two-bottle-choice) and recently, intermittent access operant self-administration procedures have been used to produce more intense and binge-like self-administration of intravenous psychostimulant and opioid drugs. In the present study, we sought to systematically manipulate the intermittency of operant self-administered alcohol access to determine the feasibility of promoting more intensified, binge-like alcohol consumption. To this end, 24 male and 23 female NIH Heterogeneous Stock rats were trained to self-administer 10% w/v ethanol, before being split into three different-access groups. Short Access (ShA) rats continued receiving 30-min training sessions, Long Access (LgA) rats received 16-h sessions, and Intermittent Access (IntA) rats received 16-h sessions, wherein the hourly alcohol-access periods were shortened over sessions, down to 2 min. IntA rats demonstrated an increasingly binge-like pattern of alcohol drinking in response to restriction of alcohol access, while ShA and LgA rats maintained stable intake. All groups were tested on orthogonal measures of alcohol-seeking and quinine-punished alcohol drinking. The IntA rats displayed the most punishment-resistant drinking. In a separate experiment, we replicated our main finding, that intermittent access promotes a more binge-like pattern of alcohol self-administration using 8 male and 8 female Wistar rats. In conclusion, intermittent access to self-administered alcohol promotes more intensified self-administration. This approach may be useful in developing preclinical models of binge-like alcohol consumption in AUD.
... However, short-access to cocaine SA proved sufficient to recapitulate the predictive value of impulsivity and D 2/3 R deficits for cocaine consumption [16] and the tolerance-related blunting of DA responses [85] previously evidenced using an extendedaccess procedure to cocaine SA. Future studies are needed to investigate whether RHA rats are more susceptible to developing DSM-like features that are relevant to addiction in rats [84] using SA paradigms that better model human patterns of cocaine intake, and that are more effective than the short-access model used here at producing addiction-like behaviors in rats, such as the extended- [86] or intermittent-access models [87]. ...
Current research indicates that altered dopamine (DA) transmission in the striatum contributes to impulsivity and novelty-seeking, and it may mediate a link concerning a higher susceptibility to drug abuse. Whether increased susceptibility to drug abuse results from a hyperdopaminergic or hypodopaminergic state is still debated. Here, we simultaneously tracked changes in DA D2/3 receptor (D2/3R) availability and amphetamine-(AMPH)-induced DA release in relation to impulsivity and novelty-seeking prior to, and following, cocaine self-administration (SA) in Roman high- (RHA) and low- (RLA) avoidance rats. We found that high-impulsive/high novelty-seeking RHA rats exhibited lower D2/3R availabilities and higher AMPH-induced DA release in the striatum that predicted higher levels of cocaine intake compared with RLAs. Cocaine SA did not alter striatal D2/3R availability or impulsivity in RHA or RLA rats. Critically, cocaine exposure led to a baseline-dependent blunting of stimulated DA release in high-impulsive/high novelty-seeking RHA rats only, and to a baseline-dependent increase in novelty-seeking in low-impulsive/low novelty-seeking RLA rats only. Altogether, we propose that susceptibility to drug abuse results from an innate hyper-responsive DA system, promoting impulsive action and novelty-seeking, and producing stronger initial drug-reinforcing effects that contribute to the initiation and perpetuation of drug use. However, with repeated cocaine use, a tolerance to drug-induced striatal DA elevations develops, leading to a compensatory increase in drug consumption to overcome the reduced reward effects.
... This is in contrast to studies showing that compared to ContA, IntA to cocaine [1,3,7,14,16,17,20], opioids [22,23,41] or nicotine [21] is especially effective in promoting the pursuit of drugs. Intermittent drug access produces repeated spikes in brain drug concentrations, and these are thought to trigger sensitization-related neuroadaptations that then cause increased motivation for drug [2][3][4]6,7,12,42]. Given this, our findings suggest that intermittent intake of non-drug rewards does not produce these neuroadaptations, because ContA vs. IntA produced similar levels of responding for water and sucrose during progressive ratio and extinction tests. ...
Self-administration procedures have been developed to model the intermittency of cocaine use in humans. These procedures involve intermittent, predictable access to cocaine during daily self-administration sessions. However, human drug use often involves intermittent and unpredictable patterns of drug access. Here, we introduce a new procedure to study the effects of unpredictable, intermittent access (UIntA) to a reinforcer, and we compare this procedure to two existing ones that provide predictable reinforcer availability; continuous (ContA) or intermittent (IntA) access. Three groups of rats self-administered water or a 5% sucrose solution in daily hour-long sessions. UIntA rats had alternating periods of reinforcer ON and OFF of unpredictable duration (1, 5 or 9 min/period). During reinforcer ON periods, reinforcer quantities were also unpredictable (0, 0.1 or 0.2 ml of solution) and were available under a variable ratio 3 schedule of reinforcement (1-6 responses). Both IntA and ContA rats had access to a fixed volume of water or sucrose (0.1 ml), under a fixed ratio 3 schedule of reinforcement. IntA rats had alternating and predictable 5-min reinforcer ON and OFF periods, while ContA rats had 60 minutes of reinforcer access during each session. Following 14 daily self-administration sessions, we found that UIntA rats had the highest rates of responding for water or sucrose reward under progressive ratio and extinction conditions, and the highest levels of cue-induced reinstatement of sucrose seeking. Thus, uncertain, intermittent access to reward promotes increased reward-seeking and -taking behaviours. This has implications for modeling addiction and other disorders of increased reward seeking.
... 17 Although frequently studied in addiction, little is known about how elasticity of demand curves change in mood disorders, particularly when comparing essential goods to luxury items. [66][67][68][69][70] Our data show that resilient individuals can better promote subjective value without sacrificing gains in food intake, although it is still intriguing that we find such differences in decision policies only in the OZ and not WZ. ...
Economic stress can serve as a “second-hit” for those who already accumulated a history of adverse life experiences. How one recovers from a setback is a core feature of resilience but is seldom captured in animal studies. We challenged mice in a novel two-hit stress model by exposing animals to chronic social defeat stress (first-hit) and then testing how mice adapt to reward scarcity on a neuroeconomic task (second-hit). Mice were tested longitudinally across months on the Restaurant Row task during which mice foraged daily for their sole source of food while on a limited time budget. An abrupt transition into a reward-scarce environment on this task elicits an economic crisis, precipitating a massive drop in food intake and body weight to which mice must respond in order to survive. We found that mice with a history of social defeat mounted a robust behavioral response to this economic challenge. This recovery was achieved through a complex redistribution of how time was allocated among competing opportunities via multiple valuation algorithms. Interestingly, we found that mice with a history of social defeat displayed changes in the development of decision-making policies during the recovery process important for not only ensuring food security necessary for survival but also prioritizing subjective value. These findings indicate that an individual’s capacity to “bounce back” from economic stress depends on one’s prior history of stress and can affect multiple aspects of subjective well-being, highlighting a motivational balance that may be altered in stress-related disorders such as depression.
In Brief
Durand-de Cuttoli et al. found that after chronic social defeat stress, when mice were subsequently challenged on a neuroeconomic foraging task, an economic stressor can serve as a “second hit” and reveal changes in the development of complex decision-making strategies important for maintaining the balance between food security and subjective well-being.
... To address these possibilities, we used intravenous cocaine self-administration procedures to examine drug-taking and drug-seeking behavior, and motivation for cocaine before and after intermittent access (IntA) self-administration experience in obesity-prone and obesity-resistant male rats. An IntA procedure was used because it has been shown to be particularly good at inducing addiction-like behaviors and associated neuroplasticity (Algallal et al. 2020;Allain et al. 2021;Calipari et al. 2013Calipari et al. , 2014Calipari et al. , 2015Carr et al. 2020;Samaha et al. 2021;Kawa et al. 2016;Kawa and Robinson 2019;Kawa et al. 2019a, b). Motivation in the current study was measured using a within session threshold procedure that captures demand for cocaine (i.e., how consumption changes as a function of price) and the preferred level of consumption when price is negligible (Bentzley et al. 2013). ...
Rationale
Compared to obesity-resistant rats, obesity-prone rats consume more food, work harder to obtain food, show greater motivational responses to food-cues, and show greater striatal plasticity in response to eating sugary/fatty foods. Therefore, it is possible that obesity-prone rats may also be more sensitive to the motivational properties of cocaine and cocaine-paired cues, and to plasticity induced by cocaine.
Objective
To examine baseline differences in motivation for cocaine and effects of intermittent access (IntA) cocaine self-administration on cocaine motivation, neurobehavioral responsivity to cocaine-paired cues, and locomotor sensitization in male obesity-prone vs obesity-resistant rats.
Methods
Intravenous cocaine self-administration was used to examine drug-taking and drug-seeking in males. Motivation for cocaine was measured using a within session threshold procedure. Cue-induced c-Fos expression in mesocorticolimbic regions was measured.
Results
Drug-taking and drug-seeking, cue-induced c-Fos, locomotor sensitization, and preferred level of cocaine consumption (Q0) were similar between obesity-prone and obesity-resistant groups. Maximal responding during demand testing (Rmax) was lower in obesity-prone rats. IntA experience enhanced motivation for cocaine (Pmax) in obesity-prone rats.
Conclusions
The results do not support robust inherent differences in motivation for cocaine, cue-induced cocaine seeking, or neurobehavioral plasticity induced by IntA in obesity-prone vs obesity-resistant rats. This contrasts with previously established differences seen for food and food cues in these populations and shows that inherent enhancements in motivation for food and food-paired cues do not necessarily transfer to drugs and drug-paired cues.
... In patients, a positive correlation has been shown between craving and anhedonia in detoxified users, suggesting a strong association between hedonic capability and craving (Janiri et al., 2005). Several studies in humans and animal models have also suggested that incubation in cocaine seeking and craving during abstinence may be associated with alterations in DA neurotransmission (Alonso et al., 2021;Calipari et al., 2015;Shin et al., 2016). In particular, a withdrawal-dependent decrease in cue-induced DA release has been shown in cocaine-seeking rats (Shin et al., 2016). ...
Background and Purpose
Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug‐seeking behaviour. Decreases of dopamine (DA) release and DA neuronal activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence, but the mechanisms underlying these neuroadaptations are not well understood. We investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala [BLA]–ventral pallidum [VP] pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine.
Experimental Approach
In a model of cocaine self‐administration, we performed in vivo electrophysiological recordings of DA VTA neurons and BLA neurons from anaesthetised rats during early and protracted abstinence and evaluated the involvement of the BLA–VP pathway using a pharmacological approach.
Key Results
We found significant decreases in VTA DA population activity and significant increases in BLA activity after protracted but not after short‐term abstinence from chronic cocaine. The decrease in VTA DA activity was restored by pharmacological inhibition of the activity of either the BLA or the VP, suggesting that these regions exert a negative influence on DA activity.
Conclusion and Implications
Our study sheds new lights on neuroadaptations occurring during incubation of craving leading to relapse. In particular, we describe the involvement of the BLA–VP pathway in cocaine‐induced decreases of DA activity in the VTA. This study adds important information about the specific brain network dysfunctions underlying hypodopaminergic activity during abstinence.
Intermittent access (IntA) models of cocaine self-administration were developed to better model in rodents how cocaine is used by human drug users. Compared to traditional continuous access (ContA) models, IntA has been shown to enhance several pharmacological and behavioral effects of cocaine, but few studies have examined sex differences in IntA. Moreover, no one has examined the efficacy of cue extinction to reduce cocaine seeking in the IntA model, which has previously shown to be ineffective in other models that promote habit-like cocaine seeking. Therefore, rats were implanted with jugular vein catheters and dorsolateral striatum (DLS) cannulae and trained to self-administer cocaine paired with an audiovisual cue with ContA or IntA. In subsets of rats, we evaluated: the ability of Pavlovian cue extinction to reduce cue-induced drug seeking; motivation for cocaine using a progressive ratio procedure; punishment-resistant cocaine taking by pairing cocaine infusions with footshocks; and dependence of drug-seeking on DLS dopamine (a measure of habit-like behavior) with the dopamine antagonist cis-flupenthixol. Overall, cue extinction reduced cue-induced drug seeking after ContA or IntA. Compared to ContA, IntA resulted in increased motivation for cocaine exclusively in females, but IntA facilitated punished cocaine self-administration exclusively in males. After 10 days of IntA training, but not fewer, drug-seeking was dependent on DLS dopamine most notably in males. Our results suggest that IntA may be valuable for identifying sex differences in the early stages of drug use and provide a foundation for the investigation of the mechanisms involved.
The intermittent-access (IntA) self-administration procedure has been reported to produce intensified addiction-like behavior compared to continuous-access (ContA) procedures. In a common variation of the IntA procedure, cocaine is available for 5 min at the beginning of each half hour of a 6-h session. In contrast, during ContA procedures, cocaine is available continuously throughout a session, typically lasting one or more hours. Previous studies comparing procedures have used between-subjects designs, where separate groups of rats self-administer cocaine on either IntA or ContA procedures. The present study used a within-subjects design where subjects self-administered cocaine on the IntA procedure in one context and self-administered cocaine on the continuous short-access (ShA) procedure in another context during separate sessions. Across sessions, rats escalated cocaine intake in the IntA, but not ShA, context. Following sessions eight and 11, rats were administered a progressive ratio test in each context to monitor the change in cocaine motivation. Rats obtained more cocaine infusions on the progressive ratio test in the IntA context than in the ShA context following 11 sessions. These results suggest that addiction-like behaviors following IntA self-administration may be influenced by context-specific learning factors.
AimsFunctional magnetic resonance imaging research has attempted to elucidate the neurobehavioral underpinnings of cocaine dependence by evaluating differences in brain activation to cocaine and response inhibition cues between cocaine-dependent individuals and controls. This study investigated associations between task-related brain activation and cocaine use characteristics. DesignCross-sectional. SettingThe Center for Biomedical Imaging at the Medical University of South Carolina, USA. ParticipantsFifty-one cocaine users (41 dependent). MeasurementsBrain activation to cocaine-cue exposure and Go No-Go tasks in six a priori selected brain regions of interest and cocaine use characteristics (i.e. cocaine dependence status, years of cocaine use, cocaine use in the past 90 days) assessed via standardized interviews. FindingsParticipants demonstrated elevated activation to cocaine (bilateral ventral striatum, dorsal caudate, amygdala) and response inhibition (bilateral anterior cingulate, insula, inferior frontal gyrus) cues in all hypothesized brain regions. Years of cocaine use was associated with task-related brain activation, with more years of cocaine use associated with greater activation to cocaine cues in right (F=7.97, P=0.01) and left (F=5.47, P=0.02) ventral striatum and greater activation to response inhibition cues in left insula (F=5.10, P=0.03) and inferior frontal gyrus (F=4.12, P=0.05) controlling for age, cocaine dependence status and cocaine use in the past 90 days. Conclusions
Years of cocaine use may be more centrally related to cocaine cue and response inhibition brain activation than cocaine dependence diagnosis or amount of recent use.
Rapid drug delivery to the brain might increase the risk for developing addiction. In rats, increasing the speed of intravenous cocaine delivery (5 vs. 90 s) increases drug intake and the subsequent motivation to self-administer cocaine. Increased motivation for cocaine could result not only from more extensive prior drug intake and operant responding for drug, but also from neuroplasticity evoked by rapid drug uptake.
We determined the contributions of prior drug intake and operant responding to the increased motivation for cocaine evoked by rapid delivery. We also investigated the effects of cocaine delivery speed on corticostriatal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) mRNA.
Rats self-administered cocaine (0.25 mg/kg/infusion) delivered over 5 or 90 s during short-access (1 h/session; ShA) or long-access (6 h; LgA) sessions. Motivation for cocaine was then assessed by measuring responding under a progressive ratio schedule of reinforcement. Next, BDNF and TrkB mRNA levels were measured in 5- and 90-s rats.
Five-second ShA and 5-s-LgA rats were more motivated for cocaine than their 90-s counterparts. This effect was dissociable from previous levels of drug intake or of operant responding for cocaine. In parallel, only rats self-administering rapid cocaine injections had altered BDNF and TrkB mRNA levels in corticostriatal regions.
Rapid drug delivery augments the motivation for cocaine independently of effects on the levels of drug intake or operant responding for drug. We suggest that rapid delivery might increase the motivation for drug by promoting neuroplasticity within reward pathways. This neuroplasticity could involve increased regulation of BDNF/TrkB.
In light of recent studies suggesting that amphetamine (AMPH) increases electrically evoked dopamine release ([DA]o), we examined discrepancies between these findings and literature that has demonstrated AMPH-induced decreases in [DA]o. The current study has expanded the inventory of AMPH actions by defining two separate mechanisms of AMPH effects on [DA]o at high and low doses, one dopamine transporter (DAT) independent and one DAT dependent, respectively. AMPH concentrations were measured via microdialysis in rat nucleus accumbens after intraperitoneal injections of 1 and 10 mg/kg and yielded values of ∼10 and 200 nm, respectively. Subsequently, voltammetry in brain slices was used to examine the effects of low (10 nm), moderate (100 nm), and high (10 μm) concentrations of AMPH across a range of frequency stimulations (one pulse; five pulses, 20 Hz; 24 pulses, 60 Hz). We discovered biphasic, concentration-dependent effects in WT mice, in which AMPH increased [DA]o at low concentrations and decreased [DA]o at high concentrations across all stimulation types. However, in slices from DAT-KO mice, [DA]o was decreased by all concentrations of AMPH, demonstrating that AMPH-induced increases in [DA]o are DAT dependent, whereas the decreases at high concentrations are DAT independent. We propose that low AMPH concentrations are insufficient to disrupt vesicular sequestration, and therefore AMPH acts solely as a DAT inhibitor to increase [DA]o. When AMPH concentrations are high, the added mechanism of vesicular depletion leads to reduced [DA]o. The biphasic mechanisms observed here confirm and extend the traditional actions of AMPH, but do not support mechanisms involving increased exocytotic release.
Previous literature investigating neurobiological adaptations following cocaine self-administration has shown that the development of pharmacodynamic tolerance, characterized by reduced cocaine potency at the dopamine transporter (DAT), results from high, continuous levels of intake (long-access; LgA), while sensitization of cocaine potency is caused by intermittent patterns of cocaine administration (intermittent-access; IntA). Here we aimed to determine if the changes observed following cocaine self-administration were specific to cocaine, or translated to other psychostimulants as well. Potency was assessed by fast scan cyclic voltammetry in brain slices containing the nucleus accumbens following control, IntA, short-access (ShA), and LgA. We assessed the potency of amphetamine, a releaser, and methylphenidate (MPH), a DAT blocker that is functionally similar to cocaine and structurally related to amphetamine. Changes in MPH potency can give information as to the importance of functional or structural aspects of compounds as related to the expression of tolerance/sensitization effects. MPH and amphetamine potencies were increased following IntA, while neither was changed following LgA. Here we demonstrate that while LgA-induced tolerance at the DAT is specific to cocaine, the sensitizing effects of IntA are conferred to cocaine, MPH, and amphetamine. The unchanged potency of MPH following LgA suggests that the expression of tolerance does not rely on the function of the compound as blocker/releaser. This demonstrates that the pattern with which cocaine is administered is important in determining the neurochemical consequences of not only cocaine effects, but cross-sensitization/cross-tolerance effects of other psychostimulants as well.
Methylphenidate (MPH) is commonly diverted for recreational use, but the neurobiological consequences of exposure to MPH at high, abused doses are not well defined. Here we show that MPH self-administration in rats increases dopamine transporter (DAT) levels and enhances the potency of MPH and amphetamine on dopamine responses and drug-seeking behaviours, without altering cocaine effects. Genetic overexpression of the DAT in mice mimics these effects, confirming that MPH self-administration-induced increases in DAT levels are sufficient to induce the changes. Further, this work outlines a basic mechanism by which increases in DAT levels, regardless of how they occur, are capable of increasing the rewarding and reinforcing effects of select psychostimulant drugs, and suggests that individuals with elevated DAT levels, such as ADHD sufferers, may be more susceptible to the addictive effects of amphetamine-like drugs.
Much work has focused on determining the consequences of cocaine self-administration on specific neurotransmitter systems, thus neglecting the global changes that occur. Previous imaging studies have focused on the effects of cocaine self-administration in the presence of high blood levels of cocaine, but have not determined the functional effects of cocaine self-administration after cocaine has cleared. Extended-access cocaine self-administration, where animals administer cocaine for 6 h each day, results in escalation in the rate of cocaine intake and is believed to model the transition from recreational use to addiction in humans. We aimed to determine the functional changes following acute (48 h) withdrawal from an extended-access, defined-intake self-administration paradigm (5 days, 40 injections/day, 6 h/day), a time point when behavioral changes are present. Using the 2-[(14) C]deoxyglucose method to measure rates of local cerebral glucose metabolism, an indicator of functional activity, we found reductions in circuits related to learning and memory, attention, sleep, and reward processing, which have important clinical implications for cocaine addiction. Additionally, lower levels of functional activity were found in the dorsal raphe and locus coeruleus, suggesting that cocaine self-administration may have broader effects on brain function than previously noted. These widespread neurochemical reductions were concomitant with substantial behavioral differences in these animals, highlighted by increased vertical activity and decreased stereotypy. These data demonstrate that behavioral and neurochemical impairments following cocaine self-administration are present in the absence of drug and persist after cocaine has been cleared.
Understanding the neurobiological mechanisms of addiction requires an integration of basic neuroscience with social psychology, experimental psychology, and psychiatry. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and a loss of control over drug-taking. Sensitization and counteradaptation are hypothesized to contribute to this hedonic homeostatic dysregulation, and the neurobiological mechanisms involved, such as the mesolimbic dopamine system, opioid peptidergic systems, and brain and hormonal stress systems, are beginning to be characterized. This framework provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and to relapse in individuals with a history of addiction.
Drug addition is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling, which are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug naïve rats during a test of cue-evoked incentive motivation for food - the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and dopamine release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.Neuropsychopharmacology accepted article preview online, 07 May 2014; doi:10.1038/npp.2014.96.
Tolerance to the neurochemical and psychoactive effects of cocaine after repeated use is a hallmark of cocaine addiction in humans. However, comprehensive studies on tolerance to the behavioral, psychoactive, and neurochemical effects of cocaine following contingent administration in rodents are lacking. We outlined the consequences of extended access cocaine self-administration as it related to tolerance to the psychomotor activating, dopamine (DA) elevating, and DA transporter (DAT) inhibiting effects of cocaine. Cocaine self-administration (1.5 mg/kg/inj; 40 inj; 5 days), which resulted in escalation of first hour intake, caused reductions in evoked DA release and reduced maximal rates of uptake through the DAT as measured by slice voltammetry in the nucleus accumbens core. Further, we report reductions in cocaine-induced uptake inhibition as measured by fast scan cyclic voltammetry, and a corresponding increase in the dose of cocaine required for 50% inhibition of DA uptake (Ki ) at the DAT. Cocaine tolerance at the DAT translated to reductions in cocaine-induced DA overflow as measured by microdialysis. Additionally, cocaine-induced elevations in locomotor activity and stereotypy were reduced, while rearing behavior was enhanced in animals with a history of cocaine self-administration. Here we demonstrate both neurochemical and behavioral cocaine tolerance in an extended-access rodent model of cocaine abuse, which allows for a better understanding of the neurochemical and psychomotor tolerance that develops to cocaine in human addicts. This article is protected by copyright. All rights reserved.