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Data reflect % change from baseline levels of NAcc dopamine plotted across 10-minute sample collections during the 3 samples prior to and the 6 samples following intra-VTA bicuculline administration in adolescent and adult rats (n=7-8 per group). Asterisks (*) denote significant differences relative to the 3 samples collected prior to bicuculline administration (Ps < 0.05), and daggers ( †) denote significant differences between age groups (Ps < 0.05).
Source publication
The behavioral effects of nicotine withdrawal are lower in adolescent versus adult rats. However, the neurochemical mechanisms that mediate these developmental differences are unknown. Previous studies have shown that extracellular levels of dopamine in the nucleus accumbens (NAcc) are reduced in adult rats experiencing withdrawal. This study compa...
Context in source publication
Context 1
... results revealed that mecamylamine did not produce changes in extracellular levels of NAcc 5-HIAA in nicotine-dependent adolescent or adult rats. Figure 6 illustrates % change from baseline levels of NAcc dopamine during the 3 samples prior to and the 6 samples following intra-VTA administration of bicuculline in adolescent and adult rats. Overall, the results revealed that blockade of GABA A receptors in the VTA produced an increase in extracellular levels of NAcc dopamine of adult but not adolescent rats. ...
Similar publications
The aim of the present study was to examine the effects of two neuronal nicotinic acetylcholine receptor ligands on acute ethanol-induced dopamine (DA) function in the C57BL/6J mouse ventral striatumusing an ex vivo assay and high-performance liquid chromatography coupled with electrochemicaldetection. Acute systemic injection of ethanol (2.5 g/kg)...
Citations
... The dopamine hypothesis suggests multiple repeated drug use induces homeostatic changes in the brain, leading to a hypodopaminergic state, a hallmark of SUDs [50]. Evidence from clinical and preclinical studies supports reduced dopaminergic activity in brain areas like the NAc and PFC following chronic drug use [51,52,53]. Differences in the dopamine states between AUD and OUD groups may stem from variations in substance use recency. ...
Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously.
... In rodents, cessation of nicotine reduces locomotor activity [4], increases immobility time in the forced swim test [5], and elevates the brain reward threshold in the intracranial self-stimulation test [6]. In other studies, nicotine withdrawal was shown to reduce tonic dopamine (DA) neuron activity in the ventral tegmental area (VTA) [7] and extracellular DA levels in the nucleus accumbens (NAc) [8,9]. Decreased DA activity in the mesolimbic system may be involved in the mediation of withdrawal signs [10]. ...
Alterations in the various neuropeptide systems in the mesocorticolimbic circuitry have been implicated in negative effects associated with drug withdrawal. The corticotropin-releasing factor (CRF) and α-melanocyte-stimulating hormone are two peptides that may be involved. This study investigated the regulatory effects of chronic nicotine exposure and withdrawal on the mRNA levels of melanocortin receptors (MC3R, MC4R), CRF, and CRF receptors (CRFR1 and CRFR2) expressed in the mesocorticolimbic system. Rats were given drinking water with nicotine or without nicotine (control group) for 12 weeks, after which they continued receiving nicotine (chronic exposure) or were withdrawn from nicotine for 24 or 48 h. The animals were decapitated following behavioral testing for withdrawal signs. Quantitative real-time PCR analysis demonstrated that nicotine exposure (with or without withdrawal) increased levels of CRF and CRFR1 mRNA in the amygdala, CRF mRNA in the medial prefrontal cortex, and CRFR1 mRNA in the septum. Nicotine withdrawal also enhanced MC3R and MC4R mRNA levels in different brain regions, while chronic nicotine exposure was associated with increased MC4R mRNA levels in the nucleus accumbens. These results suggest that chronic nicotine exposure and withdrawal regulate CRF and melanocortin signaling in the mesocorticolimbic system, possibly contributing to negative affective state and nicotine addiction.
... Consistent with a role for mesoaccumbens dopamine transmission in nicotine withdrawal, extracellular dopamine levels were markedly reduced in rats undergoing nicotine withdrawal compared with nicotine-naıve animals (Hildebrand et al., 1998), opposite to the stimulatory effects of acutely administered nicotine on accumbal dopamine release (see above). Nicotine withdrawal-related deficits in accumbens dopamine release are less severe in adolescent than adult rats (Natividad et al., 2010), which may explain the attenuated withdrawal-related behaviors seen in adolescent versus adult rats (O'Dell et al., 2004(O'Dell et al., , 2007. Mecamylamine delivered into the VTA decreased extracellular dopamine levels in the accumbens and precipitated withdrawal-like physical signs in nicotine-dependent but not nicotine-naıve control rats . ...
Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the rewarding actions of nicotine contained in tobacco that establish and maintain the smoking habit. nAChRs also regulate the aversive properties of nicotine, sensitivity to which decreases tobacco use and protects against tobacco use disorder. These opposing behavioral actions of nicotine reflect nAChR expression in brain reward and aversion circuits. nAChRs containing α4 and β2 subunits are responsible for the high-affinity nicotine binding sites in the brain and are densely expressed by reward-relevant neurons, most notably dopaminergic, GABAergic, and glutamatergic neurons in the ventral tegmental area. High-affinity nAChRs can incorporate additional subunits, including β3, α6, or α5 subunits, with the resulting nAChR subtypes playing discrete and dissociable roles in the stimulatory actions of nicotine on brain dopamine transmission. nAChRs in brain dopamine circuits also participate in aversive reactions to nicotine and the negative affective state experienced during nicotine withdrawal. nAChRs containing α3 and β4 subunits are responsible for the low-affinity nicotine binding sites in the brain and are enriched in brain sites involved in aversion, including the medial habenula, interpeduncular nucleus, and nucleus of the solitary tract, brain sites in which α5 nAChR subunits are also expressed. These aversion-related brain sites regulate nicotine avoidance behaviors, and genetic variation that modifies the function of nAChRs in these sites increases vulnerability to tobacco dependence and smoking-related diseases. Here, we review the molecular, cellular, and circuit-level mechanisms through which nicotine elicits reward and aversion and the adaptations in these processes that drive the development of nicotine dependence. SIGNIFICANCE STATEMENT: Tobacco use disorder in the form of habitual cigarette smoking or regular use of other tobacco-related products is a major cause of death and disease worldwide. This article reviews the actions of nicotine in the brain that contribute to tobacco use disorder.
... It is noteworthy that the affective signs of nicotine withdrawal are reduced while nicotine reward is increased in adolescents compared to adult rats (Carcoba et al., 2014;Dickson, Miller, Rogers, Blaha, & Mittleman, 2014;Natividad, Buczynski, Parsons, Torres, & O'Dell, 2012;Natividad, Tejeda, Torres, & O'Dell, 2010;O'Dell et al., 2004O'Dell et al., , 2007, making this age group a vulnerable population for nicotine use and abuse. Moreover, nicotine exposure during this vulnerable life period alters cocaine-induced aversion (Hutchison & Riley, 2008) and reward (Kelley & Rowan, 2004;Schochet, Kelley, & Landry, 2004). ...
... The former findings support the hypothesis that nicotine is more rewarding in adolescents than in adults. In another study, levels of dopamine were lower in adolescent than adult rats that underwent nicotine withdrawal (Natividad et al., 2010), showing that adolescents might be at a greater risk of initiating drug use and becoming addicted. ...
... Proper development of central dopaminergic systems is thought to be linked to proper adult development (Andersen, 2003;Burke & Miczek, 2014;Spear, 2000;Weinberger, 1987). During withdrawal, there is a lesser decrease in dopamine levels in adolescents than in adults (Li, Mead, & Bevins, 2009;Natividad et al., 2010;Shram & Le, 2010). ...
Nicotine and alcohol abuse and co-dependence represent major public health crises. Indeed, previous research has shown that the prevalence of alcoholism is higher in smokers than in non-smokers. Adolescence is a susceptible period of life for the initiation of nicotine and alcohol use and the development of nicotine-alcohol codependence. However, there is a limited number of pharmacotherapeutic agents to treat addiction to nicotine or alcohol alone. Notably, there is no effective medication to treat this comorbid disorder. This chapter aims to review the early nicotine use and its impact on subsequent alcohol abuse during adolescence and adulthood as well as the role of neuropeptides in this comorbid disorder. The preclinical and clinical findings discussed in this chapter will advance our understanding of this comorbid disorder's neurobiology and lay a foundation for developing novel pharmacotherapies to treat nicotine and alcohol codependence.
... Nicotine withdrawal has different effects on the functioning of NAc in adolescence as compared to adulthood. Studies have shown that discontinuation of nicotine in juveniles causes less side effects than in adults [220]. This may be due to an underdevelopment of the GABA-ergic system and a weaker inhibition of dopaminergic neurons in the VTA, which, to a lesser extent, reduces the dopamine content in NAc. ...
A growing body of evidence suggests that nucleus accumbens (NAc) plays a significant role not only in the physiological processes associated with reward and satisfaction but also in many diseases of the central nervous system. Summary of the current state of knowledge on the morphological and functional basis of such a diverse function of this structure may be a good starting point for further basic and clinical research. The NAc is a part of the brain reward system (BRS) characterized by multilevel organization, extensive connections, and several neurotransmitter systems. The unique role of NAc in the BRS is a result of: (1) hierarchical connections with the other brain areas, (2) a well-developed morphological and functional plasticity regulating short- and long-term synaptic potentiation and signalling pathways, (3) cooperation among several neurotransmitter systems, and (4) a supportive role of neuroglia involved in both physiological and pathological processes. Understanding the complex function of NAc is possible by combining the results of morphological studies with molecular, genetic, and behavioral data. In this review, we present the current views on the NAc function in physiological conditions, emphasizing the role of its connections, neuroplasticity processes, and neurotransmitter systems.
... The use of each drug alone, or in combination, is the main preventable cause of premature death worldwide, with an estimated death toll of about five million individuals annually. Notably, tobacco use can lead to nicotine addiction, and nicotine can serve as a gateway drug to facilitate alcohol intake and other addictive drugs [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. In particular, nicotine has been reported to serve as a gateway drug for subsequent use and abuse of amphetamine, cocaine, and morphine [1,3,4,[7][8][9][10][11][12][19][20][21][22][23][24][25]. ...
Evidence suggests that nicotine and alcohol can each serve as a gateway drug. We determined whether prior nicotine and alcohol treatment would alter amphetamine reward. Also, we examined whether age and dopaminergic neurotransmission are important in this regard. Male and female adolescent and adult C57BL/6J mice were tested for baseline place preference. Mice then received six conditioning with saline/nicotine (0.25 mg/kg) twice daily, followed by six conditioning with saline/ethanol (2 g/kg). Control mice were conditioned with saline/saline throughout. Finally, mice were conditioned with amphetamine (3 mg/kg), once in the nicotine-alcohol-paired chamber, and tested for place preference 24 h later. The following day, mice were challenged with amphetamine (1 mg/kg) and tested for place preference under a drugged state. Mice were then immediately euthanized, their brain removed, and nucleus accumbens isolated and processed for the level of dopamine receptors and transporter and glutamate receptors. We observed a greater amphetamine-induced place preference in naïve adolescents than adult mice with no change in state-dependent place preference between the two age groups. In contrast, amphetamine induced a significant place preference in adult but not adolescent mice with prior nicotine-alcohol exposure under the drug-free state. The preference was significantly greater in adults than adolescents under the drugged state. The enhanced response was associated with higher dopamine-transporter and D1 but reduced D2 receptors’ expression in adult rather than adolescent mice, with no changes in glutamate receptors levels. These results suggest that prior nicotine and alcohol treatment differentially alters amphetamine reward in adult and adolescent mice. Alterations in dopaminergic neurotransmission may be involved in this phenotype.
... Consistently, some preclinical studies in rodents have provided evidence of a greater sensitivity of adolescents than adults to the positive rewarding properties of cocaine [45] and amphetamine [46]. In addition, adolescent rats seem to be less sensitive than adults to the aversive properties of stimuli [47] and to the negative effects of withdrawal from nicotine [48,49]. Furthermore, microdialysis studies performed across the different stages (early, mid, and late) of adolescence have revealed that mid-adolescence is the most critical window of vulnerability to the effects that specific drugs of abuse elicit on DA transmission. ...
Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability to the central effects of drugs. Despite growing concerns about the negative effects of the use of SCs, newly synthetized compounds are increasingly detected in drugs seized by the authorities, posing a serious threat to public health. 5F-MDMB-PICA has been recently detected and classified as a highly potent agonist of CB1 and CB2 cannabinoid receptors. Here, we first investigated the rewarding properties of 5F-MDMB-PICA in C57BL/6 adolescent and adult mice by in vivo brain microdialysis. Data showed that acute administration of a selected dose of 5F-MDMB-PICA (0.01 mg/kg i.p.) stimulates the release of dopamine in the nucleus accumbens shell of adolescent, but not of adult, mice. To further investigate the consequences of repeated exposure to this dose of 5F-MDMB-PICA, a separate group of adolescent mice was treated for 14 consecutive days and evaluated for behavioral abnormalities at adulthood, starting from 7 days after drug discontinuation. Data showed that this group of adult mice displayed an anxiety-like and compulsive-like state as revealed by an altered performance in the marble burying test. Our study suggests an alarming vulnerability of adolescent mice to the effects of 5F-MDMB-PICA. These findings provide a useful basis for understanding and evaluating both early and late detrimental effects that may derive from the use of SCs during adolescence.
... The use of each drug alone or in combination is the main preventable cause of premature death worldwide, with an estimated death toll of about 5 million individuals annually. Notably, tobacco use can lead to nicotine addiction and nicotine can serve as a gateway drug to facilitate intake of alcohol and other addictive drugs (Bechtholt and Mark 2002;DiFranza and Guerrera 1990;Horger et al. 1992;Hutchison and Riley 2008;Kandel and Kandel 2015;Kandel and Kandel 2014;Kelley and Rowan 2004;Kouri et al. 2001;Levine et al. 2011;Li et al. 2014;McQuown et al. 2007;McQuown et al. 2009;Meliska et al. 1995;Natividad et al. 2010;Rinker et al. 2011;Rosenberg 2014;Schindler et al. 2012;Schneider et al. 2012). In particular, nicotine has been reported to serve as a gateway drug for subsequent use and abuse of amphetamine, cocaine, and morphine (Baker et al. 2018;Baker et al. 2013;Bechtholt and Mark 2002;Gossop et al. 2006;Horger et al. 1992;Hutchison and Riley 2008;Kelley and Rowan 2004;Kouri et al. 2001;Levine et al. 2011;Li et al. 2014;Marks et al. 2015;McQuown et al. 2007;McQuown et al. 2009;Ruiz et al. 2018;Stinson et al. 2005;Storey et al. 2016). ...
Rationale
Nicotine and alcohol each can serve as the gateway to other drugs.
Objective
The current study was sought to determine if prior nicotine and alcohol exposure alters amphetamine reward and if age and dopaminergic neurotransmission are involved.
Methods
Male and female adolescent and adult C57BL/6J mice were tested for baseline place preference, received six conditioning with saline/nicotine (0.25 mg/kg) twice daily followed by six conditioning with saline/ethanol (2 g/kg) in a counterbalance manner. Control mice were conditioned with saline/saline throughout. Finally, mice were conditioned with amphetamine (3 mg/kg) once in the nicotine-alcohol-paired chamber and then tested for CPP 24 h later. The following day, mice were challenged with amphetamine (1 mg/kg) and tested for CPP under a drugged state. Mice were then immediately euthanized, brain removed and nucleus accumbens isolated and processed for the expression of dopamine receptors and transporter, and glutamate receptors.
Results
We observed a greater amphetamine-induced CPP in adolescent than adult mice but no change in state-dependent CPP between the two age groups. In contrast, amphetamine-induced CPP in mice with prior nicotine-alcohol exposure was greater in adult than adolescent mice under both drug-free and drugged states. The enhanced response in adult mice was associated with greater expression of dopamine-transporter, reduced D2 receptors, and increased D1 receptors with no changes in glutamate receptors.
Conclusions
These results suggest that prior nicotine and alcohol exposure differentially alters the rewarding action of amphetamine in adult and adolescent mice and alterations in dopaminergic neurotransmission may be involved in this phenotype.
... [9][10][11][12][13][14][15][16] Moreover, when tested for the response to aversive properties of drugs, or during withdrawal, adolescents seem to be less sensitive than adults. 13,14,[17][18][19][20][21] Similarly, functional magnetic resonance imaging (fMRI) studies in humans have shown greater activation of motivational circuits in adolescents compared with adults. 22 However, in spite of this large number of behavioral and neuroimaging studies, analyzing the different response of adolescents and adults to drugs, very few data are available about the neurochemical response to drugs during adolescence. ...
... In both compartments of NAc, we did not observe any age difference in DA basal levels, in agreement with previous studies. 18,37,38 In contrast with the present and previous studies, Badanich et al 10 Moreover, Natividad et al 18,38 using conventional microdialysis (with most of probe placements in the shell) come to the same conclusions as ours. In DLS, we detected lower basal DA levels at 5 (early adolescence) and 6 weeks (mid-adolescence) of age, thus being consistent with the lower tyrosine hydroxylase (TH) immunoreactivity observed at these ages. ...
... In both compartments of NAc, we did not observe any age difference in DA basal levels, in agreement with previous studies. 18,37,38 In contrast with the present and previous studies, Badanich et al 10 Moreover, Natividad et al 18,38 using conventional microdialysis (with most of probe placements in the shell) come to the same conclusions as ours. In DLS, we detected lower basal DA levels at 5 (early adolescence) and 6 weeks (mid-adolescence) of age, thus being consistent with the lower tyrosine hydroxylase (TH) immunoreactivity observed at these ages. ...
On the basis of epidemiological studies it has been proposed that cannabis use plays a causal role in the abuse of highly addictive drugs (Gateway Hypothesis). However, epidemiological studies are intrinsically unable to provide evidence of causality. Experimental studies can provide this evidence but they are feasible only in animal models and to date such evidence is lacking. In view of the importance of genetic factors in drug abuse, we investigated the influence of adolescent cannabis exposure on adult heroin reinforcement in two inbred rat strains differentially vulnerable to drugs of abuse, addiction prone Lewis (LEW) and addiction resistant Fischer 344 (F344) strains.
Male LEW and F344 rats aged six weeks were exposed to increasing Δ⁹-tetrahydrocannabinol (THC) doses, twice a day for 3 days (2, 4, 8 mg/kg, i.p.). At adulthood they were allowed to self-administer heroin (0.025 mg/kg) under both Fixed- (FR) and Progressive- (PR) ratio schedules of responding. Following extinction, responding was reinstated by drug-cues and/or by heroin priming.
THC pre-exposure increased responding for heroin and heroin intake under FR-3 and FR-5 as well as PR protocols and increased breaking point in PR schedules in LEW but not F344 rats. Drug cues and heroin priming reinstated responding in LEW and F344, but THC pre-exposure increased reinstatement by priming in LEW rats and by cues in F344 rats.
These observations show that in genetically predisposed individuals, adolescent cannabis exposure increases heroin reinforcing properties, thus providing a mechanism for a causal role of adolescent cannabis use in heroin abuse.
... [9][10][11][12][13][14][15][16] Moreover, when tested for the response to aversive properties of drugs, or during withdrawal, adolescents seem to be less sensitive than adults. 13,14,[17][18][19][20][21] Similarly, functional magnetic resonance imaging (fMRI) studies in humans have shown greater activation of motivational circuits in adolescents compared with adults. 22 However, in spite of this large number of behavioral and neuroimaging studies, analyzing the different response of adolescents and adults to drugs, very few data are available about the neurochemical response to drugs during adolescence. ...
... In both compartments of NAc, we did not observe any age difference in DA basal levels, in agreement with previous studies. 18,37,38 In contrast with the present and previous studies, Badanich et al 10 Moreover, Natividad et al 18,38 using conventional microdialysis (with most of probe placements in the shell) come to the same conclusions as ours. In DLS, we detected lower basal DA levels at 5 (early adolescence) and 6 weeks (mid-adolescence) of age, thus being consistent with the lower tyrosine hydroxylase (TH) immunoreactivity observed at these ages. ...
... In both compartments of NAc, we did not observe any age difference in DA basal levels, in agreement with previous studies. 18,37,38 In contrast with the present and previous studies, Badanich et al 10 Moreover, Natividad et al 18,38 using conventional microdialysis (with most of probe placements in the shell) come to the same conclusions as ours. In DLS, we detected lower basal DA levels at 5 (early adolescence) and 6 weeks (mid-adolescence) of age, thus being consistent with the lower tyrosine hydroxylase (TH) immunoreactivity observed at these ages. ...
Epidemiological studies have shown that people who begin experimenting drugs of abuse during adolescence are more likely to develop substance use disorders, and the earliest is the beginning of their use, the greatest is the likelihood to become dependent. Understanding the neurobiological changes increasing adolescent vulnerability to drug use is becoming imperative. Although all neurotransmitter systems undergo relevant developmental changes, dopamine system is of particular interest, given its role in a variety of functions related to reward, motivation, and decision making. Thus, in the present study, we investigated differences in mesolimbic and nigrostriatal dopamine transmission between adolescent (5, 6, 7 weeks of age) and adult rats (10‐12 weeks of age), in basal conditions and following drug challenge, by using in vivo brain microdialysis. Although no significant difference between adolescents and adults was observed in dopamine basal levels in the nucleus accumbens (NAc)shell and core, reduced DA levels were found in the dorsolateral striatum (DLS) of early and mid‐adolescent rats. Adolescent rats showed greater increase of dopamine in the NAc shell following nicotine (0.4 mg/kg), THC (1.0 mg/kg), and morphine (1.0 mg/kg), in the NAc core following nicotine and morphine, and in the DLS following THC, morphine, and cocaine (10 mg/kg). These results, while adding new insight in the development and functionality of the dopamine system during different stages of adolescence, might provide a neurochemical basis for the greater vulnerability of adolescents to drugs of abuse and for the postulated gateway effect of nicotine and THC toward abuse of other illicit substances.
