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Initiating alcohol use in adolescence significantly increases the likelihood of developing adult alcohol use disorder (AUD). However, it has been difficult to replicate adolescent alcohol exposure leading to increased adult alcohol intake across differing preclinical models. In the present study, differentially housed male rats (group vs. single cages) were used to determine the effects of voluntary intermittent exposure of saccharin-sweetened ethanol during adolescence on adult intake of unsweetened 20% ethanol. Adolescent male rats were assigned to group- or isolated-housing conditions and underwent an intermittent 2-bottle choice in adolescence (water only or water vs. 0.2% saccharin/20% ethanol), and again in adulthood (water vs. 20% ethanol). Intermittent 2-bottle choice sessions lasted for 24 h, and occurred three days per week, for five weeks. Rats were moved from group or isolated housing to single-housing cages for 2-bottle choice tests and returned to their original housing condition on off days. During adolescence, rats raised in isolated-housing conditions consumed significantly more sweetened ethanol than rats raised in group-housing conditions, an effect that was enhanced across repeated exposures. In adulthood, rats raised in isolated-housing conditions and exposed to sweetened ethanol during adolescence also consumed significantly higher levels of unsweetened 20% ethanol compared to group-housed rats. The effect was most pronounced over the first five re-exposure sessions. Housing conditions alone had little effect on adult ethanol intake. These preclinical results suggest that social isolation stress, combined with adolescent ethanol exposure, may play a key role in adult AUD risk.

The purpose of this study was to determine if social vs nonsocial cues (peer vs light/tone) can serve as discriminative stimuli to reinstate cocaine seeking. In addition, to assess a potential mechanism, an oxytocin (OT) promoter-linked hM3Dq DREADD was infused into the paraventricular nucleus of the hypothalamus to determine whether peer-induced cocaine seeking is decreased by activation of OT neurons. Male rats underwent twice-daily self-administration sessions, once with cocaine in the presence of one peer (S+) and once with saline in the presence of a different peer (S-). Another experiment used similar procedures, except the discriminative stimuli were nonsocial (constant vs flashing light/tone), with one stimulus paired with cocaine (S+) and the other paired with saline (S-). A third experiment injected male and female rats with OTp-hM3Dq DREADD or control virus into PVN and tested them for peer-induced reinstatement of cocaine seeking following clozapine (0.1 mg/kg). Although acquisition of cocaine self-administration was similar in rats trained with either peer or light/tone discriminative stimuli, the latency to first response was reduced by the peer S+, but not by the light/tone S+. In addition, the effect of the conditioned stimulus was overshadowed by the peer S+ but not by the light/tone S+. Clozapine blocked the effect of the peer S+ in rats receiving the OTp-hM3Dq DREADD virus, but not in rats receiving the control virus. These results demonstrate that a social peer can serve as potent trigger for drug seeking and that OT in PVN modulates peer-induced reinstatement of cocaine seeking.

Alcohol use disorder (AUD) has been shown to be associated with a dysregulated stress system. Reducing the stress hormone corticosterone (CORT), that binds to glucocorticoid receptors, may attenuate the rewarding properties of drugs of abuse. However, the effect of blocking corticosterone receptors on ethanol reward has yet to be investigated.The current study investigated whether the stress hormone receptor antagonist, PT150, would block the rewarding properties of ethanol via the glucocorticoid receptor system and attenuate other ethanol-induced effects.A conditioned place preference (CPP) procedure was used to examine the rewarding properties of ethanol in an avian preclinical model. Ethanol was paired with the least preferred chamber. On alternate days, water was paired with the preferred chamber. After eight pairings, a place preference test was given that allowed subjects to have access to both chambers. Half of the subjects received PT150 prior to ethanol administration. The other half received vehicle. Time spent in each chamber during the preference tests, locomotor activity during the pairings, and egg production in female birds was recorded.Ethanol treatment resulted in a CPP and pretreatment of PT150 blocked the acquisition of the ethanol-induced place preference. Neither ethanol nor PT150 altered locomotor activity. Pretreatment of PT150 also increased egg production in female quail treated with ethanol.These findings suggest repeated ethanol pairings with visual cues can produce a CPP. Furthermore, pretreatment of PT150 may be a potential pharmacotherapy for blocking the rewarding properties of ethanol and may enhance egg production in female quail treated with ethanol.

RATIONALE: Opioid use disorder (OUD) is highly comorbid with stress-related disorders, and stress can serve as a trigger for reinstatement of drug seeking. Glucocorticoid receptor (GR) antagonists such as mifepristone (RU-486) may be effective against stress-induced drug seeking. In the current study, PT150 (formerly ORG-34517), a more selective GR antagonist, was tested using two models of stress-induced drug seeking, namely footshock and yohimbine. METHODS: Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl (2.5 μg/kg/infusion, i.v.) in a model of escalation. Rats then received 7 days of abstinence, followed by extinction; PT150 (0, 50 or 100 mg/kg in Nutella(®); p.o.) treatment started on the first day of extinction training and continued daily until the end of the study. Following 14 days of extinction, rats were tested for reinstatement following footshock and yohimbine (0, 1 or 2 mg/kg; i.p.), tested in counterbalanced order; PT150 or placebo treatment occurred prior to each extinction and reinstatement session. RESULTS: Prior to initiation of PT150 treatment, females self-administered greater levels of fentanyl during 1-hr sessions compared to males; however, when switched to 6-hr sessions, males and females self-administered similar levels of fentanyl and showed a similar escalation of intake over time. PT150 had no effect on extinction of self-administration. While both footshock and yohimbine reinstated fentanyl seeking, only footshock-induced reinstatement was decreased by PT150 (50 and 100 mg/kg). The effect of PT150 on footshock-induced reinstatement was driven primarily by males. CONCLUSION: The glucocorticoid antagonist PT150 reduces shock-induced fentanyl seeking, suggesting it may be effective against stress-induced relapse, although the sex difference in response may need further exploration.

There is comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD), perhaps because PTSD-like stressful experiences early in life alter the hypothalamic-pituitary-adrenal stress axis to increase the risk for OUD. The present study determined if the glucocorticoid receptor antagonist PT150 reduces the escalation of fentanyl intake in rats exposed to a "two-hit" model of early-life stress (isolation rearing and acute stress). Male and female rats were raised during adolescence in either isolated or social housing and then were given either a single acute stress (restraint and cold-water swim) or control treatment in young adulthood. Rats were then treated daily with PT150 (50 mg/kg, oral) or placebo and were tested for acquisition of fentanyl self-administration in 1-hr sessions, followed by escalation across 6-hr sessions. Regardless of PT150 treatment or sex, acquisition of fentanyl self-administration in 1-hr sessions was greater in isolate-housed rats compared to social-housed rats; the acute stress manipulation did not have an effect on self-administration even though it transiently increased plasma corticosterone levels. During the 6-hr sessions, escalation of fentanyl was observed across all treatment groups; however, there was a significant PT150 Treatment × Sex interaction. While males self-administered more than females overall, PT150

Escalation of drug intake and craving are two DSM-5 hallmark symptoms of opioid use disorder (OUD). This study determined if escalation of intake as modeled by long access (LgA) self-administration (SA) and craving measured by reinstatement are related. Adult male and female Sprague–Dawley rats were trained to self-administer fentanyl across 7 daily 1-h short access (ShA) sessions, followed by 21 SA sessions of either 1- or 6-h duration (ShA or LgA). Following 14 1-h extinction sessions, Experiment 1 assessed reinstatement induced by either fentanyl (10 or 30 µg/kg) or yohimbine (1 or 2 mg/kg), and Experiment 2 assessed reinstatement induced by a drug-associated cue light. Females acquired fentanyl SA faster than males. When shifted to LgA sessions, LgA rats escalated fentanyl intake, but ShA rats did not; no reliable sex difference in the rate of escalation was observed. In extinction, compared to ShA rats, LgA rats initially responded less and showed less decay of responding across sessions. A priming injection of fentanyl induced reinstatement, with LgA rats reinstating more than ShA rats at the 30 µg/kg dose. Yohimbine (1 mg/kg) also induced reinstatement, but there was no effect of access group or sex. With cue-induced reinstatement, LgA females reinstated less than LgA males and ShA females. Among the different reinstatement tests assessed, escalation of fentanyl SA increased only drug-primed reinstatement, suggesting a limited relationship between escalation of drug intake and craving (reinstatement) for OUD.

Dysregulation of dopamine neurotransmission has been linked to the development of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND). To investigate the mechanisms underlying this phenomenon, this study used an inducible HIV-1 transactivator of transcription (Tat) transgenic (iTat-tg) mouse model, which demonstrates brain-specific Tat expression induced by administration of doxycycline. We found that induction of Tat expression in the iTat-tg mice for either 7 or 14 days resulted in a decrease (∼30%) in the Vmax of [3H]dopamine uptake via both the dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex (PFC), which was comparable to the magnitude (∼35%) of the decrease in Bmax for [3H]WIN 35,428 and [3H]nisoxetine binding to DAT and NET, respectively. The decreased Vmax was not accompanied by a reduction of total or plasma membrane expression of DAT and NET. Consistent with the decreased Vmax for DAT and NET in the PFC, the current study also found an increase in the tissue content of DA and dihydroxyphenylacetic acid in the PFC of iTat-tg mice after 7 days’ administration of doxycycline. Electrophysiological recordings in layer V pyramidal neurons of the prelimbic cortex from iTat-tg mice found a significant reduction in action potential firing, which was not sensitive to selective inhibitors for DAT and NET, respectively. These findings provide a molecular basis for using the iTat-tg mouse model in the studies of NeuroHIV. Determining the mechanistic basis underlying the interaction between Tat and DAT/NET may reveal novel therapeutic possibilities for preventing the increase in comorbid conditions as well as HAND. SIGNIFICANCE STATEMENT Human immunodeficiency virus (HIV)-1 infection disrupts dopaminergic neurotransmission, leading to HIV-associated neurocognitive disorders (HANDs). Based on our in vitro and in vivo studies, dopamine uptake via both dopamine and norepinephrine transporters is decreased in the prefrontal cortex of HIV-1 Tat transgenic mice, which is consistent with the increased dopamine and dihydroxyphenylacetic acid contents in this brain region. Thus, these plasma membrane transporters are an important potential target for therapeutic intervention for patients with HAND.

Concomitant use of tobacco and opioids represents a growing public health concern. In fact, the mortality rate due to smoking-related illness approaches 50% among SUD patients. Cumulative evidence demonstrates that the vulnerability to drugs of abuse is influenced by behavioral, environmental, and genetic factors. This review explores the contribution of genetics and neural mechanisms influencing nicotine and opioid reward, respiration, and antinociception, emphasizing the interaction of cholinergic and opioid receptor systems. Despite the substantial evidence demonstrating nicotine-opioid interactions within the brain and on behavior, the currently available pharmacotherapies targeting these systems have shown limited efficacy for smoking cessation on opioid-maintained smokers. Thus, further studies designed to identify novel targets modulating both nicotinic and opioid receptor systems may lead to more efficacious approaches for co-morbid nicotine dependence and opioid use disorder.

Alcohol is one of the most widely used recreational substances worldwide, with drinking frequently initiated during adolescence. The developmental state of the adolescent brain makes it vulnerable to initiating alcohol use, often in high doses, and particularly susceptible to alcohol-induced brain changes. Microglia, the brain parenchymal macrophages, have been implicated in mediating some of these effects, though the role that these cells play in the progression from alcohol drinking to dependence remains unclear. Microglia are uniquely positioned to sense and respond to central nervous system insult, and are now understood to exhibit innate immune memory, or “priming,” altering their future functional responses based on prior exposures. In alcohol use disorders (AUDs), the role of microglia is debated. Whereas microglial activation can be pathogenic, contributing to neuroinflammation, tissue damage, and behavioral changes, or protective, it can also engage protective functions, providing support and mediating the resolution of damage. Understanding the role of microglia in adolescent AUDs is complicated by the fact that microglia are thought to be involved in developmental processes such as synaptic refinement and myelination, which underlie the functional maturation of multiple brain systems in adolescence. Thus, the role microglia play in the impact of alcohol use in adolescence is likely multifaceted. Long-term sequelae may be due to a failure to recover from EtOH-induced tissue damage, altered neurodevelopmental trajectories, and/or persistent changes to microglial responsivity and function. Here, we review critically the literature surrounding the effects of alcohol on microglia in models of adolescent alcohol misuse. We attempt to disentangle what is known about microglia from other neuroimmune effectors, to which we apply recent discoveries on the role of microglia in development and plasticity. Considered altogether, these studies challenge assumptions that proinflammatory microglia drive addiction. Alcohol priming microglia and there by perturbing their homeostatic roles in neurodevelopment, especially during critical periods of plasticity such as adolescence, may have more serious implications for the neuropathogenesis of AUDs in adolescents.

Background Although pharmacotherapies are available for alcohol (EtOH) or tobacco use disorders individually, it may be possible to develop a single pharmacotherapy to treat heavy drinking tobacco smokers by capitalizing on the commonalities in their mechanisms of action. Methods Female alcohol-preferring (P) rats were trained for EtOH drinking and nicotine self-administration in two phases: (1) EtOH alone (0 vs. 15% EtOH, 2-bottle choice) and (2) concomitant access, during which EtOH access continued with access to nicotine (0.03 mg/kg/infusion, i.v.) using a 2-lever choice procedure (active vs. inactive lever) in which the fixed ratio (FR) requirement was gradually increased to FR30. When stable co-use was obtained, rats were pretreated with varying doses of naltrexone, varenicline, or r-bPiDI, an α6β2* subtype-selective nicotinic acetylcholine receptor antagonist shown previously to reduce nicotine self-administration. Results While EtOH intake was initially suppressed in phase 2 (co-use), pharmacologically relevant intake for both substances was achieved by raising the “price” of nicotine to FR30. In phase 2, naltrexone decreased EtOH and water consumption but not nicotine intake; in contrast, naltrexone in phase 1 (EtOH only) did not significantly alter EtOH intake. Varenicline and r-bPiDI in phase 2 both decreased nicotine self-administration and inactive lever pressing, but neither altered EtOH or water consumption. Conclusions These results indicate that increasing the “price” of nicotine increases EtOH intake during co-use. Additionally, the efficacy of naltrexone, varenicline, and r-bPiDI was specific to either EtOH or nicotine, with no efficacy for co-use. Nevertheless, future studies on combining these treatments may reveal synergistic efficacy.

This study examined the behavioral effects of d-amphetamine and recreational activities, alone and in combination, in high and low impulsive sensation seekers. Healthy 18-27 year-old participants, scoring in the upper (N=8) or lower (N=8) third of college students on the impulsive sensation-seeking scale of the Zuckerman-Kuhlman Personality Questionnaire, completed eight test days in which sessions were completed before (i.e., baseline) and 60, 120 and 180 minutes after d-amphetamine (0, 10 mg/70 kg) administration. Between sessions, subjects completed recreational activities (movies, music, reading, videogames) identified as high or low in sensation value. Each of four conditions (low and high sensation value activities combined with placebo and active drug) was administered under double-blind conditions on 2 days according to a randomized-block design. Typical stimulant-like cardiovascular and task performance effects were engendered by d-amphetamine; consistent with previous research, the magnitude of drug effects were greater among high sensation seekers. High sensation value activities engendered independent stimulant-like effects on subject ratings. These results suggest that d-amphetamine and high sensation stimulus materials may activate a common neurobiological substrate, likely the mesolimbic dopamine system, and that individual differences in sensation seeking status play a role in vulnerability to stimulant drug abuse.

International audience; Rationale: In rodents, environmental enrichment (EE) produces both preventive and curative effects on drug addiction, and this effect is believed to depend at least in part on EE's actions on the stress system.Objectives: This study investigated whether exposure to EE during abstinence reduces methamphetamine seeking after extended self-administration. In addition, we investigated whether these effects are associated with alterations in the levels of glucocorticoid receptors (GR) in the brain and whether administration of GR antagonists blocks methamphetamine relapse.Methods: We allowed rats to self-administer methamphetamine for twenty 14-h sessions. After 3 weeks of abstinence either in standard (SE) or EE conditions, we measured methamphetamine seeking in a single 3-h session. Then, we used western blot techniques to measure GR levels in several brain areas. Finally, in an independent group of rats, after methamphetamine self-administration and abstinence in SE, we administered the GR antagonist mifepristone, and we investigated methamphetamine seeking.Results: Exposure to EE reduced methamphetamine seeking and reversed methamphetamine-induced increases in GR levels in the ventral and dorsal hippocampus. In addition, EE decreased GR levels in the amygdala in drug-naive animals, but this effect was prevented by previous exposure to methamphetamine. Administration of mifepristone significantly decreased methamphetamine seeking.Conclusions: The anti-craving effects of EE are paralleled by restoration of methamphetamine-induced dysregulation of GR in the hippocampus. These results provide support for the hypothesis that the effect of EE on methamphetamine relapse is at least in part mediated by EE's action on the brain stress system.

BACKGROUND: Preclinical models simulating adolescent substance use leading to increased vulnerability for substance use disorders in adulthood are needed. Here, we utilized a model of alcohol and nicotine co-use to assess adult addiction vulnerability following adolescent alcohol exposure. METHODS: In Experiment 1, adolescent (PND30) male and female Sprague-Dawley rats received 25% ethanol (EtOH) or a control solution via oral gavage every 8 h, for 2 days. In young adulthood, animals were tested with a 2-bottle choice between H20% and 15% EtOH or 0.2% saccharin/15% EtOH, followed by co-use of oral Sacc/EtOH and operant-based i.v. nicotine (0.03 mg/kg/infusion) self-administration. In Experiment 2, adolescents received control gavage, EtOH gavage, or no-gavage, and were tested in young adulthood in a 2-bottle choice between H20% and 15% EtOH, Sacc/EtOH, or 0.2% saccharin. RESULTS: In Experiment 1, the adolescent EtOH gavage reduced adult EtOH consumption in the 2-bottle choice, but not during the co-use phase. During co-use, Sacc/EtOH served as an economic substitute for nicotine. In Experiment 2, the control gavage increased adult EtOH drinking relative to the no-gavage control group, an effect that was mitigated in the EtOH gavage group. In both experiments, treatment group differences in EtOH consumption were largely driven by males. CONCLUSIONS: EtOH administration via oral gavage in adolescence decreased EtOH consumption in adulthood without affecting EtOH and nicotine co-use. Inclusion of a no-gavage control in Experiment 2 revealed that the gavage procedure increased adult EtOH intake and that including EtOH in the gavage buffered against the effect.

Early life adversity can set the trajectory for later psychiatric disorders, including substance use disorders. There are a host of neurobiological factors that may play a role in the negative trajectory. The current review examines preclinical evidence suggesting that early life adversity specifically involving social factors (maternal separation, adolescent social isolation and adolescent social defeat) may influence drug abuse vulnerability by strengthening corticotropin-releasing factor (CRF) systems and weakening oxytocin (OT) systems. In adulthood, pharmacological and genetic evidence indicates that both CRF and OT systems are directly involved in drug reward processes. With early life adversity, numerous studies show an increase in drug abuse vulnerability measured in adulthood, along a concomitant strengthening of CRF systems and a weakening of OT systems. Mechanistic studies, while relatively few in number, are generally consistent with the theme that strengthened CRF systems and weakened OT systems mediate, at least in part, the link between early life adversity and drug abuse vulnerability. Establishing a direct role of CRF and OT in mediating the relation between early life social stressors and drug abuse vulnerability will inform clinical researchers and practitioners toward the development of intervention strategies to reduce risk among those suffering from early life adversities. This article is part of the special issue on ‘Vulnerabilities to Substance Abuse’.

Escalation of drug intake and craving are two DSM-5 hallmark symptoms of opioid use disorder (OUD).This study determined if escalation of intake as modeled by long access (LgA) self-administration (SA) and craving measured by reinstatement are related.Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl across 7 daily 1-h short access (ShA) sessions, followed by 21 SA sessions of either 1- or 6-h duration (ShA or LgA). Following 14 1-h extinction sessions, Experiment 1 assessed reinstatement induced by either fentanyl (10 or 30 µg/kg) or yohimbine (1 or 2 mg/kg), and Experiment 2 assessed reinstatement induced by a drug-associated cue light.Females acquired fentanyl SA faster than males. When shifted to LgA sessions, LgA rats escalated fentanyl intake, but ShA rats did not; no reliable sex difference in the rate of escalation was observed. In extinction, compared to ShA rats, LgA rats initially responded less and showed less decay of responding across sessions. A priming injection of fentanyl induced reinstatement, with LgA rats reinstating more than ShA rats at the 30 µg/kg dose. Yohimbine (1 mg/kg) also induced reinstatement, but there was no effect of access group or sex. With cue-induced reinstatement, LgA females reinstated less than LgA males and ShA females.Among the different reinstatement tests assessed, escalation of fentanyl SA increased only drug-primed reinstatement, suggesting a limited relationship between escalation of drug intake and craving (reinstatement) for OUD.

Although developed from a common antecedent, conditioned place preference (CPP) and intravenous drug self-administration (SA) represent different behavioral paradigms, each with strong face validity. The field has treated results from these studies largely interchangeably; however, there is considerable evidence of opposite modulation of CPP vs. SA. This review outlines four manipulations that differentially affect CPP and SA based on alterations of motivation. These examples are contrasted with one example of differential CPP and SA results that can be explained by simple parallel shifts in dose-response functions. The final two examples have yet to be classified as motivation-based or parallel shifts. Important aspects, including motivation, volitional control of drug administration, reward, and the role of cues are discussed. One major conclusion of this paper is that explanations for apparent discrepancies between CPP and SA require full dose effect functions and assessment of PR breakpoints. Overall, this manuscript offers a more nuanced insight into how CPP and SA can be used to study different aspects of substance use disorders.

Background As alcohol and nicotine use disorders are entwined, it may be possible to develop a single medication to treat both. We previously developed a model for ethanol (EtOH) and nicotine co-use in female selectively bred alcohol-preferring (P) rats. To model co-use in a genetically diverse population, we adapted the model to outbred Sprague-Dawley rats of both sexes and assessed the effect of drug pretreatments. Methods In phase 1, rats were trained in a 2-bottle choice between water and a sweetened or unsweetened EtOH solution in operant chambers. In phase 2, rats were trained in nicotine self-administration under an increasing fixed ratio (FR) schedule with 2 bottles containing water or saccharin-sweetened EtOH also available. In phase 3, rats were pretreated with EtOH (0.5, 1.5 g/kg), naltrexone (0.3 mg/kg), nicotine (0.2, 0.6 mg/kg), varenicline (3.0 mg/kg) or vehicle before the session. Results Sweetening the EtOH solution was required to obtain pharmacologically relevant levels of consumption in Phase 1, with males showing increased sweetened EtOH preference compared to females. In Phase 2, increasing the FR requirement for nicotine decreased nicotine infusions, but increased EtOH consumption. In Phase 3, EtOH, naltrexone, and nicotine failed to alter EtOH consumption; however, varenicline decreased both EtOH and nicotine intake. Conclusions The co-use model was successfully adapted to Sprague-Dawley rats by adding saccharin to the EtOH solution. In contrast to previous results in P rats, varenicline reduced both EtOH and nicotine intake, indicating it may be a useful monotherapy for co-use in a genetically diverse population.

BACKGROUND: Negative urgency is a facet of impulsivity associated with negative affect and risky behavior that may involve the amygdala. The current study determined if social isolation during development alters negative urgency and c-Fos activity in the basolateral amygdala (BLA). METHODS: Female Sprague-Dawley rats were raised in an isolated condition (IC), a standard social condition (SC), or an enriched condition (EC), and then were tested for locomotor activity, novelty place preference and negative urgency using a reward omission task. Following performance on the reward omission task, brains were analyzed for c-Fos expression in Ca(2+)/calmodulin kinase II (CaMKII) and calbindin (CB) neurons, as well as in parvalbumin (PV) neurons associated with perineuronal nets (PNNs) in BLA. RESULTS: IC rats exhibited enhanced locomotion compared to both SC and EC rats, as well as enhanced novelty place preference compared to EC rats; only IC rats showed increased responding following omission of an expected reward (negative urgency). Following completion of the reward omission task, IC rats also displayed increased percent of c-Fos neurons in BLA associated with CaMKII, CB and PV neurons compared to SC and EC rats. In IC rats, c-Fos activation in BLA occurred following omission of an expected reward. Finally, IC rats displayed reduced PNN intensity associated with PV neurons compared to EC rats, but the percent of these neurons co-expressing c-Fos was greater in IC rats; SC rats were intermediate between IC and EC rats. CONCLUSIONS: Negative urgency was observed in IC rats, but not SC or EC rats. While multiple mechanisms are likely involved, this behavioral effect was associated with an isolation-induced increase in activity of excitatory neurons in BLA, as well as decreased PNN intensity surrounding GABAergic neurons in the same region.

Background Social peers influence human drug use at every stage of addiction. Using a dual-compartment apparatus that allows for limited social contact, recent work has shown that cocaine self-administration is enhanced when two rats are trained to self-administer at the same time compared to rats trained alone or trained in the presence of a saline self-administration control peer. The current study measured social influence on self-administration of the short-acting opioid remifentanil using a dual-compartment operant conditioning chamber. Methods Adult male rats were placed in one of five groups: (1) REMI-REMI group, in which both rats self-administered remifentanil; (2) REMI-SAL group, in which rats self-administered remifentanil in the presence of a peer that self-administered saline; (3) SAL-REMI group, in which rats self-administered saline in the presence of a peer that self-administered remifentanil; and (4) REMI ALONE and (5) SAL ALONE groups, in which rats administered their respective drugs alone (no peer). Self-administration was measured using a 2-lever procedure during acquisition, maintenance, increasing fixed-ratio, and dose-response phases. Results The presence of a social peer enhanced drug intake during acquisition, regardless of the drug exposure of their peer. Additionally, active lever position significantly affected remifentanil intake during acquisition and maintenance, with the greatest influence occurring when the active lever was close to the peer. Conclusion The presence of a social peer in the drug-taking context potentiates remifentanil self-administration, regardless of the peer’s drug access. Future studies utilizing the dual-compartment apparatus will help elucidate the neural mechanisms underlying social influence on opioid abuse.

Adolescence is a period associated with increased risk taking and peer relations. Research has shown that age is correlated with vulnerability to peer pressure, with youth being more influenced by peers compared with adults, leading to exacerbated risk taking, including risk for drug abuse. Preclinical research suggests that these findings may also be applicable to rodents, as younger rats find social interaction rewarding and are prone to risky behavior. However, there is little research on the effect of social interaction on rodent models of risky decision making. This study examined risky decision making utilizing a dual-compartment apparatus that consisted of two adjacent operant conditioning chambers separated by a wire mesh screen partition that allowed for limited social interaction. Male rats performed a risky decision making task in which they had a choice between a small reinforcer and larger reinforcer that was associated with a mild footshock, which increased in probability across the session. Rats were initially trained during adolescence and performance on the task was assessed in the presence or absence of a peer in the adjacent chamber during young adulthood. Results revealed that there was less risk discounting, leading to greater preference for the larger, risky reinforcer, in rats that had daily exposure to a social peer during training. These results provide evidence that social influence on risk taking can be modeled in rats, perhaps having implications for drug abuse risk. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

BACKGROUND: An important factor that can lead to drug relapse is to re-associate with drug-using social peers, but there is little literature on the effect of social peers on relapse in animal models. METHODS: The current study used a dual-compartment operant conditioning apparatus that allowed adult male rats to respond for cocaine in the presence of a conspecific. In Experiment 1, rats were trained to self-administer cocaine in the presence of a social peer that was separated by a wire screen partition and then that peer was used as a reinstatement cue following a period of extinction. In the next experiments, rats were trained on alternating sessions to self-administer cocaine in the presence of one peer and to self-administer saline in the presence of a different peer using either a single active lever procedure (Experiment 2) or a double active lever procedure (Experiment 3). Following extinction of responding in the absence of the peers, the effect of re-exposure to the cocaine- and saline-associated peers on reinstatement of drug seeking was determined. This was tested using both single- and double-active lever procedures. RESULTS: In Experiment 1, a peer that was present throughout cocaine self-administration was able to reinstate cocaine seeking following a period of extinction. In Experiments 2 and 3, drug seeking was reinstated by the cocaine-associated peer (S+), but not the saline-associated peer (S-). This discrimination occurred when using either the single active lever procedure or double active lever procedure. CONCLUSION: These results indicate that a social peer can be used as a discriminative stimulus to signal cocaine availability and that re-introduction of a peer previously paired with cocaine can reinstate cocaine seeking, confirming clinical reports that peer affiliation among abstinent cocaine users is an important determinant of relapse.

Until recently, there were few rodent models available to study the interaction of post-traumatic stress disorder (PTSD) and drug taking. Like PTSD, single prolonged stress (SPS) produces hypothalamic-pituitary-adrenal (HPA) axis dysfunction and alters psychostimulant self-administration. Other stressors, such as isolation stress, also alter psychostimulant self-administration. However, it is currently unknown if isolation housing combined with SPS can alter the acquisition or maintenance of cocaine self-administration. The current study applied modified SPS (modSPS; two hours restraint immediately followed by cold swim stress) to rats raised in an isolation condition (Iso), enrichment condition (Enr), or standard condition (Std) to measure changes in cocaine self-administration and HPA markers. Regardless of rearing condition, rats exposed to modSPS had greater corticosterone (CORT) release and reduced cocaine self-administration during initial acquisition compared to non-stressed controls. In addition, during initial acquisition, rats that received both Iso rearing and modSPS showed a more rapid increase in cocaine self-administration across sessions compared to Enr and Std rats exposed to modSPS. Following initial acquisition, a dose response analysis showed that Iso rats were overall most sensitive to changes in cocaine unit dose; however, modSPS had no effect on the cocaine dose response curve. Further, there was no effect of either modSPS or differential rearing on expression of glucocorticoid receptor (GR) in hypothalamus, medial prefrontal cortex, amygdala, or nucleus accumbens. By using modSPS in combination with Iso housing, this study identified unique contributions of each stressor to acquisition of cocaine self-administration.

Rats raised in an enriched condition (EC) show decreased stimulant self-administration relative to rats reared in an isolated condition (IC). However, few studies have examined the behavioral mechanisms underlying this environment-induced difference in self-administration. Because economic demand for drugs of abuse predicts addiction-like behavior in both humans and animals, we applied a behavioral economic analysis to cocaine self-administration data in EC and IC rats. During cocaine self-administration, the dose decreased across blocks of trials (0.75-0.003 mg/kg/inf), which allowed for a determination of demand intensity and demand elasticity. Demand intensity did not differ between EC and IC rats; however, cocaine was more elastic in EC rats relative to IC rats (i.e. EC rats were less willing to respond for cocaine as the unit price increased). When EC rats were placed in an isolated condition, demand elasticity decreased, whereas elasticity increased for IC rats placed in an enriched condition. Additionally, we applied behavioral economic analyses to previously published self-administration data and found that our results replicate past findings with cocaine and methylphenidate. To determine if differences in demand elasticity are specific to drug reinforcement, a separate group of rats was tested in sucrose or saccharin self-administration. Results showed that sucrose and saccharin were more elastic in EC rats relative to IC rats, and demand intensity was lower for saccharin in EC rats relative to IC rats. Overall, drug and nondrug reinforcers are more elastic in EC rats, which may account for the protective effects of environmental enrichment against stimulant self-administration.

Nucleus accumbens core (NAcc) has been implicated in impulsive choice, as measured in delay discounting. The role of dopamine (DA) in impulsive choice has received considerable attention, whereas glutamate (Glu) has recently been shown to be an important mediator of discounting. However, research has not examined how DA or Glu receptors in NAcc mediate different aspects of delay discounting performance, that is, (a) sensitivity to reinforcer magnitude and (b) sensitivity to delayed reinforcement. Adult male Sprague-Dawley rats were first trained in a delay discounting task, in which the delay to a large magnitude food reinforcer increased across blocks of trials. Following behavioral training, rats received bilateral implantation of guide cannulas into NAcc. Half of the rats (n = 12) received infusions of the DA-selective ligands SKF 38393 (D1-like agonist: 0.03 or 0.1 μg), SCH 23390 (D1-like antagonist: 0.3 or 1.0 μg), quinpirole (D2-like agonist: 0.3 or 1.0 μg), and eticlopride (D2-like antagonist: 0.3 or 1.0 μg). The other half received infusions of the ionotropic Glu ligands MK-801 (NMDA uncompetitive antagonist: 0.3 or 1.0 μg), AP-5 (NMDA competitive antagonist: 0.3 or 1.0 μg), ifenprodil (noncompetitive antagonist at NR2B-containing NMDA receptors: 0.3 or 1.0 μg), and CNQX (AMPA competitive antagonist: 0.2 or 0.5 μg). Results showed that SCH 23390 (0.3 μg) decreased sensitivity to reinforcer magnitude without altering impulsive choice, whereas ifenprodil (1.0 μg) decreased sensitivity to delayed reinforcement (i.e., impulsive choice). The current results show that DA and NMDA receptors in NAcc mediate distinct aspects of discounting performance. (PsycINFO Database Record

Background Individuals with opioid use disorder (OUD) exhibit high levels of economic demand for opioids, with high levels of consumption and relative insensitivity to changes in price. Because the medications used to treat OUD in medication-assisted therapy (MAT) act as antagonists or agonists at μ opioid receptors, they may alter the relationship between price and opioid intake. Methods This study examined demand for a commonly abused synthetic prescription opioid, fentanyl, in male rats following s.c. pre-treatment with naltrexone (0.1–1.0 mg/kg), morphine (0.3–3.0 mg/kg) or buprenorphine (0.3–3.0 mg/kg). We normalized demand curves to intake at the lowest price and estimated effects on elasticity (sensitivity to changes in price). Rats were first trained to earn fentanyl (5 μg/kg/infusion) on a fixed ratio schedule, then they underwent daily training under a threshold procedure designed to produce within-session demand curve estimates. Rats received 14 threshold sessions before undergoing a series of tests encompassing each drug, at each dose. Results Elasticity was increased by pretreatment with naltrexone, morphine or buprenorphine. Morphine also decreased initial intake, when the price for fentanyl was lowest. In contrast, initial intake was increased by naltrexone (according to an inverted-U shaped curve). The effects of naltrexone did not persist after the test session, but morphine and buprenorphine continued affecting demand elasticity 24 h or 48 h after the test, respectively. Conclusions These results indicate that fentanyl demand is sensitive to blockade or activation of opioid receptors by the drug classes used for MAT in humans.

Nicotine, a major psychoactive component of tobacco smoke, alters gamma-aminobutyric acid (GABA) modulation of dopamine neurons in the ventral tegmental area (VTA). Changes in structural neuroplasticity can occur in GABAergic parvalbumin (PRV) positive neurons, which are enveloped by structures of the extracellular matrix called perineuronal nets (PNNs). In the current study, rats were trained to self-administer intravenous nicotine (0.03 mg/kg/infusion) for 21 days in 1-hour daily sessions with an incrementing fixed ratio requirement; a control group received saline infusions. At either 45 minutes or 72 hours after the last session, immunofluorescence measurements for PNNs, PRV and c-Fos were conducted. In VTA, nicotine self-administration reduced the number of PRV+ cells surrounded by PNNs at 45 minutes, as well as reducing the intensity of PNNs, suggesting a remodeling of GABA interneurons in this region; the number of PRV+ cells surrounded by PNNs was also reduced at 72 hours. A similar reduction of PNNs occurred in orbitofrontal cortex (OFC) but not in medial prefrontal cortex (prelimbic or infralimbic), 45 minutes after the last session; PNNs were not detected in nucleus accumbens (shell or core). The reduction of PNNs in VTA and OFC was unrelated to c-Fos + cells, as the percent of wisteria floribunda agglutinin + cells co-expressing c-Fos was decreased in OFC but not in VTA. Thus, nicotine self-administration remodeled PNNs surrounding GABA interneurons in VTA and its indirect connections to OFC, suggesting a new possible molecular target where nicotine-induced neuroplasticity takes place. PNN manipulations may prevent or reverse the different stages of tobacco addiction.

Polysubstance abuse of alcohol and nicotine has been overlooked in our understanding of the neurobiology of addiction and especially in the development of novel therapeutics for its treatment. Estimates show that as many as 92% of people with alcohol use disorders also smoke tobacco. The health risks associated with both excessive alcohol consumption and tobacco smoking create an urgent biomedical need for the discovery of effective cessation treatments, as opposed to current approaches that attempt to independently treat each abused agent. The lack of treatment approaches for alcohol and nicotine abuse/dependence mirrors a similar lack of research in the neurobiology of polysubstance abuse. This review discusses three critical needs in medications development for alcohol and nicotine co-abuse: (1) the need for a better understanding of the clinical condition (i.e. alcohol and nicotine polysubstance abuse), (2) the need to better understand how these drugs interact in order to identify new targets for therapeutic development and (3) the need for animal models that better mimic this human condition. Current and emerging treatments available for the cessation of each drug and their mechanisms of action are discussed within this context followed by what is known about the pharmacological interactions of alcohol and nicotine. Much has been and will continue to be gained from studying comorbid alcohol and nicotine exposure.

Impulsivity and hyperactivity are two facets of attention deficit/hyperactivity disorder (ADHD). Impulsivity is expressed as reduced response inhibition capacity, an executive control mechanism that prevents premature execution of an intermittently reinforced behavior. During methylphenidate treatment, impulsivity and hyperactivity are decreased in adolescents with ADHD, but there is little information concerning levels of impulsivity and hyperactivity in adulthood after adolescent methylphenidate treatment is discontinued. The current study evaluated impulsivity, hyperactivity as well as cocaine sensitization during adulthood after adolescent methylphenidate treatment was discontinued in the Spontaneously Hypertensive Rat (SHR) model of ADHD. Treatments consisted of oral methylphenidate (1.5 mg/kg) or water vehicle provided Monday-Friday from postnatal day 28–55. During adulthood, impulsivity was measured in SHR and control strains (Wistar Kyoto and Wistar rats) using differential reinforcement of low rate (DRL) schedules. Locomotor activity and cocaine sensitization were measured using the open-field assay. Adult SHR exhibited decreased efficiency of reinforcement under the DRL30 schedule and greater levels of locomotor activity and cocaine sensitization compared to control strains. Compared to vehicle, methylphenidate treatment during adolescence reduced hyperactivity in adult SHR, maintained the lower efficiency of reinforcement, and increased burst responding under DRL30. Cocaine sensitization was not altered following adolescent methylphenidate in adult SHR. In conclusion, adolescent treatment with methylphenidate followed by discontinuation in adulthood had a positive benefit by reducing hyperactivity in adult SHR rats; however, increased burst responding under DRL compared to SHR given vehicle, i.e., elevated impulsivity, constituting an adverse consequence associated with increased risk for cocaine abuse liability.

Rationale. Methamphetamine (METH) abuse is generally attributed to the d-isomer. Self-administration of l-METH has been examined only in rhesus monkeys with a history of cocaine self-administration or drug-naïve rats using high toxic doses. Objectives. In this study, the ability of l-METH and, for comparison, d-METH to engender self-administration in experimentally-naïve rats, as well as to decrease d-METH self-administration and food-maintained responding were examined. Methods. Male Sprague-Dawley rats were used in 3 separate experiments. In Experiment 1, the acquisition of l- or d-METH self-administration followed by dose-response determinations was studied. In Experiment 2, rats were trained to self-administer d-METH (0.05 mg/kg/infusion) and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (30 mg/kg) also was examined. In Experiment 3, rats were trained to respond for food reinforcement and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (3 mg/kg) also was examined. Results. Reliable acquisition of l- and d-METH self-administration was obtained at unit doses of 0.5 and 0.05 mg/kg/infusion respectively. The dose-response function for l-METH self-administration was flattened and shifted rightward compared to d-METH self-administration, with peak responding for l- and d-METH occurring at unit doses of 0.17 and 0.025 respectively. l-METH also was approximately 10-fold less potent than d-METH in decreasing d-METH self-administration and 2-fold lower in decreasing food-maintained responding. Tolerance did not occur to repeated l-METH pretreatments on either measure. Conclusions. As a potential pharmacotherapeutic, l-METH has less abuse liability than d-METH and its efficacy in decreasing d-METH self-administration and food-maintained responding is sustained with repeated treatment.

INTRODUCTION EXPERIMENT 1 Method Results Discussion EXPERIMENT 2 Method Results Discussion GENERAL DISCUSSION REFERENCES ACKNOWLEDGMENTS TABLE OF CONTENTS

RATIONALE: Co-users of alcohol and nicotine are the largest group of polysubstance users worldwide. Commonalities in mechanisms of action for ethanol (EtOH) and nicotine proposes the possibility of developing a single pharmacotherapeutic to treat co-use. OBJECTIVES: Toward developing a preclinical model of co-use, female alcohol-preferring (P) rats were trained for voluntary EtOH drinking and i.v. nicotine self-administration in three phases: (1) EtOH alone (0 vs. 15%, 2-bottle choice); (2) nicotine alone (0.03 mg/kg/infusion, active vs. inactive lever); and (3) concurrent access to both EtOH and nicotine. Using this model, we examined the effects of (1) varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist with high affinity for the α4β2 subtype; (2) r-bPiDI, a subtype-selective antagonist at α6β2* nAChRs; and (3) (R)-modafinil, an atypical inhibitor of the dopamine transporter (DAT). RESULTS: In Phases 1 and 2, pharmacologically relevant intake of EtOH and nicotine was achieved. In the concurrent access phase (Phase 3), EtOH consumption decreased while nicotine intake increased relative to Phases 1 and 2. For drug pretreatments, in the EtOH access phase (Phase 1), (R)-modafinil (100 mg/kg) decreased EtOH consumption, with no effect on water consumption. In the concurrent access phase, varenicline (3 mg/kg), r-bPiDI (20 mg/kg), and (R)-modafinil (100 mg/kg) decreased nicotine self-administration, but did not alter EtOH consumption, water consumption, or inactive lever pressing. CONCLUSIONS: These results indicate that therapeutics which may be useful for smoking cessation via selective inhibition of α4β2 or α6β2* nAChRs, or DAT inhibition, may not be sufficient to treat EtOH and nicotine co-use.

Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3-30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.