Anti-cocaine Vaccine Development: Where Are We Now and Where Are We Going?

Cocaine is one of the oldest and most widely used illicit drugs in the world and is responsible for major worldwide medical and social problems. Drug addiction is a disease state where the body relies on a substance for normal functioning and develops a physical dependence leading to compulsive and repetitive use despite negative consequences to the user's health, mental state, or social life. The primary driver for the development of anti-cocaine vaccines has been the failure to develop effective pharmacological treatments to combat cocaine dependence. Despite several decades of research, no approved pharmacological treatments for cocaine dependence are available to assist addicts to overcome cocaine withdrawal or to prevent drug relapse. This Perspective highlights the challenges associated with anti-cocaine vaccines, including the current state of anti-cocaine vaccines and catalytic antibody research to aid in the fight against cocaine addiction.

Exploring protective associations between the use of classic psychedelics and cocaine use disorder: a population-based survey study.

Cocaine Use Disorder (CUD) is a significant public health problem associated with elevated morbidity and mortality within the United States. Current behavioral treatments have limited efficacy and there are currently no FDA approved pharmacological treatments for CUD. Classic psychedelics might be associated with lowered odds of substance misuse and may effectively treat various forms of addiction. Thus, the goal of this study is to assess protective associations that lifetime use of classic psychedelics may share with CUD within a nationally representative sample of the U.S. We used data from The National Survey on Drug Use and Health (NSDUH) (2015-2019) and conducted survey-weighted multivariable logistic regression to test whether each of four classic psychedelics (peyote, mescaline, psilocybin, LSD) conferred lowered odds of CUD and its related 11 sub-criteria. Participants were 214,505 adults in the NSDUH (2015-2019) aged 18 and older. Peyote conferred lowered odds of CUD, reducing the odds of CUD by over 50% (aOR: 0.47). All other substances (including other classic psychedelics) either shared no association to CUD or conferred increased odds of CUD. Furthermore, sensitivity analyses revealed peyote to confer sharply lowered odds of the majority (seven of 11) of CUD criteria as well (aOR range: 0.26-0.47). Peyote use is associated with lowered odds of CUD. Future inquiries into third variable factors (i.e., demographic/personality profiles of individuals who use peyote, motivational/contextual factors surrounding peyote use) that may underlie our observed associations may reveal protective factors that can inform treatment development for CUD. Additionally, future longitudinal studies can shed further light on whether there is a temporal link between peyote use and lowered odds of CUD.

Inhibition of CSF1R, a receptor involved in microglia viability, alters behavioral and molecular changes induced by cocaine.

Different data suggest that microglia may participate in the drug addiction process as these cells respond to neurochemical changes induced by the administration of these substances. In order to study the role of microglia in drug abuse, Swiss mice aged 8-9 weeks were treated with the CSF1R inhibitor PLX3397 (40 mg/kg, p.o.) and submitted to behavioral sensitization or conditioned place preference (CPP) induced by cocaine (15 mg/kg, i.p.). Thereafter, brains were used to evaluate the effects of CSF1R inhibition and cocaine administration on morphological, biochemical and molecular changes. CSF1R inhibition attenuated behavioral sensitization, reduced the number of Iba-1+ cells and increased ramification and lengths of the branches in the remaining microglia. Additionally, both cocaine and PLX3397 increased the cell body to total cell size ratio of Iba-1+ cells, as well as CD68+ and GFAP+ stained areas, suggesting an activated pattern of the glial cells. Besides, CSF1R inhibition increased CX3CL1 levels in the striatum, prefrontal cortex and hippocampus, as well as reduced CX3CR1 expression in the hippocampus. In this region, cocaine also reduced BDNF levels, an effect that was enhanced by CSF1R inhibition. In summary, our results suggest that microglia participate in the behavioral and molecular changes induced by cocaine. This study contributes to the understanding of the role of microglia in cocaine addiction.

Blockade of corticotropin-releasing factor receptor 1 in the central amygdala prevents cocaine-seeking behaviour induced by orexin-A administered to the posterior paraventricular nucleus of the thalamus in male rats.

Background: Orexin-A (OrxA) administration in the posterior paraventricular nucleus of the thalamus (pPVT) reinstates extinguished cocaine-seeking behaviour following extended access to the drug (a model of dependence). The pPVT receives and integrates information associated with emotionally salient events and sends excitatory inputs to brain regions involved in the expression of emotional states, such as those driving cocaine-seeking behaviour (i.e., the nucleus accumbens, the central nucleus of the amygdala [CeA], the basolateral amygdala, the bed nucleus of the stria terminalis [BNST] and the prefrontal cortex). Methods: We monitored the activation pattern of these regions (measured by Fos) during cocaine-seeking induced by OrxA administered to the pPVT. The BNST and CeA emerged as being selectively activated. To test whether the functionality of these regions was pivotal during OrxA-induced cocaine-seeking behaviour, we transiently inactivated these regions concomitantly with OrxA administration to the pPVT. We then tested the participation of corticotropin-releasing factor receptors (CRF1) in the CeA during OrxA-induced cocaine-seeking using the CRF1 antagonist CP154526. Results: We observed selective activation of the CeA and BNST during cocaine-seeking induced by OrxA administered to the pPVT, but only transient inactivation of the CeA prevented cocaine-seeking behaviour. Administration of CP154526 to the CeA prevented OrxAinduced cocaine-seeking behaviour. Limitations: The use of only male rats could have been a limitation. Other limitations could have been the use of an indirect approach to test the hypothesis that administration of OrxA to the pPVT drives cocaine-seeking via CRF1 signalling in the CeA, and a lack of analysis of the participation of CeA subregions. Conclusion: Cocaine-seeking behaviour induced by OrxA administered to the pPVT is driven by activation of the CeA via CRF1 signalling.

Initial development of a brief assessment of cocaine demand.

Cocaine demand is a behavioral economic measure assessing drug reward value and motivation to use drug. The purpose of the current study was to develop a brief assessment of cocaine demand (BACD). Results from the BACD were compared with self-report measures of cocaine use. Participants consisted of treatment-seeking individuals with cocaine use disorder (N = 22). Results revealed that indices of brief demand were significantly associated with various self-report measures of cocaine use. Overall, these results support the utility of a BACD for assessing cocaine demand.

Cocaine vaccine dAd5GNE protects against moderate daily and high-dose "binge" cocaine use.

The cocaine vaccine dAd5GNE is comprised of a disrupted serotype 5 adenovirus gene therapy vector covalently conjugated to the cocaine analog GNE. The vaccine evokes a high titer of circulating anti-cocaine antibodies that prevent cocaine from reaching its cognate receptors in the central nervous system. Prior studies have demonstrated the efficacy of dAd5GNE in models of occasional, moderate cocaine use. However, previous studies have not sufficiently evaluated the efficacy of dAd5GNE in models of the repetitive and high-dose "binge" use patterns common in human addicts. In the present study, we evaluated the capacity of dAd5GNE vaccination to protect against "binge" cocaine use and circumstances where vaccinated addicts attempt to override the vaccine. We modeled repetitive daily cocaine use in vaccinated Balb/c mice and African green monkeys, and evaluated high-dose "binge" scenarios in Balb/c mice. In each model of daily use the dAd5GNE vaccine prevented cocaine from reaching the central nervous system. In the high-dose "binge" model, vaccination decreased cocaine-induced hyperactivity and reduced the number of cocaine-induced seizures. Based on this data and our prior data in rodents and nonhuman primates, we have initiated a clinical trial evaluating the dAd5GNE anti-cocaine vaccine as a potential therapy for cocaine addicts who wish to stop cocaine use. If dAd5GNE vaccination is safe and produces high anti-cocaine antibody titers in the clinic, we hypothesize that the vaccine will restrict the access of cocaine to the central nervous system and inhibit cocaine-induced "highs" even in the context of moderate daily and high-dose "binge" use that might otherwise cause a drug-induced overdose.

Xie2-64, a novel CB2 receptor inverse agonist, reduces cocaine abuse-related behaviors in rodents.

Cocaine abuse remains a public health threat around the world. There are no pharmacological treatments approved for cocaine use disorder. Cannabis has received growing attention as a treatment for many conditions, including addiction. Most cannabis-based medication development has focused on cannabinoid CB1 receptor (CB1R) antagonists (and also inverse agonists) such as rimonabant, but clinical trials with rimonabant have failed due to its significant side-effects. Here we sought to determine whether a novel and selective CB2R inverse agonist, Xie2-64, has similar therapeutic potential for cocaine use disorder. Computational modeling indicated that Xie2-64 binds to CB2R in a way similar to SR144528, another well-characterized but less selective CB2R antagonist/inverse agonist, suggesting that Xie2-64 may also have CB2R antagonist profiles. Unexpectedly, systemic administration of Xie2-64 or SR144528 dose-dependently inhibited intravenous cocaine self-administration and shifted cocaine dose-response curves downward in rats and wild-type, but not in CB2R-knockout, mice. Xie2-64 also dose-dependently attenuated cocaine-enhanced brain-stimulation reward maintained by optical stimulation of ventral tegmental area dopamine (DA) neurons in DAT-Cre mice, while Xie2-64 or SR144528 alone inhibited optical brain-stimulation reward. In vivo microdialysis revealed that systemic or local administration of Xie2-64 into the nucleus accumbens reduced extracellular dopamine levels in a dose-dependent manner in rats. Together, these results suggest that Xie2-64 has significant anti-cocaine reward effects likely through a dopamine-dependent mechanism, and therefore, deserves further study as a new pharmacotherapy for cocaine use disorder.

Preliminary examination of the orexin system on relapse-related factors in cocaine use disorder.

RATIONALE: Current evidence and literature reviews provide a strong justification for examining the orexin receptor (OXR) system as a therapeutic target in substance use disorders, including cocaine and other psychostimulants. OBJECTIVES: In this preliminary, proof-of-concept examination of orexin modulation in humans with cocaine use disorder, we measured changes in domains tied to relapse: stress, sleep, cue reactivity, and inhibitory control. Additionally, mood symptoms (anxiety, depression), medication compliance, and side effects were assessed. METHODS: Twenty non-treatment seeking subjects with cocaine use disorder (CUD) received either the OX1R / OX2R antagonist suvorexant PO or placebo at 10 PM daily for two weeks (10 mg week 1, 20 mg week 2). Using psychometrics, smart-watch actigraphy, a cold-pressor stress challenge, and eye-tracking technology, the following domains were examined: sleep, stress/anxiety, cue-reactivity (attentional bias, craving), and inhibitory control. Psychometric data were collected every M/W/F (7 time points). Laboratory data were collected weekly (3 time points). RESULTS: Bayesian and frequentist generalized linear models were employed in parallel to examine the effects of suvorexant compared to placebo, with a Bayesian posterior probability threshold >80% as evidence of a signal for suvorexant. Notable results favoring suvorexant over placebo included fewer total anti-saccade errors, improved sleep actigraphy (sleep/awake periods), pre/post cold-pressor change in heart rate and salivary cortisol (all posterior probabilities >94%), and craving (posterior probability >87%). CONCLUSIONS: Initial but restricted evidence is provided supporting the orexin system as a modulator of relapse-related processes in cocaine use disorder. Baseline differences in the main outcome variables were not experimentally controlled and differences in craving were observed at baseline. This, in combination with a limited sample size, constrain the nature of the project. The results may serve to inform more comprehensive future research.

Activation of AMPK-dependent autophagy in the nucleus accumbens opposes cocaine-induced behaviors of mice.

Cocaine is a strong central nervous system stimulant, which can induce drug addiction. Previous studies have reported that cocaine-induced autophagy is involved in neuroinflammation and cell death. However, the role of autophagy in psychomotor sensitivity to cocaine has not been explored. Here, we reported that D1 receptor -CaMKII-AMPK-FoxO3a signaling pathway was involved in acute cocaine application-induced autophagy in the nucleus accumbens (NAc) both in vitro and in vivo. Furthermore, we found that knockdown of the ATG5 gene in the NAc augmented behavioral response to cocaine, and induction of autophagy in the NAc with rapamycin attenuated cocaine-induced behavioral response, which was coincident with the alterations of dendritic spine density in neurons of NAc. These results suggest that cocaine exposure leads to the induction of autophagy, which is a protective mechanism against behavioral response to cocaine of male mice.

Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels.

Cocaine-associated memories are critical drivers of relapse in cocaine-dependent individuals that can be evoked by exposure to cocaine or stress. Whether these environmental stimuli recruit similar molecular and circuit-level mechanisms to promote relapse remains largely unknown. Here, using cocaine- and stress-primed reinstatement of cocaine conditioned place preference to model drug-associated memories, we find that cocaine drives reinstatement by increasing the duration that mice spend in the previously cocaine-paired context whereas stress increases the number of entries into this context. Importantly, both forms of reinstatement require Cav1.2 L-type Ca2+ channels (LTCCs) in cells of the prelimbic cortex that project to the nucleus accumbens core (PrL→NAcC). Utilizing fiber photometry to measure circuit activity in vivo in conjunction with the LTCC blocker, isradipine, we find that LTCCs drive differential recruitment of the PrL→ NAcC pathway during cocaine- and stress-primed reinstatement. While cocaine selectively activates PrL→NAcC cells prior to entry into the cocaine-paired chamber, a measure that is predictive of duration in that chamber, stress increases persistent activity of this projection, which correlates with entries into the cocaine-paired chamber. Using projection-specific chemogenetic manipulations, we show that PrL→NAcC activity is required for both cocaine- and stress-primed reinstatement, and that activation of this projection in Cav1.2-deficient mice restores reinstatement. These data indicate that LTCCs are a common mediator of cocaine- and stress-primed reinstatement. However, they engage different patterns of behavior and PrL→NAcC projection activity depending on the environmental stimuli. These findings establish a framework to further study how different environmental experiences can drive relapse, and supports further exploration of isradipine, an FDA-approved LTCC blocker, as a potential therapeutic for the prevention of relapse in cocaine-dependent individuals.

Adult hippocampal neurogenesis as a target for cocaine addiction: a review of recent developments.

Basic research in rodents has shown that adult hippocampal neurogenesis (AHN) plays a key role in neuropsychiatric disorders that compromise hippocampal functioning. The discovery that dependence-inducing drugs regulate AHN has led to escalating interest in the potential involvement of AHN in drug addiction over the last decade, with cocaine being one of the most frequently investigated drugs. This review argues that, unlike other drugs of abuse, preclinical studies do not, overall, support that cocaine induces a marked or persistent impairment in AHN. Nevertheless, experimental reduction of AHN consistently exacerbates vulnerability to cocaine. Interestingly, preliminary evidence suggests that, on the contrary, increasing AHN might help both to prevent and treat addiction.

Central nucleus of the amygdala as a common substrate of the incubation of drug and natural reinforcer seeking.

Relapse into drug use is a major problem faced by recovering addicts. In humans, an intensification of the desire for the drug induced by environmental cues-incubation of drug craving-has been observed. In rodents, this phenomenon has been modeled by studying drug seeking under extinction after different times of drug withdrawal (or using a natural reinforcer). Although much progress has been made, an integrated approach simultaneously studying different drug classes and natural reward and examining different brain regions is lacking. Lewis rats were used to study the effects of cocaine, heroin, and sucrose seeking incubation on six key brain regions: the nucleus accumbens shell/core, central/basolateral amygdala, and dorsomedial/ventromedial prefrontal cortex. We analyzed PSD95 and gephyrin protein levels, gene expression of glutamatergic, GABAergic and endocannabinoid elements, and amino acid transmitter levels. The relationships between the areas studied were examined by Structural Equation Modelling. Pathways from medial prefrontal cortex and basolateral complex of the amygdala to central nucleus of the amygdala, but not to the nucleus accumbens, were identified as common elements involved in the incubation phenomenon for different substances. These results suggest a key role for the central nucleus of amygdala and its cortical and amygdalar afferences in the incubation phenomenon, and we suggest that by virtue of its regulatory effects on glutamatergic and GABAergic dynamics within amygdalar circuits, the endocannabinoid system might be a potential target to develop medications that are effective in the context of relapse.

Responding to global stimulant use: challenges and opportunities.

We did a global review to synthesise data on the prevalence, harms, and interventions for stimulant use, focusing specifically on the use of cocaine and amphetamines. Modelling estimated the effect of cocaine and amphetamine use on mortality, suicidality, and blood borne virus incidence. The estimated global prevalence of cocaine use was 0·4% and amphetamine use was 0·7%, with dependence affecting 16% of people who used cocaine and 11% of those who used amphetamine. Stimulant use was associated with elevated mortality, increased incidence of HIV and hepatitis C infection, poor mental health (suicidality, psychosis, depression, and violence), and increased risk of cardiovascular events. No effective pharmacotherapies are available that reduce stimulant use, and the available psychosocial interventions (except for contingency management) had a weak overall effect. Generic approaches can address mental health and blood borne virus infection risk if better tailored to mitigate the harms associated with stimulant use. Substantial and sustained investment is needed to develop more effective interventions to reduce stimulant use.

Telephone counseling for young Brazilian cocaine and/or crack users. Who are these users? / Aconselhamento telefônico para jovens brasileiros usuários de cocaína e/ou crack. Quem são esses usuários?

Abstract Objective: To describe the users' drug abuse characteristics, problematic behaviors associated with addiction, the motivation of teenagers and young adults to quit cocaine and/or crack abuse, and then compare these characteristics. Methods: A cross-section study was conducted with 2390 cocaine/crack users (teenagers from 14 to 19 years of age, and young adults from 20 to 24 years of age); 1471 were young adults and 919 were teenagers who had called a phone counseling service between January 2006 and December 2013. Semi-structured interviews were performed via phone calls. The questionnaires included sociodemographic information; assessment of the characteristics of cocaine/crack abuse; assessment of the problematic behaviors; also, the Contemplation Ladder was used to evaluate the stages of readiness to cease substance abuse. Results: Participants reported using cocaine (48.2%), crack and other smoking forms (36.7%) and combined consumption of both drugs (15%). Young adults were more prone to using crack or crack associated with cocaine (OR = 1.9; CI 95% = 1.05-1.57) and they were exposed to substance abuse for longer than two years (OR = 3.45; CI 95% = 2.84-4.18), when compared to teenagers. On the other hand, they showed higher readiness to quit. Conclusion: Data shows important differences in drug abuse characteristics, problematic behaviors and motivation to cease substance abuse between teenager and young adult cocaine and/or crack users. Behaviors displayed by young adults involve greater physical, mental and social health damages. These findings reinforce the importance of public policy to act on prevention and promoting health, to increase protection factors among teenagers and lower risks and losses during adult life.

Resumo Objetivo: Descrever as características de consumo, comportamentos problemáticos associados ao uso e motivação para cessar o consumo entre adolescentes e jovens usuários de cocaína e/ou crack e comparar essas características. Métodos: Realizou-se um estudo transversal, com 2.390 usuários de cocaína/crack (adolescentes: 14 - 19 anos e jovens: 20 - 24 24 anos) sendo 1471 jovens e 919 adolescentes, que ligaram para um serviço de aconselhamento telefônico entre janeiro de 2006 e dezembro de 2013. Foram realizadas entrevistas semiestruturadas por telefone. Os questionários incluíram informações sociodemográficas; avaliação das características do consumo de cocaína/crack; avaliação dos comportamentos problemáticos e escala de Contemplação Ladder para avaliar os estágios de motivação. Resultados: Os participantes relataram uso de cocaína (48,2%), crack e outras formas fumadas (36,7%) e uso associado de ambas as formas (15%). Os jovens faziam maior uso de crack ou crack associado à cocaína (OR = 1,19; IC 95% = 1,05-1,57) e estavam expostos ao uso da droga havia mais de 2 anos (OR = 3,45; IC 95% = 2,84-4,18) quando comparados aos adolescentes. Por outro lado, mostraram-se mais motivados para cessar o consumo. Conclusão: Os dados mostraram haver importantes diferenças nas características de consumo, comportamentos problemáticos e motivação para cessar o consumo entre adolescentes e jovens usuários de cocaína e/ou crack. Os jovens apresentaram comportamentos que envolvem maiores prejuízos para a saúde física, mental e aspectos sociais. Esses achados reforçam a importância de ações de políticas públicas de prevenção e promoção de saúde para aumentar os fatores de proteção entre os adolescentes e reduzir riscos e prejuízos para a vida adulta.

Glutathione peroxidase-1 overexpressing transgenic mice are protected from cocaine-induced drug dependence.

Converging evidence has demonstrated that oxidative burdens are associated with drug dependence induced by psychostimulants. Here, we investigated whether oxidative stress directly mediates conditioned place preference and behavioral sensitization (drug dependence) induced by cocaine and whether glutathione peroxidase-1 (GPx-1), a major GPx, modulates cocaine-induced psychotoxic changes in mice. Cocaine-induced drug dependence was followed by increases in c-Fos-immunoreactivity (c-Fos-IR) in the nucleus accumbens. Simultaneously, cocaine significantly increased oxidative parameters and nuclear factor κB (NFκB) activity (i.e. nuclear translocation and DNA binding activity) in the striatum (including nucleus accumbens). Genetic depletion of GPx-1 made mice susceptible to drug dependence induced by cocaine in mice, while genetic overexpression of GPx-1 protected the mice from drug dependence. Pyrrolidine dithiocarbamate (PDTC), a NFκB inhibitor, significantly attenuated the sensitivity induced by the genetic depletion of GPx-1 in mice. However, PDTC did not exhibit any additive effects against the protection afforded by the genetic overexpression of GPx-1. Our results suggest that drug dependence induced by cocaine requires oxidative stress and NFκB activation, and that the GPx-1 gene is a potential protective factor against cocaine-induced drug dependence through positive modulation of NFκB.

Telephone counseling for young Brazilian cocaine and/or crack users. Who are these users?

OBJECTIVE: To describe the users' drug abuse characteristics, problematic behaviors associated with addiction, the motivation of teenagers and young adults to quit cocaine and/or crack abuse, and then compare these characteristics. METHODS: A cross-section study was conducted with 2390 cocaine/crack users (teenagers from 14 to 19 years of age, and young adults from 20 to 24 years of age); 1471 were young adults and 919 were teenagers who had called a phone counseling service between January 2006 and December 2013. Semi-structured interviews were performed via phone calls. The questionnaires included sociodemographic information; assessment of the characteristics of cocaine/crack abuse; assessment of the problematic behaviors; also, the Contemplation Ladder was used to evaluate the stages of readiness to cease substance abuse. RESULTS: Participants reported using cocaine (48.2%), crack and other smoking forms (36.7%) and combined consumption of both drugs (15%). Young adults were more prone to using crack or crack associated with cocaine (OR=1.9; CI 95%=1.05-1.57) and they were exposed to substance abuse for longer than two years (OR=3.45; CI 95%=2.84-4.18), when compared to teenagers. On the other hand, they showed higher readiness to quit. CONCLUSION: Data shows important differences in drug abuse characteristics, problematic behaviors and motivation to cease substance abuse between teenager and young adult cocaine and/or crack users. Behaviors displayed by young adults involve greater physical, mental and social health damages. These findings reinforce the importance of public policy to act on prevention and promoting health, to increase protection factors among teenagers and lower risks and losses during adult life.

Predictors of initiation of nicotine, alcohol, cannabis, and cocaine use: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

BACKGROUND AND OBJECTIVES: There may be substantial overlap in the risk factors for substance use and substance use disorders (SUD). Identifying risk factors for substance use initiation is essential for understanding the etiology and natural history of SUD and to develop empirically-based preventive interventions to reduce initiation. METHODS: Analyses were done on Wave 1 participants of the National Epidemiological Survey of Alcohol and Related Conditions (NESARC) (n = 43,093). Estimates of the cumulative probability of substance use initiation were obtained separately for nicotine, alcohol, cannabis, and cocaine. Survival analyses with time-varying covariates were implemented to identify risk factors for substance initiation. RESULTS: The lifetime cumulative probabilities of substance initiation were 45.5% for nicotine, 82% for alcohol, 19.6% for cannabis, and 6.4% for cocaine. Among respondents with lifetime nicotine use, 50% had used it by age 15.3, whereas for alcohol, cannabis, and cocaine the respective ages were 17.8, 16.6, and 19.8. Previous use of another substance, being male, having a cluster B personality disorder, family history of SUD, and being separated, divorced, or widowed increased the risk of use of all the substances assessed, whereas social anxiety disorder and some personality disorders were associated with specific substances. DISCUSSION AND CONCLUSIONS: Although the age of substance use initiation varies by substance, in more than 50% of cases initiation of use occurs in the first two decades of life. Although most risk factors for substance use initiation are common across substances, some are substance-specific. SCIENTIFIC SIGNIFICANCE: This information may help in the development of empirically-based preventive interventions. (Am J Addict 2018;27:477-484).

Exercise Reduces Dopamine D1R and Increases D2R in Rats: Implications for Addiction.

INTRODUCTION: Exercise has been shown to be effective for preventing and treating substance abuse in both clinical and preclinical studies. Less is known, however, regarding the underlying neurobiological mechanisms driving these changes in drug-seeking behavior. One possibility is that exercise may alter the mesolimbic dopamine pathway in such a way that makes drugs of abuse less salient and/or rewarding. METHODS: To examine possible exercise-induced changes in dopamine signaling, male and female Lewis rats were split into exercise and sedentary groups at 8 wk of age. Exercise rats were run on a treadmill at 10 m·min, 5 d·wk, for 6 wk, whereas sedentary rats remained in their home cage. Rats were killed after the 6 wk of treatment, and their brains were used for in vitro autoradiography using [H]SCH 23,390, [H]Spiperone, and [H]WIN55,428 ligands to quantify dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and dopamine transporter binding, respectively. RESULTS: Exercised rats had 18% and 21% lower D1R-like binding levels compared to sedentary rats within the olfactory tubercle and nucleus accumbens shell, respectively. In addition, male and female exercise rats showed greater D2R-like binding levels within the dorsomedial caudate putamen (30%), ventrolateral caudate putamen (24%), and ventromedial caudate putamen (27%), as well as the olfactory tubercle (19%). Greater D2R-like binding in the nucleus accumbens core (24%) and shell (25%) of exercised rats compared with sedentary rats approached significance. No effects were found for dopamine transporter binding. CONCLUSIONS: These findings support the hypothesis that aerobic exercise results in changes in the mesolimbic pathway that could mediate exercise-induced attenuation of drug-seeking behavior.

A single, extinction-based treatment with a kappa opioid receptor agonist elicits a long-term reduction in cocaine relapse.

Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the therapeutic potential of the KOR agonist U50,488 (U50) to reduce cocaine seeking in a self-administration model. Following cocaine self-administration and 7 days of forced home-cage abstinence, rats were administered a single dose of U50 (5 mg/kg, i.p.) 30 min prior to the first extinction training session, wherein cocaine and the discrete cocaine-paired cues were no longer available. U50 reduced cocaine seeking on this first extinction session, but did not alter extinction training over subsequent days. 2 weeks after U50 treatment, rats underwent a test of cue-induced reinstatement, and rats that had received U50 reinstated less than controls. Central inhibition of p38 MAPK at the time of U50 administration prevented its long-term therapeutic effect on reinstatement, but not its acute reduction in drug seeking on extinction day 1. The long-term therapeutic effect of U50 required operant extinction during U50 exposure, extended to cocaine-primed reinstatement, and was not mimicked by another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction.