A multivariate regressor of patterned dopamine release predicts relapse to cocaine.

Understanding mesolimbic dopamine adaptations underlying vulnerability to drug relapse is essential to inform prognostic tools for effective treatment strategies. However, technical limitations have hindered the direct measurement of sub-second dopamine release in vivo for prolonged periods of time, making it difficult to gauge the weight that these dopamine abnormalities have in determining future relapse incidence. Here, we use the fluorescent sensor GrabDA to record, with millisecond resolution, every single cocaine-evoked dopamine transient in the nucleus accumbens (NAc) of freely moving mice during self-administration. We reveal low-dimensional features of patterned dopamine release that are strong predictors of cue-induced reinstatement of cocaine seeking. Additionally, we report sex-specific differences in cocaine-related dopamine responses related to a greater resistance to extinction in males compared with females. These findings provide important insights into the sufficiency of NAc dopamine signaling dynamics-in interaction with sex-for recapitulating persistent cocaine seeking and future relapse vulnerability.

Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity.

Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks. The goal of this study was to examine how these circuits are involved in decision-making in animals with defined trait impulsivity. To this end, we trained adolescent male rats to stable behavior on a DD procedure and then re-trained them in adulthood to assess trait-like, conserved impulsive choice across development. We then used chemogenetic tools to selectively and reversibly target corticostriatal projections during performance of the DD task. The prelimbic region of the medial prefrontal cortex (mPFC) was injected with a viral vector expressing inhibitory designer receptors exclusively activated by designer drugs (Gi-DREADD), and then mPFC projections to the nucleus accumbens core (NAc) were selectively suppressed by intra-NAc administration of the Gi-DREADD actuator clozapine-n-oxide (CNO). Inactivation of the mPFC-NAc projection elicited a robust increase in impulsive choice in rats with lower vs. higher baseline impulsivity. This demonstrates a fundamental role for mPFC afferents to the NAc during choice impulsivity and suggests that maladaptive hypofrontality may underlie decreased executive control in animals with higher levels of choice impulsivity. Results such as these may have important implications for the pathophysiology and treatment of impulse control, SUDs, and related psychiatric disorders.

Prefrontal dynamics and encoding of flexible rule switching.

Behavioral flexibility, the ability to adjust behavioral strategies in response to changing environmental contingencies and internal demands, is fundamental to cognitive functions. Despite a large body of pharmacology and lesion studies, the underlying neurophysiological correlates and mechanisms that support flexible rule switching remain elusive. To address this question, we trained mice to distinguish complex sensory cues comprising different perceptual dimensions (set shifting). Endoscopic calcium imaging revealed that medial prefrontal cortex (mPFC) neurons represented multiple task-related events and exhibited pronounced dynamic changes during rule switching. Notably, prominent encoding capacity in the mPFC was associated with switching across, but not within perceptual dimensions. We then showed the involvement of the ascending modulatory input from the locus coeruleus (LC), as inhibiting the LC impaired rule switching behavior and impeded mPFC dynamic processes and encoding. Our results highlight the pivotal role of the mPFC in set shifting processes and demonstrate the profound impact of ascending neuromodulation on shaping prefrontal neural dynamics and behavioral flexibility.

Reducing short- and long-term cocaine craving with voluntary exercise in male rats.

BACKGROUND: In a previous study in female rats, voluntary wheel running attenuated incubation of cocaine craving after 30 but not 3 days (Zlebnik and Carroll Zlebnik and Carroll, Psychopharmacology 232:3507-3413, 2015). The present study in male rats, using the same procedure, showed that wheel running reduced incubated craving after both 30 and 3 days of abstinence. METHODS: Male rats self-administered i.v. cocaine (0.4 mg/kg) during 6-h sessions for 10 days. They were then moved from the operant chamber to a home cage with an attached running wheel or stationary wheel, for 6 h daily for a 3- or 30-day period when cocaine craving was hypothesized to incubate. Rats were then returned to the operant chamber for a 30-min test of cocaine seeking, or "craving," indicated by responses on the former "drug" lever was formerly associated with drug stimulus lights and responses (vs. no drug stimuli), and lever responding was compared to responses on the "inactive" that was illuminated and counted lever pressing. RESULTS: Mean wheel revolutions were similar across the 3- and 30-day incubation groups, when both groups of rats were given access to wheel running vs. access to a stationary wheel in controls. Subsequently, when rats were tested in the operant chamber for "relapse" responding (drug-lever responding) on the lever formerly associated with drug access, cocaine craving was reduced by recent running wheel access (vs. stationary wheel access) in both the 3- and 30-day wheel exposure groups. CONCLUSION: Voluntary, self-initiated, and self-sustained physical exercise reduced cocaine craving after short- (3 days) and long-term (30 days) abstinence periods in male rats that previously self-administered cocaine. This was contrasted with reduction of cocaine seeking in females after 30-day, but not 3-day, incubation periods under the wheel running vs. stationary wheel conditions in a previous study (Zlebnik and Carroll Zlebnik and Carroll, Psychopharmacology 232:3507-3413, 2015). These initial findings suggest males may be more sensitive to incubated craving for cocaine than females.

Sex Differences in Opioid and Psychostimulant Craving and Relapse: A Critical Review.

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinction of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones' role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women.The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not sufficiently powered, and not a priori designed to detect sex differences. Additionally, imaging studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed provide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving but not cue- or cocaine-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or opioids in rodent models. SIGNIFICANCE STATEMENT: This systematic review summarizes clinical and preclinical studies on sex differences in psychostimulant and opioid craving and relapse. Results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. Results of preclinical studies reviewed provide evidence for sex differences in reinstatement and incubation of cocaine seeking but not for reinstatement or incubation of methamphetamine or opioid seeking.

Cocaine-induced increases in motivation require 2-arachidonoylglycerol mobilization and CB1 receptor activation in the ventral tegmental area.

A wide body of evidence supports an integral role for mesolimbic dopamine (DA) in motivated behavior. In brief, drugs that increase DA in mesolimbic terminal regions, like cocaine, enhance motivation, while drugs that decrease DA concentration reduce motivation. Data from our laboratory and others shows that phasic activation of mesolimbic DA requires signaling at cannabinoid type-1 (CB1) receptors in the ventral tegmental area (VTA), and systemic delivery of CB1 receptor antagonists reduces DA cell activity and attenuates motivated behaviors. Recent findings demonstrate that cocaine mobilizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the VTA to cause phasic activation of DA neurons and terminal DA release. It remains unclear, however, if cocaine-induced midbrain 2-AG signaling contributes to the motivation-enhancing effects of cocaine. To examine this, we trained male and female rats on a progressive ratio (PR) task for a food reinforcer. Each rat underwent a series of tests in which they were pretreated with cocaine alone or in combination with systemic or intra-VTA administration of the CB1 receptor antagonist rimonabant or the 2-AG synthesis inhibitor tetrahydrolipstatin (THL). Cocaine increased motivation, measured by augmented PR breakpoints, while rimonabant dose-dependently decreased motivation. Importantly, intra-VTA administration of rimonabant or THL, at doses that did not decrease breakpoints on their own, blocked systemic cocaine administration from increasing breakpoints in male and female rats. These data suggest that cocaine-induced increases in motivation require 2-AG signaling at CB1 receptors in the VTA and may provide critical insight into cannabinoid-based pharmacotherapeutic targets for the successful treatment of substance abuse.

Age-specific treatment effects of orexin/hypocretin-receptor antagonism on methamphetamine-seeking behavior.

BACKGROUND: Worldwide methamphetamine (METH) use has increased significantly over the last 10 years, and in the US, METH dependence has sky-rocketed among individuals with opioid use disorder. Of significant concern, METH use is gaining popularity among groups with susceptibility to developing severe substance use disorders, such as women and adolescents. Nevertheless, there is no established pharmacotherapy for METH addiction. Emerging evidence has identified the orexin/hypocretin system as an important modulator of reward-driven behavior and a potential target for the treatment of drug addiction and relapse. However, to date, there have been no investigations into the therapeutic efficacy of orexin/hypocretin receptor antagonists for METH-motivated behavior in adolescents or adults. In the present study, we examined the effects of selective antagonists of the orexin-1 (SB-334867, 20 mg/kg) and orexin-2 (TCS-OX2-29, 20 mg/kg) receptors on the reinstatement of METH seeking in both adolescent and adult male and female rats. METHODS: Rats were trained to self-administer METH (0.05 mg/kg/inf, iv) during two 2-h sessions/day for 5 days. Following 20 sessions of extinction over 10 days, a within-subjects design was used to test for METH seeking precipitated by METH (1 mg/kg, ip) or METH cues after systemic pretreatment with SB-334867 or TCS-OX2-29. RESULTS: SB-334867 reduced cue-induced reinstatement in males and females, regardless of age. Additionally, METH-induced METH seeking was attenuated by SB-334867 in adolescents and by TCS-OX2-29 in adults. CONCLUSION: Selective orexin/hypocretin receptor antagonists have significant therapeutic potential for diminishing METH-seeking behavior, although their treatment efficacy may be influenced by age.

Motivational Impairment is Accompanied by Corticoaccumbal Dysfunction in the BACHD-Tg5 Rat Model of Huntington's Disease.

Neuropsychiatric symptoms, such as avolition, apathy, and anhedonia, precede the onset of debilitating motor symptoms in Huntington's disease (HD), and their development may give insight into early disease progression and treatment. However, the neuronal and circuit mechanisms of premanifest HD pathophysiology are not well-understood. Here, using a transgenic rat model expressing the full-length human mutant HD gene, we find early and profound deficits in reward motivation in the absence of gross motor abnormalities. These deficits are accompanied by significant and progressive dysfunction in corticostriatal processing and communication among brain areas critical for reward-driven behavior. Together, our results define early corticostriatal dysfunction as a possible pathogenic contributor to psychiatric disturbances and may help identify potential pharmacotherapeutic targets for the treatment of HD.

Cannabinoid receptor-1 signaling contributions to sign-tracking and conditioned reinforcement in rats.

RATIONALE: Endocannabinoids (eCBs) are critical gatekeepers of dopaminergic signaling, and disrupting cannabinoid receptor-1 (CB1) signaling alters DA dynamics to attenuate cue-motivated behaviors. Prior studies suggest that dopamine (DA) release plays a critical role in driving sign-tracking. OBJECTIVES: Here, we determine whether systemic injections of rimonabant, a CB1 receptor inverse agonist, during Pavlovian lever autoshaping impair the expression of sign-tracking. We next examine whether rimonabant blocks the reinforcing properties of the Pavlovian lever cue in a conditioned reinforcement test. METHODS: In Exp. 1, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1, 3 mg/kg) during early and late Pavlovian lever autoshaping sessions. In Exp. 2, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1 mg/kg) during a conditioned reinforcement test. RESULTS: Rimonabant dose-dependently decreased lever contact and probability, and increased sign-tracker's latency to approach the lever cue early in Pavlovian training. With extended training, many previously goal-tracking and intermediate rats shifted to lever approach, which remained dose-dependently sensitive to rimonabant. Rimonabant attenuated cue-evoked food cup approach early, but not late, in conditioning, and did not affect pellet retrieval or consumption. The inserted lever cue served as a robust conditioned reinforcer after Pavlovian lever autoshaping, and 1 mg/kg rimonabant blocked conditioned reinforcement. CONCLUSIONS: Together, our results suggest that CB1 signaling mediates two critical properties of incentive stimuli; their ability to attract (Exp. 1) and their ability to reinforce (Exp. 2) behavior.

Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5.

In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5). Hence, we sought to determine whether mGluR5 activation was essential for estradiol-mediated enhancement of cocaine self-administration. Ovariectomized (OVX) female rats were allowed to freely self-administer cocaine under extended access conditions (6 h/d) for 10 consecutive days. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) or vehicle was administered before estradiol (or oil), on a 2 d on/2 d off schedule throughout the extended access period. MPEP treatment prevented the estradiol-dependent enhancement of cocaine self-administration in OVX females. In a separate experiment, potentiation of mGluR5 function with the positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (in the absence of estradiol treatment) failed to increase cocaine self-administration. These data suggest that mGluR5 activation is necessary for estradiol-mediated enhancement of responses to cocaine, but that direct mGluR5 activation is insufficient to mimic the female response to estradiol. Building on previous studies in male animals, these findings further highlight the therapeutic potential of mGluR5 antagonism in the treatment of addiction and suggest that there may be added therapeutic benefit in females.

Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions.

The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward-related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotransmitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability.

Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease.

UNLABELLED: Huntington's disease (HD) is a heritable neurodegenerative disorder caused by expansion of CAG (glutamine) repeats in the HTT gene. A prodromal stage characterized by psychiatric disturbances normally precedes primary motor symptoms and suppressed motivation represents one of the earliest and most common psychiatric symptoms. Although dopamine in the nucleus accumbens (NAc) critically regulates motivation and altered dopamine signaling is implicated in HD, the nature of dopaminergic deficits and contribution to symptoms in HD is poorly understood. We therefore tested whether altered NAc dopamine release accompanies motivational deficits in the Q175 knock-in HD mouse model. Q175 mice express a CAG expansion of the human mutant huntingtin allele in the native mouse genome and gradually manifest symptoms late in life, closely mimicking the genotypic context and disease progression in human HD. Sub-second extracellular dopamine release dynamics were monitored using fast-scan cyclic voltammetry, whereas motivation was assessed using a progressive ratio reinforcement schedule. As the response ratio (lever presses per reward) escalated, Q175 mice exerted less effort to earn fewer rewards versus wild-type (WT). Moreover, dopamine released at reward delivery dynamically encoded increasing reward cost in WT but not Q175 mice. Deficits were specific to situations of high effortful demand as no difference was observed in locomotion, free feeding, hedonic processing, or reward seeking when the response requirement was low. This compromised dopaminergic encoding of reward delivery coincident with suppressed motivation to work for reward in Q175 mice provides novel, neurobiological insight into an established and clinically relevant endophenotype of prodromal HD. SIGNIFICANCE STATEMENT: Psychiatric impairments in Huntington's disease (HD) typically manifest early in disease progression, before motor deficits. However, the neurobiological factors contributing to psychiatric symptoms are poorly understood. We used a mouse HD model and assessed whether impaired dopamine release in the nucleus accumbens (NAc), a brain region critical to goal-directed behaviors, accompanies motivational deficits, one of the most common early HD symptoms. HD mice exhibited blunted motivation to work for food reward coincident with diminished dopamine release to reward receipt. Motivational and NAc dopaminergic deficits were not associated with gross motor deficits or impaired food seeking when effortful demands were low. This work identifies a specific prodromal HD phenotype associated with a prominent and previously unidentified neurobiological impairment.

Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation?

The Cannabis sativa plant has been used to treat various physiological and psychiatric conditions for millennia. Current research is focused on isolating potentially therapeutic chemical constituents from the plant for use in the treatment of many central nervous system disorders. Of particular interest is the primary nonpsychoactive constituent cannabidiol (CBD). Unlike Δ(9)-tetrahydrocannabinol (THC), CBD does not act through the cannabinoid type 1 (CB1) receptor but has many other receptor targets that may play a role in psychiatric disorders. Here we review preclinical and clinical data outlining the therapeutic efficacy of CBD for the treatment of motivational disorders such as drug addiction, anxiety, and depression. Across studies, findings suggest promising treatment effects and potentially overlapping mechanisms of action for CBD in these disorders and indicate the need for further systematic investigation of the viability of CBD as a psychiatric pharmacotherapy.

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine.

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes.

Cocaine-induced reward enhancement measured with intracranial self-stimulation in rats bred for low versus high saccharin intake.

Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug-abuse vulnerability, with HiS rats being more likely to consume sweets and cocaine than LoS rats. Still, the nature of these differences is poorly understood. This study examined whether the motivational consequences of cocaine exposure are differentially expressed in HiS and LoS rats by measuring intracranial self-stimulation (ICSS) thresholds following acute injections of cocaine (10 mg/kg). Reductions in ICSS thresholds following cocaine injection were greater in HiS rats than in LoS rats, suggesting that the reward-enhancing effects of cocaine are greater in the drug-vulnerable HiS than LoS rats. Higher cocaine-induced reward, indicated by lower ICSS thresholds, may explain the higher rates of drug consumption in sweet-preferring animal models, providing a clue to the etiology of cocaine addiction in vulnerable populations.

Prevention of the incubation of cocaine seeking by aerobic exercise in female rats.

BACKGROUND: Recent research has demonstrated that aerobic exercise can attenuate craving for drugs of abuse and reduce escalation and reinstatement of drug-seeking behavior in animal models. The present study examined the effects of aerobic exercise on the development of the incubation of cocaine-seeking behavior or the progressive increase in cocaine seeking over a protracted withdrawal period from cocaine self-administration. METHODS: Female rats were trained to self-administer cocaine (0.4 mg/kg/inf) during daily 6-h sessions for 10 days. Subsequently, access to cocaine and cocaine-paired cues was discontinued during a 3- or 30-day withdrawal period when rats had access to either a locked or unlocked running wheel. At the end of the withdrawal period, rats were reintroduced to the operant conditioning chamber and reexposed to cocaine-paired cues to examine cocaine-seeking behavior under extinction conditions. RESULTS: Rats with access to a locked running wheel during 30 days of withdrawal had significantly greater cue-induced cocaine-seeking behavior than rats that had access to an unlocked running wheel for 30 days. Further, there was robust incubation of cocaine seeking in rats with access to a locked running wheel as cocaine seeking was notably elevated at 30 vs. 3 days of withdrawal. However, cocaine-seeking behavior did not differ between rats with access to an unlocked running wheel for 30 vs. 3 days, indicating that incubation of cocaine seeking was suppressed following access to exercise for 30 days. CONCLUSION: Aerobic exercise during extended withdrawal from cocaine self-administration decreased incubation of cue-induced cocaine-seeking behavior and may reduce vulnerability to relapse.

Intracranial self-stimulation reward thresholds during morphine withdrawal in rats bred for high (HiS) and low (LoS) saccharin intake.

RATIONALE: Sweet preference is a marker of vulnerability to substance use disorders, and rats selectively bred for high (HiS) vs. low saccharin (LoS) intake display potentiated drug-seeking behaviors. Recent work indicated that LoS rats were more responsive to the negative effects of drugs in several assays. OBJECTIVE: The current study used the intracranial self-stimulation (ICSS) procedure to investigate the anhedonic component of morphine withdrawal in male HiS and LoS rats. METHODS: Rats were administered morphine (10mg/kg) or saline for 8 days. To evaluate withdrawal effects, reward thresholds were measured 24 and 28h following the 8th morphine injection (spontaneous withdrawal) and again for 4 days following daily acute morphine and naloxone (1mg/kg) administration (precipitated withdrawal). RESULTS: 24h following the final morphine injection, reward thresholds in LoS rats were significantly elevated compared to reward thresholds in LoS controls, indicating spontaneous withdrawal. This effect was not observed in HiS rats. LoS rats also showed greater elevations of reward thresholds on several days during naloxone-precipitated withdrawal compared to their HiS counterparts. CONCLUSIONS: LoS rats were more sensitive to morphine withdrawal-mediated elevations in ICSS thresholds than HiS rats. While these differences were generally modest, our data suggest that severity of the negative affective component of opiate withdrawal may be influenced by genotypes related to addiction vulnerability.

Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity.

BACKGROUND: Aerobic exercise and the attention-deficit/hyperactivity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstatement of cocaine-seeking in an animal model of relapse. The present study investigated the effects of combining wheel running and ATO versus each treatment alone on cocaine-seeking precipitated by cocaine and cocaine-paired cues in rats with differing susceptibility to drug abuse (i.e., high vs. low impulsive). METHODS: Rats were screened for high (HiI) or low impulsivity (LoI) based on their performance on a delay-discounting task and then trained to self-administer cocaine (0.4 mg/kg/inf) for 10 days. Following 14 days of extinction, both groups were tested for reinstatement of cocaine-seeking precipitated by cocaine or cocaine-paired cues in the presence of concurrent running wheel access (W), pretreatment with ATO, or both (W+ATO). RESULTS: HiI rats acquired cocaine self-administration more quickly than LoI rats. While both individual treatments and W+ATO significantly attenuated cue-induced cocaine seeking in HiI and LoI rats, only W+ATO was effective in reducing cocaine-induced reinstatement compared with vehicle treatment. There were dose-dependent and phenotype-specific effects of ATO with HiI rats responsive to the low but not high ATO dose. Floor effects of ATO and W on cue-induced reinstatement prevented the assessment of combined treatment effects. CONCLUSIONS: These findings demonstrated greater attenuation of cue- versus cocaine-induced reinstatement by ATO and W alone and recapitulate impulsivity phenotype differences in both acquisition of cocaine self-administration and receptivity to treatment.