Inactivation of posterior but not anterior dorsomedial caudate-putamen impedes learning with self-administered nicotine stimulus in male rats.

The rodent caudate-putamen is a large heterogeneous neural structure with distinct anatomical connections that differ in their control of learning processes. Previous research suggests that the anterior and posterior dorsomedial caudate-putamen (a- and p-dmCPu) differentially regulate associative learning with a non-contingent nicotine stimulus. The current study used bilateral NMDA-induced excitotoxic lesions to the a-dmCPu and p-dmCPu to determine the functional involvement of a-dmCPu and p-dmCPu in appetitive learning with contingent nicotine stimulus. Rats with a-dmCPu, p-dmCPu, or sham lesions were trained to lever-press for intravenous nicotine (0.03 mg/kg/inf) followed by access to sucrose 30 s later. After 1, 3, 9, and 20 nicotine-sucrose training sessions, appetitive learning in the form of a goal-tracking response was assessed using a non-contingent nicotine-alone test. All rats acquired nicotine self-administration and learned to retrieve sucrose from a receptacle at equal rates. However, rats with lesions to p-dmCPu demonstrated blunted learning of the nicotine-sucrose association. Our primary findings show that rats with lesions to p-dmCPu had a blunted goal-tracking response to a non-contingent nicotine administration after 20 consecutive days of nicotine-sucrose pairing. Our findings extend previous reports to a contingent model of nicotine self-administration and show that p-dmCPu is involved in associative learning with nicotine stimulus using a paradigm where rats voluntarily self-administer nicotine infusions that are paired with access to sucrose-a paradigm that closely resembles learning processes observed in humans.

Assessment of individual differences in response to acute bupropion or varenicline treatment using a long-access nicotine self-administration model and behavioral economics in female rats.

Bupropion and varenicline are widely prescribed pharmacological treatments for smoking cessation. These treatments are only marginally effective in clinical populations but most preclinical studies show that they are effective in decreasing self-administration in rats on a group level. The present study investigated individual differences in responding to bupropion or varenicline in a preclinical model of long-access to nicotine (0.03 mg/kg/inf; 12 h/day) in female rats. Rats were first assessed for their individual economic demand for nicotine and for their individual performance in open field and elevated plus maze prior to nicotine access and during withdrawal. Rats were then tested for the acute effects of bupropion, varenicline, and yohimbine. We found that neither bupropion nor varenicline decreased responding for nicotine on test days. On the contrary, a moderate dose of bupropion (30 mg/kg) significantly increased responding for nicotine. We also found that rats with higher demand for nicotine were more sensitive to pretreatment with yohimbine which resulted in increased responding for nicotine during the dose-effect tests. Finally, we show that rats that had a higher demand for nicotine also were more persistent in seeking nicotine during extinction and reinstatement tests with nicotine or yohimbine as triggers. Our findings suggest that the length of access to daily nicotine may be an important factor underlying the response to pharmacological treatments like bupropion or varenicline. Future studies modeling chronic treatment approaches that include both sexes will be needed to further extend our findings.

Individual Vulnerability to Stress Is Associated With Increased Demand for Intravenous Heroin Self-administration in Rats.

Opioid use is a widespread epidemic, and traumatic stress exposure is a critical risk factor in opioid use and relapse. There is a significant gap in our understanding of how stress contributes to heroin use, and there are limited studies investigating individual differences underlying stress reactivity and subsequent stress-induced heroin self-administration. We hypothesized that greater individual vulnerability to stress would predict higher demand for heroin self-administration in a within-subjects rodent model of stress and heroin use comorbidity. Male rats were exposed to inescapable intermittent swim stress (ISS) and individual biological (corticosterone) or behavioral [open field, social exploration, and forced swim tests (FSTs)] measures were assessed before and after the stress episode. Individual demand for self-administered heroin (0.05 mg/kg/infusion; 12-h sessions) was assessed using a behavioral economics approach followed by extinction and reinstatement tests triggered by stress re-exposure, non-contingent cue presentations, and yohimbine (0, 1.0, or 2.5 mg/kg). We found that behavioral, biological, and a combination of behavioral and biological markers sampled prior to and after the stress episode that occurred weeks before the access to heroin self-administration predicted the magnitude of individual demand for heroin. Non-contingent presentation of cues, that were previously associated with heroin, reinstated heroin seeking in extinction. For the first time, we show that individual biological response to an ecologically relevant stressor in combination with associated behavioral markers can be used to predict subsequent economic demand for heroin.

Individual differences in responding to bupropion or varenicline in a preclinical model of nicotine self-administration vary according to individual demand for nicotine.

Bupropion and varenicline are the top two smoking cessation interventions that are marginally successful in increasing abstinence rates when compared to placebo. Although smokers vary in their history and pattern of tobacco use, there is a significant gap in addressing this individual variability with individually targeted treatments. The present study takes the initial step towards a better understanding of individual differences in treatment outcomes by assessing the effect of bupropion or varenicline on nicotine self-administration in rats. Rats were first assessed for their individual economic demand for sucrose and then for self-administered nicotine (0.03 mg/kg/inf; 2 h sessions). We then examined the effect of bupropion (0, 10, 30, 60 mg/kg) or varenicline (0, 0.1, 1.0, 3.0 mg/kg) pretreatment on individual rates of nicotine self-administration using progressive ratio schedule of reinforcement. Thereafter, rats were subjected to four rounds of extinction and reinstatement tests. We found that individual demand for sucrose did not predict individual demand for nicotine. Acute pretreatments with bupropion or varenicline were most effective at decreasing nicotine self-administration in rats that had a higher demand for nicotine. Rats with higher demand for nicotine also showed higher magnitude of responding in extinction and during nicotine-triggered reinstatement tests. Although the acute treatment protocol employed in this study is an important initial step towards a better understanding of individual treatment effects, future research modeling chronic treatment approaches will be needed to further extend our findings.