Cocaine addiction involves an escalation in drug intake which alters many brain functions. The present study documented cocaine-induced changes in brain metabolic activity as a function of cocaine self-administration history. Experimentally naive rhesus monkeys (N=6) were given increasing access to cocaine under a fixed-ratio schedule of i.v. drug self-administration. PET imaging with F-18 labeled fluorodeoxyglucose (FDG) was used to measure acute i.m. cocaine-induced changes in brain metabolism in the cocaine-naïve state, following 60 sessions under limited-access conditions (1hr/day), following 60 sessions under extended-access conditions (4hr/day), and following 4 weeks of drug withdrawal. In the cocaine-naïve state, cocaine-induced increases in brain metabolism were restricted to the prefrontal cortex. As cocaine exposure increased from limited to extended access, metabolic effects expanded throughout the frontal cortex and were induced within the striatum. Conversely, cocaine-induced activation was far less robust following withdrawal. The results highlight a progressive expansion of the metabolic effects of cocaine to include previously unaffected dopamine innervated brain regions as a consequence of cocaine self-administration history. The identification of brain regions progressively influenced by drug exposure may be highly relevant toward efforts to develop treatments for cocaine addiction.

Rationale The transition from infrequent and controlled cocaine use to dependence may involve enduring changes in neurobiology as a consequence of persistent drug use. Objective The present study utilized an intravenous drug self-administration protocol of increasing cocaine access to evaluate potential changes in dopamine function in vivo, including changes in sensitivity to psychostimulants. Materials and methods Drug-naïve rhesus monkeys were provided limited access (1 h) to cocaine self-administration for 60 days followed by 60 days under an extended access condition (4 h). Basal levels of striatal extracellular dopamine and its metabolites, as well as the effectiveness of cocaine and amphetamine to elevate dopamine, were determined with in vivo microdialysis before the initiation of cocaine self-administration and during limited and extended access. The effect of cocaine and amphetamine on the acoustic startle response was also examined to assess complementary behavioral changes as a function of drug history. Results Extended access to cocaine self-administration lead to increased daily intake compared to limited access conditions but did not result in escalated intake over time. However, cocaine- and amphetamine-induced increases in striatal dopamine were diminished as a function of cocaine self-administration history. Surprisingly, there was no effect of drug-taking history on sensitivity to psychostimulant-induced enhancement of startle amplitude. Conclusions The present experiments provide evidence of a hypofunctional dopamine system that is not associated with an escalation in drug intake or reflected in measures of acoustic startle.

Background There is evidence for psychomotor and cognitive performance impairment in methadone maintenance patients (MMP), as well as in individuals with current cocaine dependence. It is unknown whether MMP with concurrent cocaine dependence perform worse on tests of cognitive function than MMP without cocaine dependence. Methods Performance was compared between MMP with and without current cocaine dependence (MMP/CD+; N=53 and MMP/CD−; N=24) on a standard battery of tasks designed to measure psychomotor performance, attention, episodic and working memory, and executive function. Results Participant characteristics were mostly similar across groups. However, the MMP/CD+ group had a shorter duration of methadone treatment, and a larger percentage of participants with self-reported 30-day poly-substance abuse and positive urine drug tests on the day of cognitive testing. There were no differences between the groups on measures of balance, psychomotor coordination, divided attention, working memory, most measures of episodic memory, or executive function. Relative to MMP/CD−, MMP/CD+ showed significant impairment on select measures of psychomotor performance/attention (simple reaction time and trail-making test A) and episodic memory (higher false alarm rates on recognition memory). Conclusions The absence of differences between MMP/CD+ and MMP/CD− on measures of higher order cognitive functions, and the relatively small magnitude between-group differences on other measures suggest that current cocaine dependence, in the absence of cocaine intoxication, is unlikely to be associated with clinically meaningful increases in performance impairment in MMP.

Rationale The progression of addiction from controlled to compulsive drug use leads to serious adverse consequences, including a greater propensity to relapse to drug use after sustained periods of abstinence. Objective The present study assessed the potential effects of cocaine self-administration history on the magnitude and persistence of cocaine-induced reinstatement in rhesus monkeys (n=6). Methods During a 3-month period of limited access to cocaine self-administration under a second-order schedule, subjects could take a maximum of 0.5 mg/kg per session 5 days per week. During a subsequent 3-month period of extended access to cocaine self-administration, subjects could take an additional 3.0 mg/kg under a fixed-ratio 20 schedule 3 days per week. Reinstatement effects were evaluated on six separate occasions that included limited and extended access conditions. Saline was substituted for cocaine, and once extinction criteria were met (response rates <20% of cocaine-maintained rates), response-independent cocaine (0.1 mg/kg) was administered i.v. prior to extinction sessions. Reinstatement was defined as a restoration of drug-appropriate responding above extinction criteria. Reinstatement experiments were conducted repeatedly on a daily basis until response rates returned to extinction levels. Peak response rates provided a measure of reinstatement magnitude whereas number of sessions required to meet extinction levels provided a measure of reinstatement persistence. Results Both the magnitude and persistence of reinstatement were consistent across all determinations regardless of drug history. Conclusions The results indicate that reinstatement under the second-order schedule is remarkably stable even when supplemental drug intake is provided over several months.