Long-term cocaine self-administration under fixed-ratio and second-order schedules in monkeys.
ABSTRACT Studies in rodents have demonstrated that increased access to cocaine can result in increases in drug intake per unit time.
The present studies characterized long-term changes in cocaine self-administration associated with quantitatively and qualitatively different conditions of cocaine availability in monkeys.
Separate groups of rhesus monkeys (n = 6/group) self-administered cocaine (0.2 mg/kg per injection) under a fixed ratio (FR) 30 schedule for 3 h twice daily for two consecutive days each week for 1 year, or responded under a second-order FR 10 (fixed interval 3-min:S) schedule of 0.2 mg/kg per injection cocaine during daily sessions. After 18 weeks, probe sessions were conducted once per week, in which responding was maintained under a fixed interval (FI) 30-min schedule in the presence of distinct stimuli.
Weekly cocaine intakes under the FR schedule were stable in three subjects, but increased progressively in three monkeys over 1 year. In contrast, response rates under the second-order schedule were low and stable over time. Responding under the FI 30-min schedule was higher for monkeys in the FR group and pattern of responding was not indicative of FI performance, perhaps due to experimental history.
These data suggest that increases in cocaine intake can be observed under ratio schedules in monkeys. The use of an FI 30-min "probe" to assess changes in "drug seeking" appeared to be influenced by experimental history. These data may aid in the development of behavioral models of cocaine abuse, which focus on the compulsive nature of drug taking.
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ABSTRACT: Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ∼6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [(11)C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy α4β2* subtype-selective agonist varenicline and the high-efficacy α7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'.Neuropharmacology 08/2012; 64(1):479-88. DOI:10.1016/j.neuropharm.2012.08.004 · 4.82 Impact Factor
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ABSTRACT: Chronic cocaine use is associated with neurobiological and cognitive deficits that persist into abstinence, hindering success of behavioral treatment strategies and perhaps increasing likelihood of relapse. The effects of current cocaine use and abstinence on neurobiology and cognition are not well characterized. Adult male rhesus monkeys with an extensive cocaine self-administration history (∼ 5 years) and age-matched control animals (n = 4/group) performed cognitive tasks in morning sessions and self-administered cocaine or food in afternoon sessions. Positron emission tomography and [(18)F]-fluorodeoxyglucose were employed to assess cerebral metabolic rates of glucose utilization during cognitive testing. Cocaine-experienced monkeys required significantly more trials and committed more errors on reversal learning and multidimensional discriminations, compared with control animals. Cocaine-naive, but not cocaine-experienced, monkeys showed greater metabolic rates of glucose utilization during a multidimensional discrimination task in the caudate nucleus, hippocampus, anterior and posterior cingulate, and regions associated with attention, error detection, memory, and reward. Using a delayed match-to-sample task, there were no differences in baseline working memory performance between groups. High-dose cocaine self-administration disrupted delayed match-to-sample performance but tolerance developed. Acute abstinence from cocaine did not affect performance, but by day 30 of abstinence, accuracy increased significantly, while performance of cocaine-naive monkeys was unchanged. These data document direct effects of cocaine self-administration on cognition and neurobiological sequelae underlying cognitive deficits. Improvements in working memory can occur in abstinence, albeit across an extended period critical for treatment seekers, suggesting pharmacotherapies designed to enhance cognition may improve success of current behavioral modification strategies.Biological psychiatry 06/2012; 72(10):856-63. DOI:10.1016/j.biopsych.2012.05.001 · 9.47 Impact Factor
Chapter: Escalation of Drug Use[Show abstract] [Hide abstract]
ABSTRACT: Among the different behavioral criteria used to discriminate substance dependence (or drug addiction) from other non-disordered forms of drug use, drug intake escalation presents a number of unique features that makes it particularly suitable for modeling in nonhuman animals. This criterion has stood the passage of time despite major revisions of diagnostic systems, it is common to all known drugs of abuse and it can be readily and unambiguously operationalized in laboratory animals. Here I exhaustively review evidence showing that escalation to heavy consumption of different drugs (except perhaps nicotine) can be rapidly induced in the majority of individual animals (i.e., rats) by increased drug availability. Such an escalation of drug use is probably paralleled by an authentic escalation to drug addiction, as it is associated with the co-occurrence of other addiction-like changes (i.e., increased motivation for drug use; increased difficulty to abstain from drug use; decreased sensitivity to negative consequences). In addition, during escalation of drug intake, most individual animals become increasingly responsive to drug- and stress-primed, but apparently not cue-primed, reinstatement of drug seeking after extinction. Finally, following increased drug use, most individuals present selective cognitive dysfunctions (e.g., deficits in executive functions) that may contribute to the establishment and/or persistence of addiction. Thus, the study of individuals with escalating patterns of drug use should provide a unique and valid approach to investigate, experimentally, the behavioral and neurobiological mechanisms that underlie the progression to addiction. Key wordsCocaine–Heroin–Nicotine–Tolerance–Compulsion–Self-regulation–Reward–Punishment12/2010: pages 267-292;