Rationale.-Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., Nacetylcysteine [NAC]) may attenuate CUD-related relapse behavior. Objectives.-The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. Methods.-First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. Results.-Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. Conclusions.-The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.

Background: Prescription opioid abuse continues to be a public health concern of epidemic proportions. Notwithstanding the extensive literature regarding opioid action, there has been little systematic research regarding the effects of opioid dependence and withdrawal on aspects of cognition-related behavior in laboratory animals. The present studies examined the effects of the prescription opioid oxycodone on learning processes in nonhuman primates. Methods:The ability of subjects to repeatedly learn novel touchscreen-based visual discriminations was examined during three conditions of opioid exposure. Discrimination learning was examined, first, during oxycodone self-administration (3-hr sessions, 0.1 mg/kg/infusion) and, next, during non-contingent chronic treatment with oxycodone (10 mg/kg/day). Finally, discrimination learning was re-examined during antagonist-precipitated opioid withdrawal (0.001-0.1 mg/kg naltrexone) and, subsequently, following abrupt discontinuation of oxycodone treatment.Results: Although motoric behavior was disrupted by oxycodone, neither the development of discrimination learning nor steady-state performance were impaired following oxycodone selfadministration or during non-contingent chronic oxycodone treatment. However, discrimination learning was substantially impaired during oxycodone withdrawal, whether elicited by naltrexone or by abrupt oxycodone discontinuation. Moreover, these learning impairments were concordant with autonomic signs of opioid withdrawal.

Behavioral economic procedures, e.g., demand curve analysis, provide powerful quantitative metrics for scaling the strength of drugs of abuse. Most studies that have utilized such procedures employ simple fixed ratio (FR) schedules of reinforcement to generate demand curves. However, second‐order schedules, in which a subject responds under one schedule of conditioned reinforcement (e.g., for presentation of a brief light stimulus) that is nested within a second schedule of primary reinforcement, have been suggested to more accurately reflect the complex patterns of behavior that accompany human drug taking. Further, the conditioned stimulus presented during second order schedules may develop conditioned reinforcer properties that serve to maintain drug‐taking behavior in their own right. The objective of the present study was to begin to compare self‐administration and demand for intravenous methamphetamine and methcathinone under both simple FR and second‐order schedules of reinforcement in nonhuman primates. Adult male squirrel monkeys (N=4) with histories of stimulant self‐administration responded for intravenous methamphetamine and methcathinone injections under FR10 and FR10(FR5:S) schedules of reinforcement. After self‐administration of vehicle and a range of methamphetamine (0.001–0.1 mg/kg) and methcathinone (0.001–0.1 mg/kg) doses were evaluated under each schedule, two doses of each drug (0.01 and 0.03 mg/kg/inj) were studied using a demand procedure; for the FR condition, the response requirement for drug delivery increased across multiple sessions in an ascending order, i.e. FR 10, 30, 56, 100, etc. For the second‐order condition, the response requirement for the drug delivery schedule increased according to a similar progression (i.e., FR10(FR5:S), FR30(FR5:S), FR56(FR5:S), etc.). Each condition was presented in a random order that was counterbalanced across subjects. Results indicate that methamphetamine and methcathinone self‐administration followed an inverted‐U shaped pattern with similar total intake (mg/kg) under the two schedules of reinforcement. During demand procedures, both methamphetamine and methcathinone self‐administration gradually decreased as the response requirement was increased. Application of the exponential model of demand shows that the higher dose of methamphetamine (0.03 mg/kg) produced slightly greater breakpoints than the lower dose (0.01 mg/kg) under both schedule conditions whereas demand for methcathinone was generally higher under FR than second‐order schedules regardless of dose. Interestingly, demand for the high doses of the two drugs was less elastic under the FR condition, whereas demand for the lower doses was more elastic under the second‐order schedule. These results suggest that the demand for self‐administered drugs may be influenced by schedule of reinforcement in a manner that varies across drugs. Further, the present results do not support a facilitative influence of conditioned reinforcement on the reinforcing strength of self‐administered drugs.Support or Funding InformationThis work was funded by National Institutes of Health grants DA002519 and DA039306This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.