Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates

Abstract

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., N-acetylcysteine [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.

Keywords: Cocaine; Cognitive flexibility; Learning; N-acetylcysteine; Nonhuman Primates; Reinstatement; Self-administration.

Figure 1.

Experimental timeline. Protocols included repeated acquisition (RA) and discrimination reversal (DR) training, determinations of cocaine dose-response functions, extended cocaine self-administration conditions, intermittent touchscreen-based probes, reinstatement, and cocaine discontinuation (washout). See Procedures for additional information.

Figure 2.

Average (±SEM) cocaine infusions (upper panel) and total cocaine intake (lower panel) during 1-h sessions in which different unit doses of cocaine (mg/kg/inj) and saline (S) were self-administered (n=6). The insets in show the same data from the larger panels divided by subjects that would, in later conditions, comprise the NAC (n=3) and saline (n=3) groups.

Figure 3.

Average (±SEM) number of trials to master five discriminations (Repeated Acquisition [RA], open bars) and subsequent reversals (Discrimination Reversal [DR], filled bars) during probe sessions conducted before cocaine exposure (C), following each 30^th session of cocaine self-administration, and after a 30-d washout (abstinence) period (Ab) (n=6). (*p<.05; **p<.01; ***p<.001)

Figure 4.

Percent change from baseline in average trials to master 5 discriminations (left panel) and 5 reversals (right panel) following 30 days of cocaine self-administration, plotted as a function of average daily cocaine intake during the sessions in which those 5 discriminations were mastered. Each data point represents that relationship for an individual subject. The solid line represents a standard linear regression fit to the data.

Figure 5.

Left panel: Mean cocaine intake (mg/kg) during the last 10 sessions of self-administration for all subjects prior to saline or NAC treatment (gray bar, n=6), and during the 10 sessions of saline (white bar, n=3) or NAC pretreatment (black bar, n=3). Right panel: Mean sessions required to meet extinction criteria. Extinction criteria were defined as a 1-hour session with fewer than 10 saline infusions earned. (p<.05)

Figure 6.

Effect of NAC treatment (filled circles, n=3) and saline treatment (open circles, n=3) on reinstatement of previously extinguished self-administration behavior induced by pre-session cocaine primes. Data are expressed as average number of saline infusions (±SEM) earned during a 1-h session after an i.m. cocaine prime (mg/kg), saline (S), or no injection (C).