Chronic Cocaine Self-Administration in Rhesus Monkeys: Impact on Associative Learning, Cognitive Control, and Working Memory

Abstract

Cocaine users display a wide range of cognitive impairments. Because treatment outcome is dependent on baseline cognitive ability, it is clinically important to understand the underlying neurobiology of these deficits. Therefore, it is crucial to determine whether cocaine exposure by itself is an etiological factor, and if so, to determine the overall nature of cognitive deficits associated with cocaine use. This will help to guide therapeutic approaches that address cognitive components of cocaine use in order to improve treatment outcome. We used rhesus monkeys in a longitudinal study in which 14 animals were characterized prior to assignment to matched control (n=6) and cocaine self-administration (n=8) groups. Self-administration took place on four consecutive days/week over nine months, with a maximum (and typical) daily cumulative intake of 3.0 mg/kg. Weekly cognitive assessments (total of 36) were conducted following a 72 hour drug free period. We employed a stimulus discrimination task with reversal to evaluate associative learning and the cognitive control/flexibility needed to adapt to changes in reward contingencies. Following extended self-administration, initial accuracy on the stimulus discrimination indicated intact associative learning. However, animals were impaired at maintaining high levels of accuracy needed to reach criterion and initiate the reversal. Increasing the reward contrast between stimuli permitted evaluation of reversal performance, and revealed striking deficits in the cocaine group. Impairments in visual working memory were also observed using a delayed-match-to-sample task. These results suggest a combination of generalized, possibly attentional, impairments, along with a more specific cognitive control impairment implicating orbitofrontal cortex dysfunction.

Psychostimulant Abuse and Neuroinflammation: Emerging Evidence of Their Interconnection

“…Thus, in addition to subcortical dysregulation, it is becoming increasingly clear that altered executive function subserved by the prefrontal cortex and its distributed networks, contributes to the behavioral and cognitive changes seen in long term, chronic usage. These changes include poor judgment, diminished decision making capacity, and repeated relapse despite severe negative social, financial, psychological, and physical consequences (Kalivas and Volkow 2005;Porter et al 2011;Porrino and Lyons 2000;Goldstein et al 2007).…”

Impact of adolescent sucrose access on cognitive control, recognition memory, and parvalbumin immunoreactivity

“…Dopamine transporter knockout mice have low rates of cocaine self-administration, but no difference in responding for sucrose (Thomsen et al 2009) and contrasting roles of subsets of NAc neurons have been observed when rats respond for natural or drug rewards (Cameron and Carelli 2012). Furthermore, chronic exposure to drugs of abuse is associated with deficits in cognitive function and behavioral control (Nelson and Killcross 2006;Parsegian et al 2011;Porter et al 2011). Thus, it is possible that consumption of diets high in sugar or exposure to psychoactive drugs during critical periods of brain development (e.g., adolescence) may produce enduring changes in the brain reward system and also in cognitive control (Smith 2003;Vendruscolo et al 2008;Iniguez et al 2009;Zamberletti et al 2014).…”

Altered cerebellar and prefrontal cortex function in rhesus monkeys that previously self-administered cocaine

“…Cumulative cocaine exposure ranged from 503 to 540 mg/kg total exposure over the 12 months of self-administration. Self-administration sessions were generally conducted 4 days per week (Tues-Fri), with cognitive assessments (reported in (Porter et al 2011) taking place on Mondays). During the self-adminstration sessions, the unit dose of cocaine available was 0.5 mg/kg.…”