Impairments of Reversal Learning and Response Perseveration after Repeated, Intermittent Cocaine Administrations to Monkeys

Abstract

The current experiments examined the effects of acute or repeated, intermittent administrations of cocaine on the acquisition and reversal of object discriminations by Vervet monkeys in order to test the hypothesis that cocaine treatment affects performance of tasks that depend upon the functions of the orbitofrontal cortex and amygdala. An acute dose of cocaine (1 mg/kg; 20 min prior to testing) impaired reversal of a previously learned object discrimination but had no effect on acquisition of a novel one. Specific impairments of reversal learning were also observed in monkeys 9 and 30 days after repeated administrations of cocaine (2 or The compulsive drug seeking and taking behavior that is characteristic of drug addiction has recently been attributed to complex, inter-related dysfunctions in neural systems mediating incentive motivation and behavioral regulation (e.g., the striatum, amygdala and ventral frontal cortex; Jentsch and Taylor 1999;Robbins and Everitt 1999; Volkow and Folwer 2000;Berke and Hyman 2000). Several lines of evidence support this hypothesis. First, drug addicts exhibit altered cerebral blood flow and metabolism within the striatum, amygdala and frontal cortex both at baseline and after drug-induced craving (c.f. Volkow and Fowler 2000;London et al. 2000). Second, chronic drug administration affects the neurochemistry and anatomy of these brain regions in animal models (Nestler and Aghajanian 1997;Robinson and Kolb 1997;Wolf 1998;Berke and Hyman 2000; Vandershuren and Kalivas 2000;Robinson et al. 2001 (Post et al. 1976), altered incentive motivation (Shippenberg and Heidbreder 1995;Taylor and Horger 1999;Robbins and Everitt 1999) and impaired cognitive and executive function (Jentsch et al. 1997(Jentsch et al. , 2000Rogers et al. 1999;Robbins and Everitt 1999;Grant et al. 2000;Ornstein et al. 2000) after chronic stimulant drug administration.Because of its important role in decision-making (Bechara et al. 2000) and inhibitory control over pre-potent behavior (Roberts and Wallis 2000), an involvement of ventromedial regions of the frontal cortex in drug abuse has been proposed. In essence, impairments of frontal lobe function are thought to effectively 'un-gate' subcortically-mediated, conditioned tendencies (such as established instrumental responses to obtain and consume drugs), resulting in the compulsive drug seeking and taking that characterize addiction (Jentsch and Taylor 1999). Nevertheless, few studies have directly investigated the long-term consequences of prolonged exposure to addictive drugs on frontal cortex cognitive function, particularly in non-human primates.The aim of the current studies was to directly evaluate the function of the prefrontocortico-amygdalo-striatal system after repeated, intermittent cocaine administrations to monkeys. Using an animal model in which drug treatment (schedule and dosing) and withdrawal can be experimentally controlled, we employed a wellcharacterized behavioral task, the acquisition and reversal of a 3-choice object discrimination. T...

Acute Cocaine Administration Depresses Cortical Activity

“…Furthermore, transient changes in cortical excitability may have a role in mediating some of the short-term behavioral effects of cocaine. For example, acute cocaine administration to monkeys has been shown to impair performance in a behavioral paradigm that involves new learning as well as behavioral flexibility (Thompson and Moerschbaecher, 1970;Evans and Wenger, 1992;Jentsch et al, 2002). The cocaine-induced decrease in cortical bistability reported here could contribute to decrease efficiency of information processing in prefrontal cortex and compromise functions such as working memory and attention.…”

“…However, the acute administration of psychostimulants also produces important cognitive deficits. A recent study by Jentsch and colleagues (Jentsch et al, 2002) suggested that acute cocaine administration disrupts reversal learning in monkeys, although chronic treatment is required for longlasting deficits. Supporting their hypothesis that acutely administered cocaine is sufficient to alter learning, other investigators have shown that a single cocaine exposure can induce context-dependent behavioral sensitization (Jackson and Nutt, 1993;Alesdatter and Kalivas, 1993;Ungless et al, 2001).…”

Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys

“…In a classic two-choice discrimination, an error is by definition perseverative; however, in a three-choice discrimination, we can separate the strictly perseverative errors from the type of errors that would occur during a random search strategy (equal numbers of perseverative and neutral errors). The usefulness of this approach in detecting stimulant drug-induced increases on perseverative responding in a discrimination reversal task has been demonstrated previously (Jentsch et al, 2002).…”

Impulsivity in animal models for drug abuse disorders

“…It is important to note that many studies have examined the effects of acute administration of drugs of abuse on impulsive action and decision-making in rats, but this manuscript focuses on studies utilizing chronic drug exposure, given the greater relevance for drug addiction. The first study on this topic examined how repeated, intermittent cocaine exposure affected the ability of monkeys to adaptively modify a behavioral response in a discrimination reversal task; we showed that even short-term exposure to cocaine (twice-daily injections for 2 weeks) produced relatively long-lasting impairments in response updating [20]. Our group has extended these results by showing that cocaine-exposed monkeys exhibit perseverative deficits in a number of variations on the reversal task [30].…”

“…Other tests measure the ability to adaptively inhibit one response in favor of another when contingencies are adjusted during performance, i.e. reversal of a learned discrimination [18][19][20][21][22]. Collectively, these procedures, along with others, are used to measure the ability to cognitively control responding or behavior.…”