Cocaine‐experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions

Abstract

Addictive drugs, such as cocaine, cause long-lasting neural changes in prefrontal cortex. It has been hypothesized that these changes affect the behavioural control mediated by orbitofrontal cortex. To test this hypothesis, rats were given injections of cocaine (30 mg/kg/d, i.p.) or vehicle for 14 days and then trained after a 2-week withdrawal period in an odor discrimination task sensitive to the effects of orbitofrontal cortex lesions. We found that cocaine-treated rats, who demonstrated long-lasting sensitization to the locomotor activating effects of cocaine, failed to show normal changes in response latency during discrimination learning and were also slower than controls to acquire serial reversals. These behavioural impairments are identical to the effects of orbitofrontal cortex lesions in this task and show that cocaine exposure in rats can cause long-lasting effects on orbitofrontal-dependent functions. Notably, these effects were not correlated with increases in locomotor activity linked to cocaine-induced psychomotor sensitization observed before or after training, suggesting that the brain changes underlying the behavioural effects in the discrimination task are different from those mediating psychomotor sensitization.

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…In addicts, dysfunction in decision-making and development of compulsive drug-seeking behaviors despite negative outcomes is similar to that observed in individuals with OFC damage (Bechara, 2005;Bechara and Van Der Linden, 2005;Rogers et al, 1999a). Impaired reversal learning has been found in animals following repeated intermittent cocaine treatment, indicating a malfunction of the lOFC (Jentsch et al, 2002;Schoenbaum et al, 2004). In addition, persistent metabolic and neurochemical changes have been observed in the OFC of both drug addicts and drug abstinent subjects, suggesting that functional changes of the OFC may contribute to the development of drug addiction (Volkow et al, 2004).…”

Extended Access to Cocaine Self-Administration Produces Long-Lasting Prefrontal Cortex-Dependent Working Memory Impairments

“…There is accumulating evidence that repeated passive exposure to psychostimulants leads to deficits in tasks that depend on intact prefrontal cortex function (Fletcher et al, 2005(Fletcher et al, , 2007Roesch et al, 2007;Schoenbaum et al, 2004;Schoenbaum and Setlow, 2005). Moreover, withdrawal from repeated passive cocaine or amphetamine treatments also decreases firing rate and bursting activity of dmPFC neurons (Nogueira et al, 2006;Homayoun and Moghaddam, 2007) and abolishes dopamine D 2 receptor-mediated regulation of dmPFC excitability (Nogueira et al, 2006) and membrane bistability of dmPFC neurons (Trantham et al, 2002).…”

Persistent Alterations in Cognitive Function and Prefrontal Dopamine D2 Receptors Following Extended, but Not Limited, Access to Self-Administered Cocaine

“…Studies using non-human animals have shown that when psychostimulant drugs are administered by an experimenter, they can produce both acute and persistent deficits in cognitive function (Crider et al, 1982;Jentsch et al, 2002;Kondrad and Burk, 2004;Schoenbaum et al, 2004;Burke et al, 2006). For example, Schoenbaum et al (2004) reported that experimenter-administered cocaine produces persistent reversal deficits on an odor discrimination task mediated by the orbital frontal cortex in rats, and similar deficits have been seen in non-human primates (Jentsch et al, 2002).…”

“…For example, Schoenbaum et al (2004) reported that experimenter-administered cocaine produces persistent reversal deficits on an odor discrimination task mediated by the orbital frontal cortex in rats, and similar deficits have been seen in non-human primates (Jentsch et al, 2002). However, with one exception (Calu et al, 2007), experiments in which animals were allowed to selfadminister cocaine have not resulted in persistent cognitive deficits.…”