Time course of cocaine-induced behavioral and neurochemical plasticity.

Factors that result in augmented reinstatement, including increased withdrawal period duration and high levels of cocaine consumption, may provide insight into relapse vulnerability. The neural basis of augmented reinstatement may arise from more pronounced changes in plasticity required for reinstatement and/or the emergence of plasticity expressed only during a specific withdrawal period or under specific intake conditions. In this study, we examined the impact of withdrawal period duration and cocaine intake on the magnitude of cocaine-primed reinstatement and extracellular glutamate in the nucleus accumbens, which has been shown to be required for cocaine-primed reinstatement. Rats were assigned to self-administer under conditions resulting in low (2 hours/day; 0.5 mg/kg/infusion, IV) or high (6 hours/day; 1.0 mg/kg/infusion, IV) levels of cocaine intake. After 1, 21 or 60 days of withdrawal, drug seeking and extracellular glutamate levels in the nucleus accumbens were measured before and after a cocaine injection. Cocaine-reinstated lever pressing and elevated extracellular glutamate at every withdrawal time point tested, which is consistent with the conclusion that increased glutamatergic signaling in the nucleus accumbens, is required for cocaine-induced reinstatement. Interestingly, high-intake rats exhibited augmented reinstatement at every time point tested, yet failed to exhibit higher levels of cocaine-induced increases in extracellular glutamate relative to low-intake rats. Our current data indicate that augmented reinstatement in high-intake rats is not due to relative differences in extracellular levels of glutamate in the nucleus accumbens, but rather may stem from intake-dependent plasticity.