Abstract :
Chronic cocaine treatment ultimately reduces metabolic responses in rat forebrain regions, which persists during early withdrawal. However, behavioral and neurochemical responses to cocaine challenge are sensitized during withdrawal, suggesting that enhanced responding is related to relapse. We used in situhybridization histochemistry to examine zif268 mRNA expression as an indicator of physiological activity in neurons of the caudate-putamen (CP), nucleus accumbens (NAc) and medial prefrontal cortex upon challenge with cocaine HCl (30 mg/kg, i.p.) or saline vehicle seven days after cessation of daily cocaine (10 mg/kg i.p.) or saline treatment for two weeks. Neuronal activity in the CP and NAc shell increased following both acute cocaine and challenge during withdrawal compared to saline treatment. In contrast, neurons in the infralimbic cortex (which innervates the NAc shell) showed little activation following acute cocaine, but augmented activity upon challenge during withdrawal; prelimbic cortical neurons (which supply the NAc core) were not sensitized. In order to determine whether zif268 mRNA expression was selectively induced in cortical neurons, fluorogold was injected into the NAc shell. This retrograde tracer labeled neurons in the infralimbic cortex, basolateral amygdala, ventral hippocampus, subiculum and other regions. Cocaine challenge during withdrawal induced zif268 mRNA expression only in labeled infralimbic cortical neurons. Thus, chronic cocaine sensitized responses in cortical neurons that innervate the NAc shell. Activation of these same cortical circuits by cocaine cues might stimulate reinforcement thereby triggering drug craving and relapse
