The neural basis of sensitization was examined by assessing the expression of zif/268 mRNA in cortical and striatal neurons following cocaine challenge (30 mg kg-1, i.p.) after 2 weeks of daily treatment with cocaine or saline vehicle. Acute cocaine challenge induced zif/268 mRNA expression in neurons of the caudate putamen (CP), nucleus accumbens (NAc) shell and prelimbic cortex. Chronic cocaine treatment attenuated zif/268 mRNA expression in these regions, although zif/268 mRNA response in CP neurons recovered after 7 days of withdrawal. In contrast, cocaine challenge during withdrawal augmented zif/268 response in neurons of the infralimbic cortex and olfactory tubercle. Sensitized activity in these regions could serve to amplify mesolimbic dopamine and NAc responses, and might provide a critical stimulus to drug craving.