Spatial and temporal profile of haloperidol-induced immediate-early gene expression and phosphoCREB binding in the dorsal and ventral striatum of amphetamine-sensitized rats.

To determine if D(2) dopamine receptor-mediated nuclear signaling is altered during the development of amphetamine sensitization, we examined the expression of immediate-early gene (IEG) products, Fos, Jun, and Fos-related antigen (FRA), in both controls and amphetamine-sensitized rats after a challenge with the D(2) antagonist haloperidol. When chronic saline- or amphetamine (5 mg/kg, i.p. for 14 days)-treated rats were challenged with 2 mg/kg haloperidol at withdrawal day 3 (w3), more 35-kDa FRA was induced in the ventral striatum of the control group than in the amphetamine-treated rats. In contrast, more Jun and 35-kDa FRA were expressed in the ventral striatum of the amphetamine-treated group than in the controls when haloperidol was given at w10. Topographical analyses indicate that the decrease in FRA immunoreactive neuronal density in amphetamine-treated rats at w3 were located in the dorsolateral caudate/putamen and the nucleus accumbens shell and core subregions. Conversely, the increase in Jun-immunoreactive neurons in amphetamine-treated rats at w10 was observed in the dorsolateral caudate/putamen; in the case of the FRAs, the increase was observed in the nucleus accumbens shell. In addition, the time-dependent profile of IEG expression paralleled the activation of an upstream regulator, cAMP-response element binding protein, in the ventral striatum after haloperidol treatment. These neurochemical changes may be associated with behavioral plasticity, since amphetamine-treated rats displayed a lower amount of locomotor activity when exposed to a novel environment at w3, but had recovered at w10. Overall, the current study reveals that there is a distinct temporal and spatial profile of haloperidol-induced IEG expression and/or CREB phosphorylation in amphetamine-treated rats, suggesting that there is a critical transition between the early and late withdrawal periods.