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 D2dopamine 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 D2antagonist 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. Synapse 45:230–244, 2002. © 2002 Wiley‐Liss, Inc.