Amphetamine-induced behavior, dopamine release, and c-fos mRNA expression:Modulation by environmental novelty

We have shown recently that the psychomotor activating effects of amphetami ne in the rat are much greater when this drug is administered in associatio n with environmental novelty than when it is given in a home environment. T he main purpose of the present study was to explore the neural basis of thi s phenomenon, We found, using in situ hybridization of c-fos mRNA, that the pattern of neuronal activation in the cortex, in the caudate, in the shell and core of the nucleus accumbens, and in other subcortical structures was markedly different when amphetamine (2.0 mg/kg, i.p.) was given in associa tion with exposure to environmental novelty relative to when it was given a t home. In most brain regions the magnitude of c-fos expression was over tw o times greater in rats given amphetamine plus novelty than in rats given a mphetamine alone. In contrast, an in vivo microdialysis study indicated tha t environmental novelty did not affect amphetamine-induced dopamine release in either caudate or nucleus accumbens. Furthermore, a unilateral 6-hydrox ydopamine lesion of the mesostriatal dopamine system reduced amphetamine- b ut not novelty-induced c-fos expression. Finally, we found no differences i n the amount of corticosterone secreted after exposure to novelty, amphetam ine, or both, suggesting that corticosterone does not play a critical role in the ability of novelty to modulate amphetamine-induced psychomotor activ ation. In conclusion, it seems that environmental novelty alters the neurob iological effects of amphetamine independently of the primary neuropharmaco logical actions of this drug in the striatum.