Amphetamine and cocaine induce different patterns of c-fos mRNA expressionin the striatum and subthalamic nucleus depending on environmental context

In the dorsal striatum, there are two major populations of medium spiny pro jection neurons. One population is positive for dynorphin mRNA (DYN+), and these cells project preferentially to the substantia nigra, forming the so- called 'direct pathway'. A second population is positive for enkephalin mRN A (ENK+), and these cells influence the substantia nigra indirectly, via th e globus pallidus and subthalamic nucleus. Psychostimulant drugs, such as a mphetamine and cocaine, are reported to induce immediate early genes (IEGs) in only one subpopulation of dorsal striatal projection neurons, DYN+ cell s. However, this apparent selectivity appears to be a function of environme ntal context. We found that when given in the animal's home cage, amphetami ne and cocaine increased expression of the IEG, c-fos, almost exclusively i n DYN+ cells. However, when given in a novel environment, amphetamine and c ocaine increased c-fos mRNA in both DYN+ and ENK+ cells. Furthermore, amphe tamine and cocaine increased c-fos mRNA expression in the subthalamic nucle us when administered in the novel environment, but not when given at home. We conclude that the neural circuitry engaged by psychostimulant drugs, and their ability to induce specific patterns of gene expression, are determin ed by the environmental context in which they are experienced. This may be related to the ability of environmental novelty to facilitate psychostimula nt drug-induced neuroplasticity.