Although cocaine shares the ability of fenfluramine to inhibit the synaptic reuptake of serotonin, previous observations from our group suggest that the genomic effects of fenfluramine in the rat striatum are primarily mediated by dopaminergic rather than serotonergic mechanisms. To compare and further understand the nerve cell type(s) targeted by psychotropic drugs, we studied, by use of immunocytochemistry and in situ hybridization, changes in c-fos in brain nerve cells of the caudate putamen and hypothalamus following acute cocaine or fenfluramine exposure. Predictably, both drugs (20 mg/kg; i.p.) evoked rapid but transient increases in c-fos in the caudate putamen. In addition, double labeling immunocytochemistry indicated that Fos-like protein was expressed preferentially in striatal neurons containing the protein phosphatase inhibitor, DARPP-32. In contrast, fenfluramine, but not cocaine, elicited c-fos mRNA and Fos-like protein in the neuroendocrine paraventricular nucleus (PVN) of the hypothalamus despite the fact that both drugs are known to be equally capable to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. This difference is discussed in terms of serotonergic, dopaminergic and DARPP-32 input to hypothalamic neurons and tanycytes associated with adrenocorticotropin hormone (ACTH) secretion. To further identify the phenotypes of nerve cells expressing c-fos by fenfluramine in the PVN, it was demonstrated that the immediate-early gene was induced in a subpopulation of neurons constitutively expressing nitric oxide synthase (NOS). Taken together, we identified a number of common and disparate actions of cocaine and fenfluramine in striatal and hypothalamic tissue, thereby suggesting that c-fos induction in these two brain structures is differentially regulated by intrinsic events in addition to neuronal phenotype. We propose that the genomic effects produced by these two drugs represent part of a general dopaminergic and glutamateric mechanism by which monoamine reuptake inhibitor drugs affect specific brain nerve cells.