Dopamine (DA) and glutamate neurotransmission is thought to be critical for psychostimulant drugs to induce immediate early genes (IEGs) in the caudate-putamen (CPu). We report here, however, that the ability of DA and glutamate NMDA receptor antagonists to attenuate amphetamine-evoked c-fos mRNA expression in the CPu depends on environmental context. When given in the home cage, amphetamine induced c-fos mRNA expression predominately in preprodynorphin and preprotachykinin mRNA-containing neurons (Dyn-SP+ cells) in the CPu. In this condition, all of the D1R, D2R and NMDAR antagonists tested dose-dependently decreased c-fos expression in Dyn-SP+ cells. When given in a novel environment, amphetamine induced c-fos mRNA in both Dyn-SP+ and preproenkephalin mRNA-containing neurons (Enk+ cells). In this condition, D1R and non-selective NMDAR antagonists dose-dependently decreased c-fos expression in Dyn-SP+ cells, but neither D2R nor NR2B-selective NMDAR antagonists had no effect. Furthermore, amphetamine-evoked c-fos expression in Enk+ cells was most sensitive to DAR and NMDAR antagonism; the lowest dose of every antagonist tested significantly decreased c-fos expression only in these cells. Finally, novelty-stress also induced c-fos expression in both Dyn-SP+ and Enk+ cells, and this was relatively resistant to all but D1R antagonists. We suggest that the mechanism(s) by which amphetamine evokes c-fos expression in the CPu varies depending on the stimulus (amphetamine vs. stress), the striatal cell population engaged (Dyn-SP+ vs. Enk+ cells), and environmental context (home vs. novel cage). Keywords: dopamine, glutamate, immediate early genes, in situ hybridization, striatum, rat. Psychostimulant drugs are reported to induce immediate early genes (IEGs) only in a specific subclass of projection neurons in the caudate-putamen (CPu) -striatonigral GABAergic neurons that co-express mRNA for dopamine (DA) D1Rs, preprodynorphin and preprotachykinin (Dyn-SP+ cells) (Berretta et al. 1992;Cenci et al. 1992;Berretta et al. 1993;Johansson et al. 1994;Ruskin and Marshall 1994; see Harlan and Garcia 1998 for review). The ability of psychostimulant drugs to induce IEGs in Dyn-SP+ cells involves both DA and glutamate receptors, because both DA (Graybiel et al. 1990;Young et al. 1991;Ruskin and Marshall 1994;LaHoste et al. 2000) and glutamate receptor antagonists (Dragunow et al. 1991;Snyder-Keller 1991;Wang et al. 1994;Konradi et al. 1996) markedly reduce amphetamine-and cocaine-evoked IEG expression in the CPu.These studies have provided important information about the neural circuits engaged by potentially addictive drugs, the neurotransmitter systems involved, and about the initial steps in the cascade of molecular changes that may contribute to Received February 18, 2003; revised manuscript received March 10, 2003; accepted March 11, 2003. Address correspondence and reprint requests to Terry E. Robinson, Department of Psychology (Biopsychology), The University of Michigan, 525 East University Ave., Ann Arbor, M...