AMPHETAMINE AND DOPAMINE-INDUCED IMMEDIATE-EARLY GENE-EXPRESSION IN STRIATAL NEURONS DEPENDS ON POSTSYNAPTIC NMDA RECEPTORS AND CALCIUM

Amphetamine and cocaine induce the expression of both immediate early genes (IEGs) and neuropeptide genes in rat striatum. Despite the demon strated dependence of these effects on D-1 dopamine receptors, which a ctivate the cyclic AMP pathway, there are several reports that ampheta mine and cocaine-induced IEG expression can be inhibited in striatum i n vivo by NMDA receptor antagonists. We find that in vivo, the NMDA re ceptor antagonist MK-801 inhibits amphetamine induction of c-fos acute ly and also prevents downregulation of IEG expression with chronic amp hetamine administration. Such observations raise the question of wheth er dopamine/glutamate interactions occur al the level of corticostriat al and mesostriatal circuitry or within striatal neurons. Therefore, w e studied dissociated striatal cultures in which midbrain and cortical presynaptic inputs are removed. In these cultures, we find that dopam ine- or forskolin-mediated IEG induction requires Ca2+ entry via NMDA receptors but not via L-type Ca2+ channels. Moreover, blockade of NMDA receptors diminishes the ability of dopamine to induce phosphorylatio n of the cyclic AMP responsive element binding protein CREB. Although these results do not rule out a role for circuit-level dopamine/glutam ate interactions, they demonstrate a requirement at the cellular level for interactions between the cyclic AMP and NMDA receptor pathways in dopamine-regulated gene expression in striatal neurons.