Amphetamine and Dopamine-Induced Immediate Early Gene Expression in Striatal Neurons Depends on Postsynaptic NMDA Receptors and Calcium

• DOI: 10.1523/jneurosci.16-13-04231.1996
• Publication Date: 2018-04-02T18:35:53Z
• Authors: Christine Konradi; Jean-Christophe L...; Steven E. Hyman
• Keywords: Male; Neurons; Binding Sites; Base Sequence; Dopamine; Receptors, Dopamine D1; Molecular Sequence Data; Gene Expression; Receptors, N-Methyl-D-Aspartate; Corpus Striatum; Rats; Rats, Sprague-Dawley; Amphetamine; 03 medical and health sciences; 0302 clinical medicine; Synapses; Animals; Calcium; Dizocilpine Maleate; Oligonucleotide Probes; Genes, Immediate-Early

Amphetamine and cocaine induce the expression of both immediate early genes (IEGs) and neuropeptide genes in rat striatum. Despite the demonstrated dependence of these effects on D1dopamine receptors, which activate the cyclic AMP pathway, there are several reports that amphetamine and cocaine-induced IEG expression can be inhibited in striatumin vivoby NMDA receptor antagonists. We find thatin vivo,the NMDA receptor antagonist MK-801 inhibits amphetamine induction ofc-fosacutely and also prevents downregulation of IEG expression with chronic amphetamine administration. Such observations raise the question of whether dopamine/glutamate interactions occur at the level of corticostriatal and mesostriatal circuitry or within striatal neurons. Therefore, we studied dissociated striatal cultures in which midbrain and cortical presynaptic inputs are removed. In these cultures, we find that dopamine- 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 phosphorylation of the cyclic AMP responsive element binding protein CREB. Although these results do not rule out a role for circuit-level dopamine/glutamate 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.