The Molecular Basis of Dopamine and Glutamate Interactions in the Striatum

Abstract

Publisher Summary Striatal neurons display a high degree of adaptability to changes in dopamine-receptor activation. Drug dependence and withdrawal symptoms after cessation of chronic drug abuse are signs of adaptation to hyperstimulation of dopamine receptors. This chapter summarizes rseveral researches to investigate the cellular components linking dopamine-receptor stimulation with the expression of a particular target gene, c-fos . C-fos is an immediate early gene that is a perfect candidate for studies of neuroplasticity. Psychostimulants, like the indirect dopamine-receptor agonists, cocaine or amphetamine, stimulate c-fos synthesis. In primary striatal cultures, direct activation of D1 receptors with dopamine or D1 agonists also lead to an increase of c-fos levels. D1 dopamine receptor stimulation leads to an increase in cyclic adenosine monophosphate (cAMP) levels, phosphorylation of 133 Ser cAMP-responsive element-binding protein (CREB), and induction of c-fos gene expression. Glutamate-receptor stimulation leads to phosphorylation of 133 Ser cAMP-CERB and induces c-fos gene expression without increasing cAMP levels. The NMDA antagonist MK 801 prevents dopamine-mediated 133 Ser CREB phosphorylation and c-fos gene expression but does not inhibit cAMP induction. Dopamine-receptor-mediated c-fos expression is dependent on functional NMDA receptors and Ca 2+ influx. The route of Ca 2+ influx into the neuron may be crucial for gene expression, because neither L-type Ca 2+ channel blockers nor KCl can reproduce the effects of NMDA antagonists or agonists. The inhibition of dopamine-mediated c-fos gene expression by MK 801 and the activation by glutamate reflect intrastriatal and intraneuronal rather than interneuronal events.