Emerging evidence indicates that group I metabotropic glutamate receptors (mGluRs) play a significant role in the addictive plasticity of striatal neurons. The plasticity is probably mediated by altered cellular gene expression in relation to stimulation of group I mGluRs and associative signaling proteins. In this study, we investigated the signaling linkage of surface group I mGluRs to the nuclear transcription factor cAMP response element-binding protein (CREB) in cultured primary striatal neurons. We found that selective activation of group I mGluRs (primarily the mGluR5 subtype) was able to up-regulate CREB phosphorylation in neurochemically identified gamma-aminobutyratergic neurons but not glia. The CREB phosphorylation was independent of kainate/AMPA receptors but partially dependent of concomitant NMDA receptor activation. Because L-type voltage-operated Ca(2+) channel inhibitors substantially blocked the CREB phosphorylation, group I receptors are believed to lead to activation of L-type Ca(2+) channels, resulting in the CREB phosphorylation. Indeed, further studies on signaling pathways showed that group I mGluRs, by activating phospholipase C, induced a rapid and transient Ca(2+) release from the 1,4,5-triphosphate-sensitive rather than ryanodine-sensitive Ca(2+) store. The transient Ca(2+) rise in turn triggered the opening of L-type Ca(2+) channels, resulting in a progressively larger increase in cytoplasmic Ca(2+) levels that is responsible for subsequent CREB phosphorylation. These results indicate that Ca(2+)-coupled group I mGluRs possess the ability to up-regulate CREB phosphorylation via the intracellular Ca(2+) release-induced activation of L-type Ca(2+) channels and, to a lesser extent, NMDA receptors in primary striatal neurons.