The role of metabotropic glutamate receptors and associated cell signaling pathways in the acute sedative-hypnotic effects of ethanol

Metabotropic glutamate receptors (mGluRs) mediate the slower, modulatory effects of glutamate neurotransmission. In this capacity, mGluRs can alter signaling at both NMDA and GABAA receptors, the receptors which are thought to mediate the majority of ethanol's sedative-hypnotic properties. The goal of the present study was to examine the role of mGluRs, and the intracellular signaling pathways with which they associate, in mediating the acute sedative-hypnotic properties of ethanol. The first set of experiments examines the effects of three selective mGluR antagonists on the sedative and hypnotic effects of acutely administered high doses of ethanol. Inhibition of mGluR5 increased both ethanol-induced locomotor deficits and loss of righting reflex (LORR). Inhibition of mGluR5 also produced an increase in ketamine-induced LORR, but did not alter pentobarbital or midazolam-induced LORR. These data suggest that inhibition of mGluR5 selectively enhances the sedative-hypnotic effects of ethanol, and that this enhancement may be related to decreased mGluR5-NMDAR interactions. The second set of experiments examines the effects of acute ethanol treatment on protein kinase C-gamma (PKC[gamma]) phosphorylation over time. Acute ethanol treatment increased phosphorylated PKC[gamma] (pPKC[gamma]) immunoreactivity in the nucleus accumbens and the central amygdala and decreased pPKC[gamma] immunoreactivity in the basolateral amygdala. Moreover, these effects were time dependent. These data suggest that acute ethanol alters the abundance of the catalytically competent form of PKC[gamma] and these changes may mediate some of the acute behavioral effects of ethanol. The third set of experiments examines the effects of acute ethanol treatment and mGluR5 inhibition on extracellular-signal regulated kinase (ERK) phosphorylation. Acute ethanol treatment rapidly increased pERK immunoreactivity in the nucleus accumbens shell and the central amygdala and produced delayed increases in the basolateral amygdala, thalamus, and hypothalamus. pERK immunoreactivity was decreased in the nucleus accumbens core. Following mGluR5 inhibition, the effects of ethanol in the nucleus accumbens were reduced and the effects of ethanol in the basolateral amygdala and the hypothalamus were enhanced. Finally, inhibition of ERK phosphorylation reduced ethanol-induced LORR, suggesting that these changes in pERK may be related to the sedative-hypnotic effects of ethanol. These studies identified signaling pathways that may mediate the sedative-hypnotic effects of ethanol.