P.6.a.007 The role of glutamatergic receptors within the dopaminergic reinforcement system in alcohol-dependent phenotypes

Abstract

Of the ionotropic glutamatergic receptors, the NMDA receptor is clearly implicated in the acute and chronic effects of ethanol; however, the role of the AMPA receptor in mediating the effects of ethanol in vivo is as yet unclear. Using mice deficient in the AMPA receptor subunit GluR1 (GluR1−/− mice), we investigated whether the AMPA receptor had a significant role in mediating the effects of ethanol. GluR1−/− mice showed greater locomotor activity in a novel environment, but by the fifth day of repeated testing their activity was the same as that of wild-type mice. In contrast to their enhanced locomotor activity, on an accelerating rotarod GluR1−/− mice performed consistently worse than wild-types. With regard to the effects of ethanol on motor responses, GluR1−/− mice did not differ significantly from wild-type mice in ethanol’s sedative or incoordinating effects. However, the GluR1−/− mice were insensitive to the hypothermic effects of a hypnotic dose of ethanol in contrast to wild-types; this effect was dissociable from the hypnotic effects of ethanol. Further, tolerance to ethanol developed equally for GluR1−/− mice versus wild-type mice. In terms of alcohol drinking behavior, compared to wild-types, GluR1−/− mice differed neither in the acquisition of voluntary ethanol consumption nor in stress-induced ethanol drinking, nor in the expression of an alcohol deprivation effect (ADE) which is used as a model of relapse-like drinking behavior. In summary, although the loss of a hypothermic effect of ethanol in GluR1−/− mice indicates a critical role for the AMPA receptors in this effect, the GluR1 subunit of the AMPA receptor does not seem to play a critical role in the etiology of alcohol dependence. However, changes observed in activity patterns may be related to the putative role of AMPA receptors in attention deficit hyperactivity disorder.