Suppressing Ethanol-Induced Inhibition

Abstract

How alcohol alters synaptic activity and the molecular mechanisms underlying alcohol addiction are issues of social and medical relevance. Maldve et al. analyzed how dopamine receptor (D1) activation modifies the N -methyl-D-aspartate (NMDA) type of glutamate receptor activity in response to ethanol in the nucleus accumbens (a region of the brain associated with addiction). Ethanol inhibited NMDA receptor activity in slice preparations and in cultured neurons. However, stimulation of D1 receptors pharmacologically before ethanol application suppressed the NMDA receptor inhibition by ethanol. Dopamine and adenosine 3′,5′-monophosphate (cAMP)-regulated phosphoprotein of 32 kD (DARPP-32) and the NR1 subunit of the NMDA receptor were phosphorylated in response to D1 agonist. Ethanol treatment of slices also stimulated DARPP-32 phosphorylation, suggesting that ethanol may activate this pathway. The importance of DARPP-32 in ethanol tolerance was confirmed using slices from DARPP-32 knockout mice, which have an NMDA response to ethanol that is unaffected by D1 agonist pretreatment. Additional details about the dopamine-DARPP-32 pathway in alcohol tolerance are discussed by Lovinger. R. E. Maldve, T. A. Zhang, K. Ferrani-Kile, S. S. Schreiber, M. J. Lippmann, G. L. Snyder, A. A. Fienberg, S. W. Leslie, R. A. Gonzales, R. A. Morrisett, DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens. Nature Neurosci. 5 , 641-648 (2002). [Online Journal] D. M. Lovinger, NMDA receptors lose their inhibitions. Nature Neurosci. 5 , 614-616 (2002). [Online Journal]