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Acamprosate (calcium acetylhomotaurine) is used therapeutically in Europe to reduce relapse in weaned alcoholics. However, the mechanisms of acamprosate action in the central nervous system are still obscure, although early studies suggested an action on GABA receptors. The nucleus accumbens (NAcc) is a brain region thought to underlie ethanol reinforcement. Recent studies from our laboratory have demonstrated that ethanol inhibits both N-methyl-D-aspartate (NMDA) and non-NMDA types of glutamatergic synaptic transmission in the NAcc.1,2 In the present study, we used voltage- and current-clamp intracellular recording of NAcc core neurons in a slice preparation to examine acamprosate actions on resting membrane properties and pharmacologically isolated synaptic responses. We isolated NMDA and non-NMDA receptor-mediated excitatory postsynaptic potentials or currents (EPSP/Cs) with 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovaler-ate (d-APV), respectively. Bicuculline was also included to block GABAA receptors. Superfusion of acamprosate (5, 50, and 300 μM) did not alter the resting membrane properties of NAcc neurons. However, 300 μM acamprosate significantly increased the NMDA receptor-mediated components of EPSP/Cs (NMDA-EPSP/Cs) with recovery on washout. In contrast, 300 μM acamprosate had no significant effect on the non-NMDA receptor component of the EPSP/Cs (non-NMDA-EPSP/Cs). To test acamprosate actions on the GABA system, we superfused 60 μM d-APV and 20 μM CNQX to block glutamatergic transmission and evoked monosynaptic GABAA receptor-mediated synaptic responses within the NAcc. Acamprosate (300 μM) did not change these monosynaptic GABAA-IPSCs. We also used a paired-pulse paradigm to test whether acamprosate could act on presynaptic GABAB, autoreceptors, in the presence of d-APV and CNQX to block glutamatergic transmission. Like 0.5 μM CGP 34358 (a GABAB receptor blocker), acamprosate significantly decreased the paired-pulse inhibition (PPI) of GABAA-IPSCs at short interstimulus intervals (ISIs). Thus, acamprosate may concomitantly enhance NMDA-EPSP/Cs while blocking presynaptic GABAB receptor-mediated inhibition of GABA release. These results suggest that acamprosate's clinical efficacy in preventing relapse in weaned alcoholics could derive from its interactions with both the glutamatergic and GABAergic systems in the NAcc.

Synaptic Transmission, Alcohol, Ethanol, EPSPs, NMDA Receptors.