Acamprosate enhances N-methyl-D-apartate receptor-mediated neurotransmission but inhibits presynaptic GABAB receptors in nucleus accumbens neurons

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-cramp 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-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovalerate (d-APV), respectively, Bicuculline was also included to block GABA(A) receptors. Superfusion of acamprosate (5, 50, and 300 mu M) did not alter the resting membrane properties of NAcc neurons. However, 300 mu M acamprosate significantly increased the NMDA receptor-mediated components of EPSP/Cs (NMDA-EPSP/Cs) with recovery on washout. In contrast, 300 mu M 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 mu M d-APV and 20 mu M CNQX to block glutamatergic transmission and evoked monosynaptic GABA(A) receptor-mediated synaptic responses within the NAcc. Acamprosate (300 mu M) did not change these monosynaptic GABA(A)-IPSCs. We also used a paired-pulse paradigm to test whether acamprosate could act on presynaptic GABA(B) autoreceptors, in the presence of d-APV and CNQX to block glutamatergic transmission, Like 0.5 mu M CGP 34358 (a GABA(B) receptor blocker), acamprosate significantly decreased the paired-purse inhibition (PPI) of GABA(A)-IPSCs at short interstimulus intervals (ISIs). Thus, acamprosate may concomitantly enhance NMDA-EPSP/Cs while blacking presynaptic GABA(B) 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.