ACAMPROSATE ENHANCES N-METHYL-D-APARTATE RECEPTOR-MEDIATED NEUROTRANSMISSION BUT INHIBITS PRESYNAPTIC GABA(B) RECEPTORS IN NUCLEUS-ACCUMBENS NEURONS

Acamprosate (calcium acetylhomotaurine) is used therapeutically in Eur ope to reduce relapse in weaned alcoholics, However, the mechanisms of acamprosate action in the central nervous system are still obscure, a lthough early studies suggested an action on GABA receptors. The nucle us accumbens (NAcc) is a brain region thought to underlie ethanol rein forcement. Recent studies from our laboratory have demonstrated that e thanol 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 NA cc 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-nitroqui noxaline-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 r esting membrane properties of NAcc neurons. However, 300 mu M acampros ate significantly increased the NMDA receptor-mediated components of E PSP/Cs (NMDA-EPSP/Cs) with recovery on washout. In contrast, 300 mu M acamprosate had no significant effect on the non-NMDA receptor compone nt of the EPSP/Cs (non-NMDA-EPSP/Cs). To test acamprosate actions on t he GABA system, we superfused 60 mu M d-APV and 20 mu M CNQX to block glutamatergic transmission and evoked monosynaptic GABA(A) receptor-me diated synaptic responses within the NAcc. Acamprosate (300 mu M) did not change these monosynaptic GABA(A)-IPSCs. We also used a paired-pul se paradigm to test whether acamprosate could act on presynaptic GABA( B) autoreceptors, in the presence of d-APV and CNQX to block glutamate rgic transmission, Like 0.5 mu M CGP 34358 (a GABA(B) receptor blocker ), acamprosate significantly decreased the paired-purse inhibition (PP I) of GABA(A)-IPSCs at short interstimulus intervals (ISIs). Thus, aca mprosate may concomitantly enhance NMDA-EPSP/Cs while blacking presyna ptic GABA(B) receptor-mediated inhibition of GABA release. These resul ts 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.