ACAMPROSATE (CALCIUM ACETYLHOMOTAURINATE) ENHANCES THE N-METHYL-D-ASPARTATE COMPONENT OF EXCITATORY NEUROTRANSMISSION IN RAT HIPPOCAMPAL CA1 NEURONS IN-VITRO

The taurinate analog acamprosate (calcium acetylhomotaurinate) has rec eived considerable attention in Europe for its ability to prevent rela pse in abstained alcoholics. To determine the mechanism of acamprosate actions in the CNS, we superfused acamprosate onto rat hippocampal CA 1 pyramidal neurons using an in vitro slice preparation, In current- a nd voltage-clamp recordings, acamprosate (100 to 1000 mu M) superfusio n had little effect on resting membrane potential or input slope resis tance. Acamprosate had no effect on Ca2+-dependent action potentials w hen tetrodotoxin was used to block Na+ spikes. In whole-cell voltage-c lamp recordings, and in the presence of tetraethylammonium and Cs+ to block K+ channels, acamprosate had little effect on a Cd2+-sensitive i nward current likely to be a high voltage-activated Ca2+ current. Howe ver, in both current- and voltage-clamp recordings, acamprosate signif icantly increased the N-methyl-D-aspartate (NMDA) component of excitat ory postsynaptic potentials evoked by stimulation of Schaffer collater als in the stratum radiatum, in the presence of the selective non-NMDA pha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid kainate) glut amate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and the GABA(A) receptor antagonist bicuculline. Acamprosate had inconsistent or no effects on the stratum radiatum-evoked non-NMDA component of th e excitatory postsynaptic potentials, in the presence of bicuculline a nd the NMDA antagonist DL-2-amino-5-phosphonovalerate. Acamprosate, on average, had little effect on the late inhibitory postsynaptic potent ials thought to be mediated by GABA(B) receptors. In the presence of t etrodotoxin to block synaptic transmission, acamprosate dramatically i ncreased inward current responses in most CA1 neurons to exogenous NMD A applied by pressure or superfusion, with reversal on washout of acam prosate. These data suggest that acamprosate may act postsynaptically to increase the NMDA component of excitatory transmission to hippocamp al CA1 pyramidal neurons. Considering the known interaction of ethanol with NMDA receptors, this acamprosate modulation of NMDA receptor-med iated neurotransmission could provide a mechanism of action underlying the clinical efficacy of acamprosate.