Biphasic effect of acamprosate on NMDA but not on GABA A receptors in spontaneous rhythmic activity from the isolated neonatal rat respiratory network

Abstract

Acamprosate (calcium acetylhomotaurinate) has been shown to be effective in attenuating relapse in human alcoholics. The precise mechanism for acamprosate has been yet to be determined as there may be multiple sites of action for this drug. We investigated the mechanism of action of acamprosate on a spontaneous rhythmic activity recorded from hypoglossal nerve rootlet (XII) in neonatal rat brainstem slices. At 30 μM, acamprosate reversibly increased burst amplitude and reduced burst frequency, whereas at higher concentrations (100–400 μM) it induced a reversible and concentration-dependent inhibition of this activity. Interestingly, acamprosate (30 μM) enhanced the effects of low NMDA-induced excitation (1.5 μM), but inhibited higher NMDA-induced excitation (2.5, 5 μM) by 50–70%, demonstrating a differential effect on NMDA-induced excitation. Blockade of GABA A receptors did not affect the increase in amplitude of 30 μM acamprosate and partially abolished the inhibitory effects of 200 μM acamprosate. At 200 μM, acamprosate reduced high NMDA-induced excitation and abolished NMDA-evoked excitatory tonic phase, suggesting that excitatory effect of low concentrations of acamprosate mainly involved NMDA receptors, while the inhibitory effects at higher concentration included an increase in GABA A-mediated inhibition with a reduction of NMDA-mediated excitation. Consequently, combined blockade of both receptors abolished all effects of acamprosate tested at all concentrations. These results show that the effects of acamprosate are mediated via both GABA A and NMDA receptors and suggest a partial co-agonist role on NMDA receptors, at the level of a spontaneously active network.