Sodium acamprosate and calcium exert additive effects on nucleus accumbens dopamine in the rat

Abstract

Acamprosate (Campral® – calcium‐bis[N‐acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously, we suggested that acamprosate reduces ethanol intake by increasing dopamine in the nucleus accumbens (nAc), thereby partly substituting for alcohol's dopamine releasing effect. An experimental study suggested the calcium moiety of acamprosate to be the active component of the drug and to mediate the relapse preventing effect. The aim of the present study was to, by means of reversed in vivo microdialysis, elucidate if the dopamine elevating properties of acamprosate are mediated by N‐acetylhomotaurine or by the calcium moiety. Male rats were equipped with a microdialysis probe in the nAc and received acute local treatment with regular acamprosate (CaAcamp 0.5 mM), calcium chloride (CaCl2 0.5 mM), sodium acamprosate (NaAcamp 0.5–1 mM), the glycine receptor (GlyR) antagonist strychnine (Stry 20 μM), or vehicle. In all experiments, extracellular levels of dopamine and taurine were examined. We found that local perfusion with both CaAcamp and CaCl2 increased dopamine levels in a GlyR‐dependent manner. NaAcamp did not influence dopamine levels, but concomitant administration with CaCl2 resulted in an additive dopamine output compared to the drugs administrated alone. We also found CaAcamp and the combination of CaCl2 and NaAcamp to increase accumbal taurine levels, suggesting that CaAcamp may act indirectly on GlyRs via taurine release. The present results indicate that both N‐acetylhomotaurine and the calcium moiety of acamprosate have dopamine elevating properties within the nAc and that, in this respect, these substances are beneficial in combination.

Acamprosate reduces ethanol intake in the rat by a combined action of different drug components

“…In the present experiments systemic administration of sodium acamprosate alone also elevated dopamine, whereas no such effect was appearant following local perfusion 15 , suggesting that the dopamine elevating property of sodium acamprosate is not mediated through local microcircuits in the nAc. While extracellular taurine was not signi cantly increased by systemic calcium administration, there was a robust increase in response to sodium acamprosate as well as to the two treatments in combination.…”

“…Hence, in the present drinking experiment dopamine should be elevated for at least 50 minutes following introduction of the ethanol bottle. Interestingly, when calcium was administered together with sodium acamprosate, the dopamine output was larger and more prolonged than observed after either agent by itself suggesting that the two substances act in concert within the mesolimbic dopamine system and in line with ndings following local drug administration 15 .…”

“…GlyRs in the nAc were previously shown to be of importance both for the dopamine elevating properties of acamprosate and for its ethanol-intake reducing effect, as local application of strychnine into the nAc reversed both effects 9,14 . Recently, we found calcium chloride to elevate dopamine in a similar GlyR sensitive manner and that calcium chloride combined with sodium acamprosate produced an additive increase in dopamine 15 . Acamprosate has also been shown to increase nAc taurine levels 15,16 , providing the possibility for an indirect activation of GlyRs.…”

“…Recently, we found calcium chloride to elevate dopamine in a similar GlyR sensitive manner and that calcium chloride combined with sodium acamprosate produced an additive increase in dopamine 15 . Acamprosate has also been shown to increase nAc taurine levels 15,16 , providing the possibility for an indirect activation of GlyRs.…”

“…In the microdialysis part of the study, the hypothesized acamprosate-induced dopamine elevation was here con rmed. Further, based on recent studies showing that calcium salts possess acamprosate-like effects 12,13 and release dopamine after local application in the nAc 15 , the hypothesis that also a systemic injection with calcium increases dopamine was con rmed, although during a comparably short time period (80 minutes). This is, however, most likely functionally relevant, since animals consume most of their daily ethanol intake during the rst hour after introduction of the ethanol bottle.…”