Effect of alcohols on G-protein coupling of serotonin 1A receptors from bovine hippocampus

Abstract

The serotonin 1A (5-hydroxytryptamine [5-HT] 1A) receptors are members of a superfamily of seven transmembrane domain receptors that couple to G-proteins. Serotonergic signalling has been shown to play an important role in alcohol intake, preference and dependence. G-protein coupling of the 5-HT 1A receptor serves as an important determinant for serotonergic signalling. We have studied the effect of alcohols on G-protein coupling of bovine hippocampal 5-HT 1A receptors in native membranes. This was done by monitoring the modulation of ligand (agonist and antagonist) binding in presence of alcohols by guanosine-5′- O-(3-thiotriphosphate) (GTP-γ-S), a non-hydrolyzable analogue of GTP. Our results show that alcohols inhibit the specific binding of the agonist 8-hydroxy-2-(di- N-propylamino)tetralin (except in case of ethanol) and the antagonist 4-(2′-methoxy)-phenyl-1-[2′-( N-2″-pyridinyl)- p-fluorobenzamido]ethyl-piperazine to 5-HT 1A receptors in a concentration-dependent manner. Further, we show here that the action of alcohols on the bovine hippocampal 5-HT 1A receptors could be modulated by guanine nucleotides and that the mode of action of ethanol on the 5-HT 1A receptor may be quite different than that of other alcohols. The effect of GTP-γ-S on the agonist and the antagonist binding is found to be markedly different. Our results could be significant in the overall context of the role of G-protein coupling in serotonergic neurotransmission and its role in alcohol tolerance and dependence.