Decreased G-protein coupling of serotonin 5-HT1A receptors in the brain of 5-HT1B knockout mouse

The firing of central serotonin (5-hydroxytryptamine, 5-HT) neurons and their capacity to release 5-HT are subjected to a receptor-mediated auto-control via 5-HT1A and 5-HT1B receptors respectively located on the somata/dendrites (5-HT1A autoreceptors) and preterminal axon arborizations (5-HT1B autoreceptors) of these neurons. To further characterize mutual adaptations of these two receptor subtypes in the absence of one of them, activation of G-protein coupling by agonist was measured and compared to wildtype (WT) in 5-HT1A and 5-HT1B homozygous knockout (KO) mice. As expected, in WT, the non-selective 5-HT1A/1B receptor agonist 5-carboxyamidotryptamine (5-CT) Stimulated guanosine 5'-O-(gamma-[S-35]thio)triphosphate ([S-35]GTP(gamma)S) incorporation in many brain regions endowed with one and/or the other receptor, In the respective KOs. no stimulation was measured in regions known to express only or mainly the deleted receptor. In the 5-HT1A KOs, the amplitude of G-protein activation in regions endowed with 5-HT1B receptors was unchanged by comparison to WT. In the 5-HT1B KOs, the magnitude of the 5-CT stimulation was the same as WT in all regions containing 5-HT1A receptors, except in the amygdala. where it was significantly lower, even if this region was one of the most strongly activated in the WT. A similar result was obtained in the amygdala. of 5-HT1B KOs after activation by the selective 5-HT1A receptor agonist R-(+)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). Under these conditions, however, there was in addition a significant lowering of the stimulated (but not basal) [S-35]GTP(gamma)S incorporation by comparison to WT in all regions endowed with 5-HT1A receptors, including the dorsal raphe nucleus. Thus, eventhough agonist radioligand binding to either 5-HT1A or 5-HT1B receptors is unchanged in the reciprocal KOs. it appears that a compensatory decrease in the efficiency of G-protein coupling to 5-HT1A receptors has developed in the 5-HT1B mutant. This could represent the first indication of a crosstalk between these two 5-HT receptor subtypes, at least in brain regions where they are co localized in the same neurons. (C) 2002 Elsevier Science Ltd. All rights reserved.