Chronic fluoxetine induces changes in G protein coupling at pre and postsynaptic 5-HT1A receptors in rat brain

Chronic treatment with the antidepressant fluoxetine may lead to changes in the properties of pre- and postsynaptic 5-HT1A receptors due to modifications in the receptor-G protein coupling process. We have evaluated, in rats, the effect of chronic fluoxetine (10 mg/kg/day) at brain 5-HT1A receptors using different techniques. The density of 5-HT1A receptors was unchanged in fluoxetine treated rats vs. vehicle group. Stimulation of [S-35]GTPgammaS binding induced by (+/-)8-OH-DPAT was significantly attenuated in dorsal raphe nucleus after fluoxetine (+3.7 vs. +31.2% in vehicle). The inhibition of dorsal raphe firing by (+/-)8-OH-DPAT (ED50 in vehicle = 2.1 mug/kg, i.v.) was also attenuated in rats treated with fluoxetine (ED50 = 4.7 mug/kg). In contrast, a significant increase on (+/-)8-OH-DPAT-induced stimulation of [S-35]GTPgammaS binding was observed in CA(1) (+53.4 vs.+20.2% in vehicle) and dentate gyrus (+105.7 vs. +52.6% in vehicle) but not in entorhinal cortex. Our data demonstrate that fluoxetine-induced desensitization of 5-HT1A autoreceptors occurs at G protein level. Moreover, a relevant finding is the region-specific hypersensitivity of postsynaptic 5-HT1A receptors, in the hippocampus but not in entorhinal cortex, following chronic fluoxetine. These differential adaptive changes in brain 5-HT1A receptors could underlie the mechanism of action of antidepressants and also contribute to their clinical effects. (C) 2002 Elsevier Science Ltd. All rights reserved.