Chronic treatment with the antidepressant fluoxetine may lead to changes in the properties of pre- and postsynaptic 5-HT 1A 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-HT 1A receptors using different techniques. The density of 5-HT 1A receptors was unchanged in fluoxetine-treated rats vs. vehicle group. Stimulation of ( 35 S)GTPγS 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 (ED 50 in vehicle = 2.1 μg/kg, i.v.) was also attenuated in rats treated with fluoxetine (ED 50 =4.7 μg/kg). In contrast, a significant increase on (±)8-OH-DPAT-induced stimulation of ( 35 S)GTPγS 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-HT 1A autoreceptors occurs at G protein level. Moreover, a relevant finding is the region-specific hypersensitivity of postsynaptic 5-HT 1A receptors, in the hippocampus but not in entorhinal cortex, following chronic fluoxetine. These differential adaptive changes in brain 5-HT 1A receptors could underlie the mechanism of action of antidepressants and also contribute to their clinical effects.
Neuropharmacology – Elsevier
Published: Jan 1, 2003
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