Desensitization of 5-HT(1A) autoreceptors by a low chronic fluoxetine dose effect of the concurrent administration of WAY-100635

摘要

Using microdialysis, receptor autoradiography and in situ hybridization, we examined the effects of fluoxetine alone or with WAY-100635 on: (a) extracellular 5-HT in frontal cortex; and (b) density and sensitivity of 5-HT(1A) autoreceptors in rat brain. WAY-100635 (0.3 mg/kg, s.c.) doubled the increase in extracellular 5-HT produced by fluoxetine (3 mg/kg, i.p.) in frontal cortex. Two-week minipump treatments with these daily doses significantly raised extracellular 5-HT to 275 +/- 33% (fluoxetine) and 245 +/- 10% (fluoxetine plus WAY-100635) of controls. Fluoxetine 3 mg/kg.day desensitized dorsal raphe 5-HT(1A) autoreceptors, an effect prevented by the concurrent WAY-100635 administration. However, WAY-100635 (alone or with fluoxetine) did not change 5-HT(1A) autoreceptor sensitivity. The density of 5-HT(1A) receptors and its encoding mRNA, was unaffected by these treatments. These results suggest that prolonged blockade of 5-HT(1A) receptors in vivo prevents the autoreceptor desensitization induced by fluoxetine but does not result in receptor sensitization.