Desensitization of 5-HT1A autoreceptors by a low chronic fluoxetine dose effect of the concurrent administration of WAY-100635

Using microdialysis, receptor autoradiography and in situ hybridization, we examined the effects of fluoxetine alone or with WAY-100635 on: (a) extrac ellular 5-HT in frontal cortex; and (b) density and sensitivity of 5-HT1A a utoreceptors in rat brain. WAY-100635 (0.3 mg/kg, s.c.) doubled the increas e in extracellular 5-HT produced by fluoxetine (3 mg/kg, i.p.) in frontal c ortex. Two-week minipump treatments with these daily doses significantly ra ised extracellular 5-HT to 275 +/- 33% (fluoxetine) and 245 +/- 10% (fluoxe tine plus WAY-100635) of controls. Fluoxetine 3 mg/kg day desensitized dors al raphe 5-HT1A autoreceptors, an effect prevented by the concurrent WAY-10 0635 administration. However, WAY-100635 (alone or with fluoxetine) did not change 5-HT1A autoreceptor sensitivity. The density of 5-HT1A receptors an d its encoding mRNA, was unaffected by these treatments. These results sugg est that prolonged blockade of 5-HT1A receptors in vivo prevents the autore ceptor desensitization induced by fluoxetine but does not result in recepto r sensitization. (C) 2000 American College of Neuropsychopharmacology. Publ ished by Elsevier Science Inc.