5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: Blunted temperature and hormone responses to ipsapirone challenge

Serotonergic receptors of the 5-HT1A subtype have been suggested to play a- pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of c linical doses of the SSRI, fluoxetine, on 5-HT1A receptor function in 75 no rmal volunteers. Hypothermic and hormone responses to the 5-HT1A receptor a gonist, ipsapirone (0.3 mg per kg, per os) were examined after two weeks of placebo and again, after the subjects had been receiving fluoxetine for fo ur weeks. On fluoxetine, the hypothermic response to ipsapirone was signifi cantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapiro ne plasma levels were significantly increased by fluoxetine but a pharmacok inetic effect could not have accounted for the observed blunting of 5-HT1A receptor mediated effects. These findings confirm and extend previous obser vations in rodents and humans and indicate that both post-synaptic 5-HT1A r eceptors in the hypothalamus, which mediate hormone responses to 5-HT1A ago nists, and pre-synaptic 5-HT1A receptors which (putatively) mediate the hyp othermic response, are rendered subsensitive by chronic SSRI administration . Since fluoxetine did not have significant effects on mood and other psych ological variables in these subjects, alterations in 5-HT1A receptor functi on induced by SSXIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopa thological states in which these drugs are therapeutically effective. (C) 1 999 American College of Neuropsychopharmacology. Published by Elsevier Scie nce Inc.