5-HT(1A) Receptor function in normal subjects on clinical doses of fluoxetine: Blunted temperature and hormone responses to ipsapirone challenge

Serotonergic receptors of the 5-HT(1A) 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 clinical doses of the SSRI, fluoxetine, on 5-HT(1A) receptor function in 15 normal volunteers. Hypothermic and hormone responses to the 5-HT(1A) receptor agonist, 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 four weeks. On fluoxetine, the hypothermic response to ipsapirone was significantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapirone plasma levels were significantly increased by fluoxetine but a pharmacokinetic effect could not have accounted for the observed blunting of 5-HT(1A) receptor mediated effects. These findings confirm and extend previous observations in rodents and humans and indicate that both post-synaptic 5-HT(1A) receptors in the hypothalamus, which mediate hormone responses to 5-HT(1A) agonists, and pre-synaptic 5-HT(1A) receptors which (putatively) mediate the hypothermic response, are rendered subsensitive by chronic SSRI administration. Since fluoxetine did not have significant effects on mood and other psychological variables in these subjects, alterations in 5-HT(1A) receptor function induced by SSRIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopathological states in which these drugs are therapeutically effective. Copyright (C) 1999 American College of Neuropsychopharmacology.