5-HT1A Receptor Function in Normal Subjects on Clinical Doses of Fluoxetine: Blunted Temperature and Hormone Responses to Ipsapirone Challenge Bernard Lerer, M.D., Yevgenia Gelfin, M.D., Malka Gorfine, M.A., Bruno Allolio, M.D., K. Peter Lesch, M.D., and Michael E. Newman, Ph.D. Serotonergic receptors of the 5-HT1A subtype have been extend previous observations in rodents and humans and suggested to play a pivotal role in the mechanism of action indicate that both post-synaptic 5-HT1A receptors in the of antidepressant drugs, including specific serotonin hypothalamus, which mediate hormone responses to 5-HT1A reuptake inhibitors (SSRIs). We examined the effect of agonists, and pre-synaptic 5-HT1A receptors which clinical doses of the SSRI, fluoxetine, on 5-HT1A receptor (putatively) mediate the hypothermic response, are rendered function in 15 normal volunteers. Hypothermic and subsensitive by chronic SSRI administration. Since hormone responses to the 5-HT1A receptor agonist, fluoxetine did not have significant effects on mood and other ipsapirone (0.3 mg per kg, per os) were examined after two psychological variables in these subjects, alterations in weeks of placebo and again, after the subjects had been 5-HT1A receptor function induced by SSRIs may have receiving fluoxetine for four weeks. On fluoxetine, the psychotropic relevance only in the context of existing hypothermic response to ipsapirone was significantly perturbations of serotonergic function which underlie the blunted, as were ACTH, cortisol and growth hormone psychopathological states in which these drugs are release. Ipsapirone plasma levels were significantly therapeutically effective. [Neuropsychopharmacology increased by fluoxetine but a pharmacokinetic effect could 20:628-639, 1999] © 1999 American College of not have accounted for the observed blunting of 5-HT1A Neuropsychopharmacology. Published by Elsevier receptor mediated effects. These findings confirm and Science Inc. KEY WORDS: Fluoxetine; Specific serotonin reuptake There is considerable interest in the role of serotonergic inhibitors (SSRIs); 5-HT1A receptors; Ipsapirone; ACTH; (5-HT) receptors of the 5-HT1A subtype in the therapeu- Cortisol; Growth hormone tic action of antidepressant drugs. 5-HT1A receptors are located presynaptically on serotonergic cell bodies in the raphe nuclei where they serve as autoreceptors From the Biological Psychiatry Laboratory, Department of Psy- which inhibit cell firing and reduce 5-HT release by a chiatry, Hadassah-Hebrew University Medical Center (BL, YG, negative feedback mechanism, and post-synaptically in MEN) and the Laboratory of Applied Statistics, Hebrew University the hippocampus, cortex and other brain areas, includ- (MG), Jerusalem, Israel; the Endocrine Laboratory, Department of Medicine (BA) and Department of Psychiatry (KPL), University of ing the hypothalamus. Based on electrophysiological Wuerzburg, Wuerzburg, Germany. studies in rats, De Montigny and colleagues (Blier and Address correspondence to: Prof. Bernard Lerer, Biological Psy- de Montigny 1994; Mongeau et al. 1997) proposed that chiatry Laboratory, Dept. of Psychiatry, Hadassah-Hebrew Univer- sity Medical Center, Ein Karem, Jerusalem 91120, Israel. each major class of antidepressants increases 5-HT neuro- Received May 15, 1998; accepted August 25, 1998. transmission by a distinct mechanism involving either NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 6 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00106-7 NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 6 Ipsapirone Challenge in Normal Subjects on Fluoxetine 629 pre- or post-synaptic 5-HT1A receptors. The selective se- of this response after a variety of antidepressant treat- rotonin re-uptake inhibitors (SSRIs), which raise 5-HT ments including ECS, the tricyclic drug, desipramine, synaptic levels when given acutely, were proposed to and fluoxetine. increase 5-HT transmission on repeated administration The effects of 5-HT1A receptor agonists on tempera- by inducing desensitization of somatodendritic 5-HT1A ture regulation and hormone release provide a useful autoreceptors in the raphe nuclei and nerve terminal 5- avenue for evaluating the functional sensitivity of HT1B autoreceptors, which also mediate feedback inhi- 5-HT1A receptors in animals and man. 8-OH-DPAT in- bition of 5-HT release. These effects would lead to a duces dose dependent hypothermia in rodents which is slow increase in 5-HT levels which corresponds to the antagonized by stereoselective 5-HT1A receptor block- delayed clinical effect of the drugs. ade (Goodwin et al. 1985a, 1987a; Hillegaart 1991). Al- Evidence for subsensitivity of somatodendritic 5-HT1A though a presynaptic mechanism has been suggested autoreceptors after chronic administration of SSRIs has (Goodwin et al. 1985a, 1987a; Hillegaart 1991), the ma- been provided by microdialysis experiments in which jority of the evidence indicates that the hypothermic ef- 5-HT levels are measured in vivo in response to a chal- fect of 8-OH-DPAT is mediated via postsynaptic 5-HT1A lenge dose of the 5-HT1A receptor agonist, 8-hydroxy-2 receptors in the hypothalamus (Hjorth 1985; Hutson et (di-n-propylamino) tetralin (8-OH-DPAT) (Rutter et al. al. 1987; O’Connell et al. 1992; Millan et al. 1993). 1994, Kreiss and Lucki 1995; Invernizzi et al. 1994). 5-HT1A receptor stimulation also evokes ACTH and cor- However, other studies using SSRIs (Hjorth and Auer- ticosterone release in rodents, via an effect on corti- bach 1994; Bosker et al. 1995a,b; Invernizzi et al. 1995, cotrophin releasing factor in the paraventricular nu- 1996) or clomipramine (Gur et al. 1999) failed to show cleus of the hypothalamus (Koenig et al. 1987; Gilbert et any change in 5-HT1A autoreceptor subsensitivity by al. 1988; Haleem et al. 1989; Bagdy and Makara 1994) this method. An increase in basal 5-HT levels after and possibly through an action at the level of the pitu- chronic SSRI administration, taken to be due to pre-syn- itary as well (Chaouloff 1993). aptic 5-HT1A and 5-HT1B receptor desensitization, has Ipsapirone, a centrally acting pyrimidinylpiperazine been observed in cortex (Bel and Artigas 1993), hippoc- derivative, (Traber and Glaser 1987; Cutler et al. 1993), ampus (Auerbach and Hjorth 1995) diencephalon (Rut- has a radioligand binding profile very similar to that of ter et al. 1994) and prefrontal cortex (Tanda et al. 1996) 8-OH-DPAT (Peroutka 1988). Orally administered ipsa- and, after chronic administration of clomipramine, in pirone (0.3 mg/kg) induces a hypothermic response in frontal cortex but not hippocampus (Gur et al. 1999). A normal human subjects (Lesch et al. 1990a; Gelfin et al. number of other studies have failed, however, to show 1995). The hypothermia is dose-related, attenuated by increases in basal 5-HT levels in terminal areas after the non-selective 5-HT receptor antagonist, meter- chronic administration of 5-HT uptake blocking drugs goline, completely antagonized by the non-selective b (unless the measurements were performed less than 24 adrenoceptor but stereoselective 5-HT1A/5-HT1B recep- hr after the last administration of the drug, in which tor antagonist, pindolol, and not affected by the selec- b case the effect is very likely due to the persistence of re- tive 1 adrenoceptor antagonist, betaxolol (Lesch et al. sidual drug) (e.g., Hjorth and Auerbach 1994; Bosker et 1990a). Ipsapirone-induced hypothermia is negatively al. 1995a,b; Invernizzi et al. 1995, 1996). related to age with no difference between males and fe- There is relatively little evidence from binding stud- males (Gelfin et al. 1995). Ipsapirone also induces re- ies for changes in the number of 5-HT1A receptors after lease of ACTH, cortisol (Lesch et al. 1989, 1990b; Gelfin chronic SSRI administration. Welner et al. (1989) ob- et al. 1995), and growth hormone (Lesch et al. 1989) in served a reduction in the dorsal raphe and decreased normal human subjects. The effects of age and gender binding in midbrain was observed by Li et al. (1994) af- on ipsapirone-induced ACTH and cortisol release are ter chronic fluoxetine. Changes have been reported by complex; whereas both responses diminished with age some authors in the hippocampus but are inconsistent, in male subjects, they increased with age in females showing increased density (Klimek et al. 1994) or de- (Gelfin et al. 1995). Hypothalamic-pituitary-adrenal creased density and increased affinity (Maj et al. 1996). (HPA) activation by ipsapirone is dose related and However, Hensler et al. (1991) failed to find binding pharmacologically attributable to 5-HT1A receptor acti- changes in any brain area after chronic administration vation, as indicated by the attenuating effect of meter- of the SSRIs, citalopram and sertraline, and a similar re- goline, complete antagonism of the response by pin- sult was obtained by Li et al. (1997) with paroxetine. dolol and absence of an effect of betaxolol (Lesch et al. A post-synaptic 5-HT1A receptor-mediated response 1990b). which has been studied after long-term antidepressant The effect of SSRI administration on temperature, be- treatment in animals, is inhibition of forskolin-stimu- havioral and hormone responses to 5-HT1A receptor ag- lated adenylate cyclase activity in hippocampal mem- onists, including ipsapirone, has been examined in a branes. Work from our laboratory (Newman and Lerer number of rodent studies. The hypothermic