Fluoxetine-induced desensitization of somatodendritic 5-HT1A autoreceptors is independent of glucocorticoid(s).
Previous in vitro studies showed that glucocorticoid receptor activation (notably by corticosterone) could induce a functional desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus [Laaris et al. (1995) Neuropharmacology 34:1201-1210], similar to that due to in vivo subchronic treatment with a 5-HT reuptake inhibitor, such as fluoxetine, in rats. In the present study, we investigated whether a link might exist between these effects, i.e., whether glucocorticoid receptor activation could be responsible for the fluoxetine-induced desensitization of 5-HT1A autoreceptors. In vitro recording in the dorsal raphe nucleus of brain-stem slices showed that subchronic treatment with fluoxetine (5 mg/kg intraperitoneally (i.p.), daily for 3-7 days) significantly reduced the potency of the 5-HT1A receptor agonist ipsapirone to inhibit the firing rate of serotoninergic neurons. Parallel experiments in adrenalectomized and sham-operated rats indicated that subchronic fluoxetine treatment produced a similar shift to the right of the ipsapirone inhibition curve in both groups of animals. Furthermore, the subchronic blockade of glucocorticoid receptors by RU 38486 (25 mg/kg subcutaneously (s.c.), daily) in intact rats treated with fluoxetine (5 mg/kg i.p., daily for 3 days) did not affect the ability of the latter treatment to reduce the potency of ipsapirone to inhibit the firing of serotoninergic neurons. These data suggest that glucocorticoid receptors (and their possible activation by corticosterone) are not involved in the functional desensitization of somatodendritic 5-HT1A autoreceptors, which occurs during long-term treatment with a serotonin reuptake inhibitor such as fluoxetine.
Le Poul
E
E
NeuroPsychoPharmacologie, INSERM U.288, CHU Pitié-Salpêtrière, Paris, France.
Laaris
N
N
Hamon
M
M
Lanfumey
L
L
D000311:Adrenal Glands / Q000502:physiology; D000315:Adrenalectomy; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D017660:Autoreceptors / Q000187:drug effects; D003345:Corticosterone / Q000097:blood / Q000502:physiology; D003712:Dendrites / Q000187:drug effects*; D005473:Fluoxetine / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
D018687:Antidepressive Agents, Second-Generation; D017660:Autoreceptors; D003345:Corticosterone; D005473:Fluoxetine; D005938:Glucocorticoids; D011743:Pyrimidines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C043077:ipsapirone