Sustained desensitization of hypothalamic 5-hydroxytryptamine(1A) receptors after discontinuation of fluoxetine: Inhibited neuroendocrine responses to 8-hydroxy-2-(dipropylamino)tetralin in the absence of changes in G(i/o/z)proteins

Long-term exposure to fluoxetine produces a desensitization of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)(1A) receptors, indicated by a subs tantial inhibition of the 5-HT1A receptor-mediated stimulation of oxytocin and adrenocorticotropic hormone (ACTH) secretion. The present study investi gated the time course and mechanism of this desensitization after discontin uation of fluoxetine administration. Male rats were injected with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days and were challenged with a 5-H T1A agonist, [8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) 50 mu g/kg, s .c.] 2, 4, 7, 14, 28, or 60 days post-treatment. In control animals, 8-OH-D PAT significantly increased (approximately 15-fold) plasma levels of oxytoc in and ACTH. At 2 days post-treatment, oxytocin and ACTH responses to 8-OH- DPAT were reduced by 74% and 68%, respectively. During further withdrawal f rom fluoxetine, there was a gradual increase in the oxytocin response towar d control levels. However, even 60 days after discontinuation of fluoxetine , the oxytocin response was still significantly reduced by 26% compared wit h controls. In contrast, the suppressed ACTH response to 8-OH-DPAT (a less- sensitive indicator of desensitization) gradually returned to control level s by day 14 of withdrawal from fluoxetine. Interestingly, the sustained red uctions in the hormone responses occurred in the absence of reductions in G (z) or G(i) protein levels in the hypothalamus. Furthermore, this desensiti zation was sustained in the absence of detectable levels of fluoxetine and norfluoxetine in plasma and brain tissue. These findings suggest that the s ustained desensitization of hypothalamic 5-HT1A receptor systems, observed during fluoxetine withdrawal, may be due to altered interactions among the protein components of the 5-HT1A receptor system, rather than their absolut e levels.