Autoradiographic quantification of serotonin_1A receptors in rat brain following antidepressant drug treatment

Abstract

There is growing evidence that the serotonergic (5-HT) system is involved in the pathogenesis and treatment of major depression. The 5-HT receptor subtype involved in the enhancing effect of antidepressant treatments, however, has not been identified. The present study was undertaken to quantify 5-HT1A sites in the rat brain by autoradiography and membrane binding, using the selective ligand [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), following long-term antidepressant treatment. Following a 21-day treatment with amitriptyline (10 mg/kg/day), there was a significant increase of [3H]8-OH-DPAT binding measured by autoradiography in the dorsal hippocampus, but there was no change in the nucleus raphe dorsalis; whole brain membrane binding revealed an increase in the number of binding sites, with no change in the affinity for [3H]8-OH-DPAT. Conversely, fluoxetine (10 mg/kg/day), a selective blocker of 5-HT reuptake, and gepirone (10 mg/kg/day), a 5-HT1A agonist, both administered for 21 days, significantly reduced [3H]8-OH-DPAT binding measured by autoradiography in the nucleus raphe dorsalis without altering hippocampal binding sites. The control active treatment with diazepam (2 mg/kg/day) did not alter [3H]8-OH-DPAT binding in the hippocampus or in the nucleus raphe dorsalis. All groups were compared to a 21-day vehicle-treated control group. These results are fully consistent with previous electrophysiological and behavioral studies and suggest that alterations of 5-HT1A receptors might underlie the enhancement of 5-HT neurotransmission by antidepressant treatments.

Effects of Repeated Treatment With Fluoxetine and Citalopram, a 5-Ht Uptake Inhibitors on 5-Ht1a and 5-Ht2 Receptors in the Rat Brain.

“…The most likely interpretation for this effect is that reuptake blockade, by increasing the intrasynaptic availability of 5-HT, results in a greater activation of terminal autoreceptors, which in turn, reduce the amount of released 5-HT. Autoradiographic studies showed that repeated doses of fluoxetine did not change the density of 5-HT1A receptors in the rat hippocampus, but amitriptyline increased the number ofthose sites (Welner et al 1989). The present results show an increase in the 5-HTIA receptor density in the hippocampus, which represents post-synaptic binding sites (Hamon et al 1987), after repeated treatment with most ofthe tested compounds.…”

5-HT1A Receptor Function in Normal Subjects on Clinical Doses of Fluoxetine Blunted Temperature and Hormone Responses to Ipsapirone Challenge

“…Welner et al (1989) observed a reduction in the dorsal raphe and decreased binding in midbrain was observed by Li et al (1994) after chronic fluoxetine. Changes have been reported by some authors in the hippocampus but are inconsistent, showing increased density (Klimek et al 1994) or decreased density and increased affinity (Maj et al 1996).…”

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

“…It should be emphasized that both observations (change in receptor sensitivity and unchanged density) have been obtained in the same animals. Previous work with SSRIs and selective 5-HT 1A agonists is inconclusive in regards to the ability of these agents to down-regulate the density of raphe 5-HT 1A autoreceptors after chronic (2-3 weeks) treatments (Welner et al 1989;Hensler et al 1991;Fanelli and McMonagle-Strucko 1992;Casanovas et al 1999a;Le Poul et al 1999), whereas there is convincing evidence on their ability to induce a functional desensitization de Montigny 1987, 1994;Hensler et al 1991;Invernizzi et al 1994;Casanovas et al 1999a; see however Sharp et al 1993).…”