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

Abstract

Using microdialysis, receptor autoradiography and in situ hybridization, we examined the effects of fluoxetine alone or with WAY-100635 on: (a) extracellular 5-HT in frontal cortex; and (b) density and sensitivity of 5-HT 1A autoreceptors in rat brain. WAY-100635 (0.3 mg/kg, s.c.) doubled the increase in extracellular 5-HT produced by fluoxetine (3 mg/kg, i.p.) (SSRI) Selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) are extensively used in the treatment of major depression. The increase in forebrain extracellular 5-HT elicited by SSRIs is limited by a negative feed-back involving raphe autoreceptors . The prevention of this inhibitory mechanism with 5-HT 1A receptor antagonists augments the neurochemical and behavioral effects of SSRIs (Gartside et al. 1995;Artigas et al. 1996;Hashimoto et al. 1997;Mitchell and Redfern 1997;Grignaschi et al. 1998;Trillat et al. 1998). At the clinical level, the ␤ -adrenoceptor/ 5-HT 1A receptor antagonist pindolol accelerates the antidepressant effects of SSRIs in open-label and placebocontrolled trials Blier and Bergeron 1995;Pérez et al. 1997;Zanardi et al. 1997Zanardi et al. , 1998Bordet et al. 1998). However, its effectiveness to potentiate antidepressant response in chronically ill or treatmentresistant patients is still controversial (Maes et al. 1996(Maes et al. , 1999Berman et al. 1997;Moreno et al. 1997;Pérez et al. 1999). Based on this rationale, selective 5-HT 1A receptor antagonists (for use with SSRIs; add-on strategy) and dual action compounds (5-HT reuptake inhibitor ϩ 5-HT 1A antagonist) are being developed for use in the treatment of major depression. The prolonged administration of SSRIs has been reported to desensitize raphe 5-HT 1A autoreceptors, as assessed by single unit recordings and brain microdialysis (Blier and de Montigny 1994;Invernizzi et al. 1994;Arborelius et al. 1995;Le Poul et al. 1995). This reduces the efficacy of the above negative feedback and increases extracellular 5-HT (Bel and Artigas 1993;Invernizzi et al. 1994;Rutter et al. 1994;Arborelius et al. 1996). Other studies, however, have failed to observe such effects even using large doses of SSRIs (Hjorth and Auerbach 1994a;Bosker et al. 1995;Invernizzi et al. 1995).To our knowledge, there are no published reports on the effects of prolonged treatments with combinations of SSRIs and 5-HT 1A receptor antagonists on these experimental paradigms, except in abstract form (Dawson et al. 1998). As with pindolol, future selective 5-HT 1A receptor antagonists would be administered for a limited period of time. Should prolonged blockade of 5-HT 1A receptor result in receptor sensitization, the withdrawal of the antagonist would increase the efficacy of the above negative feed-back and reduce the ability of the SSRI to increase extracellular 5-HT, thus increasing the possibility of a clinical relapse. Since this is crucial for the success of this therapeutic strategy, we examined the effects of two-week treatments with fluoxetine, WAY-100635 and their combination...

Acute and chronic effects of citalopram on 5‐HT1A receptor—Labeling by [18F]MPPF and—Coupling to receptors‐G proteins

“…Previous works with SSRIs were not able to determine the nature of 5-HT 1A receptor alteration that occurs with chronic treatment. Indeed, whereas one study has reported a decrease in [ 3 H]-8-OH-DPAT binding in the DR after chronic fluoxetine treatment without corresponding changes in hippocampus (Welner et al, 1989), other studies have reported no changes in 5-HT 1A binding in DR, hippocampus, or cortex following chronic treatment with either fluoxetine or citalopram (Hensler et al, 1991;Hervas et al, 2001;Jolas et al, 1994;Le Poul et al, 1995). Recent observations of rapid internalization of 5-HT 1A receptors after acute administration of fluoxetine led to new questions regarding the nature of the altered processing of 5-HT 1A receptors that occurs during chronic SSRI treatment.…”

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

“…After 21 days administration, there is a significant increase in SI at 7.5 mg/kg indicating that, if neurogenesis is playing a role in the anxiolytic behavior, 5-HT 1A receptor activation may have occurred at this time point, and a longer period of 5-HT elevation is required to overcome the SB-649915-B-mediated competitive 5-HT 1A receptor block. It could be suggested that chronic blockade of postsynaptic 5-HT 1A receptors will induce an increase in receptor population or sensitization, however, the literature dose not support a change in 5-HT 1A receptor sensitivity Hervas et al, 2001). The Duxon et al (2000) data showing an accelerated onset of effect following coadministration of paroxetine (3.0 mg/kg) and WAY100635 (0.1 mg/kg) clearly indicate that 5-HT 1A receptor antagonism does not have a negative impact on the SI responses.…”

Modulation of Serotonergic Function in Rat Brain by VN2222, a Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

“…8-OH-DPAT and WAY 100635 were injected s.c. dissolved in saline. An additional experiment in which we examined the effects of the sustained administration of fluoxetine (3 mg/kg day, dissolved in 50% DMSO) and VN2222 (6 mg/kg day, dissolved in DMSO) was carried out in which these drugs were administered with minipumps following described procedures (Hervás et al, 2001). Control rats were treated with vehicle.…”

“…The increase in the synaptic concentration of 5-HT that follows reuptake inhibition is limited by a negative feedback involving 5-HT 1A autoreceptors (Adell and Artigas, 1991;Artigas et al, 1996). Following repeated treatment, 5-HT 1A receptors desensitize (Blier and de Montigny, 1994;Invernizzi et al, 1994;Hervás et al, 2001). This effect results in a reduced efficacy of the negative feedback and therefore in an increase of the extracellular concentration of 5-HT (5-HT ext ) in the forebrain (Bel and Artigas, 1993;Invernizzi et al, 1994;Rutter et al, 1994;Kreiss and Lucki, 1995).…”