The 5-HT1A receptor antagonist (S)-UH-301 augments the increase in extracellular concentrations of 5-HT in the frontal cortex produced by both acute and chronic treatment with citalopram

Abstract

In a recent study, utilizing single cell recording techniques, we have shown that administration of 5-HT1A receptor antagonists, e.g. (S)-UH-301, to rats concomitantly treated, acute or chronically, with the selective serotonin reuptake inhibitor (SSRI) citalopram significantly increases the activity of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN). Here we report correlative experiments using microdialysis in freely moving animals to measure extracellular levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex, a major projection area for DRN-5-HT neurons. Acute administration of (S)-UH-301 (2.5 mg/kg s.c.) or citalopram (2.0 mg/kg s.c.) increased 5-HT concentrations with a maximum of about 70% and 185%, respectively, above baseline. However, when (S)-UH-301 was administered 30 min before citalopram the maximal increase in 5-HT levels was approximately 400%. In rats chronically treated with citalopram (20 mg/kg/day i.p. for 14 days) basal 5-HT concentrations in the frontal cortex were significantly increased and 5-HIAA concentrations were decreased when measured 10-12 h, but not 18-20 h, after the last injection of citalopram, as compared to basal 5-HT and 5-HIAA concentrations in chronic saline-treated rats. When (S)-UH-301 (2.5 mg/kg s.c.) was administered 12 h, but not 20 h, after the last dose of citalopram it produced a significantly larger increase in extracellular concentrations of 5-HT than in control rats. However, in rats pretreated with a single, very high dose of citalopram, 20 mg/kg i.p., administration of (S)-UH-301 at 12 h after citalopram did not increase 5-HT levels. The augmentation by (S)-UH-301 of the increase in brain 5-HT output produced by acute administration of citalopram is probably due to antagonism of the citalopram induced feedback inhibition of 5-HT cells in the DRN, as previously suggested. However, the capacity of (S)-UH-301 to further increase the already elevated extracellular concentrations of 5-HT in brain in animals maintained on a chronic citalopram regimen, in which significant tolerance to the initial feedback inhibition of DRN-5-HT cells and developed, represents a novel finding. Generally, the reduced feedback inhibition of 5-HT neurons obtained with chronic citalopram treatment, and the associated elevation of brain 5-HT concentrations, may be related to functional desensitization of somatodendritic 5-HT1A autoreceptors in the DRN. This phenomenon may also largely explain the larger increase in 5-HT output produced by (S)-UH-301 in chronic citalopram treated animals as compared to its effect in control animals. Yet, a contributory factor may be a slight, remaining feedback inhibition of the 5-HT cells caused by residual citalopram at 12, but not 20 h after its last administration. Previous clinical studies suggest that addition of a 5-HT1A receptor antagonist to an SSRI in the treatment of depression may accelerate the onset of clinical effects. Moreover, in therapy-resistant cases maintained on SSRI...

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

“…The magnitude of the change may appear moderate, but is similar to that produced by a maximal daily dose of a selective 5-HT 1A receptor agonist given for the same time period (Casanovas et al 1999a). The fact that the desensitization is not complete (i.e., the fluoxetine challenge could still significantly reduce extracellular 5-HT in fluoxetine-pretreated rats) agrees with other studies showing that 5-HT 1A autoreceptor antagonists can increase the activity of DR 5-HT cells and augment the effect of the chronic treatment with a high citalopram dose (20 mg/kgиday) on cortical extracellular 5-HT (Arborelius et al 1996;Gundlah et al 1997).…”

“…With few exceptions, most studies assessing the effects of the long-term administration of SSRIs on the 5-HT system employed relatively large daily doses (e.g., 10-20 mg/kg·day) that inhibit maximally the 5-HT reuptake and markedly increase extracellular 5-HT in forebrain when given at once (Invernizzi et al 1994(Invernizzi et al , 1995Rutter et al 1994;Arborelius et al 1996;Gundlah et al 1997).…”

“…It may be that such differences are overcome by the more marked effect of citalopram on extracellular 5-HT (1 M citalopram increased extracellular 5-HT five-fold in frontal cortex) (Hervás et al 2000). Furthermore, it has been shown that a washout period can abolish the increase in extracellular 5-HT elicited by chronic SSRI treatment (Arborelius et al 1996). Since citalopram was present in the perfusion fluid from the beginning of the experiments, we could not determine which of these factors is accountable.…”

“…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).…”

“…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).…”