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

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 se lective serotonin reuptake inhibitor (SSRI) citalopram significantly i ncreases the activity of 5-hydroxy-tryptamine (5-HT) containing neuron s in the dorsal raphe nucleus (DRN). Here we report correlative experi ments using microdialysis in freely moving animals to measure extracel lular 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 neu rons. Acute administration of (S)-UH-301 (2.5 mg/kg s.c.) or citalopra m (2.0 mg/kg s.c.) increased 5-HT concentrations with a maximum of abo ut 70% and 185%, respectively, above baseline. However, when (S)-UH-30 1 was administered 30 min before citalopram the maximal increase in 5- HT levels was approximately 400%. In rats chronically treated with cit alopram (20 mg/kg/day i.p. for 14 days) basal 5-HT concentrations in t he frontal cortex were significantly increased and 5-HIAA concentratio ns were decreased when measured 10-12 h, but not 18-20 h, after the la st injection of citalopram, as compared to basal 5-HT and 5-HIAA conce ntrations 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 cital opram it produced a significantly larger increase in extracellular con centrations of 5-HT than in control rats. However, in rats pretreated with a single, very high dose of citalopram, 20 mg/kg i.p., administra tion of (S)-UH-301 at 12 h after citalopram did not increase 5-HT leve ls. The augmentation by (S)-UH-301 of the increase in brain 5-HT outpu t produced by acute administration of citalopram is probably due to an tagonism of the citalopram induced feedback inhibition of 5-HT cells i n 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 regime n, in which significant tolerance to the initial feedback inhibition o f DRN-5-HT cells had 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 conc entrations, may be related to functional desensitization of somatodend ritic 5-HT1A autoreceptors in the DRN. This phenomenon may also largel y explain the larger increase in 5-HT output produced by (S)-UH-301 in chronic citalopram treated animals as compared to its effect in contr ol animals. Yet, a contributory factor may be a slight, remaining feed back 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 t he treatment of depression may accelerate the onset of clinical effect s. Moreover, in therapy-resistant cases maintained on SSRI treatment, addition of a 5-HT1A receptor antagonist may improve clinical efficacy . Since the therapeutic effect of SSRIs in depression has been found t o be critically linked to the availability of 5-HT in brain, our exper imental results support, in principle, both of the above clinically ba sed notions.