fluvoxamine and osemozotan

We previously reported that the fluvoxamine-induced increase in prefrontal dopamine levels is enhanced by adrenalectomy/castration (which results in circulating neurosteroid deficiency), via combined activation of serotonin1A (5-HT1A) and σ1 receptors. However, the mechanistic details of the interaction between 5-HT1A and σ1 receptors are unknown.. Because most neurosteroids have affinity for γ-aminobutyric acid (GABA)A receptors, in the present study, we examined the involvement of GABAA receptors in this process.. Adrenalectomy/castration decreased pentobarbital-induced sleeping time in mice, suggesting that it reduced GABAA receptor function. The GABAA receptor antagonist picrotoxin (1 mg/kg) enhanced the fluvoxamine-induced increase in prefrontal dopamine, but not noradrenaline or serotonin, levels in mice, suggesting that picrotoxin mimicked the effect of adrenalectomy/castration. Picrotoxin also potentiated the increase in prefrontal dopamine levels mediated by co-administration of the 5-HT1A receptor agonist osemozotan and the σ1 receptor agonist (+)-SKF-10,047, while it did not affect the co-administration-induced changes in noradrenaline and serotonin levels. Conversely, the GABAA receptor agonist diazepam (1 mg/kg) blocked the effect of adrenalectomy/castration on the fluvoxamine-induced increase in prefrontal dopamine levels. Co-administration of osemozotan and (+)-SKF-10,047 did not affect the expression of the neuronal activity marker c-Fos in the prefrontal cortex, ventral tegmental area, and nucleus accumbens in control mice, while it increased the c-Fos expression only in the prefrontal cortex and ventral tegmental area in picrotoxin-treated mice.. These results suggest that the GABAA receptor plays a key role in mediating the synergistic effects of 5-HT1A and σ1 receptor activation on prefrontal dopamine neurotransmission.

Topics: Adrenalectomy; Animals; Antipsychotic Agents; Castration; Diazepam; Dioxanes; Dioxoles; Dopamine; Fluvoxamine; GABA Antagonists; GABA Modulators; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Male; Mice; Norepinephrine; Nucleus Accumbens; Orchiectomy; Phenazocine; Picrotoxin; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Receptor, Serotonin, 5-HT1A; Receptors, GABA; Receptors, GABA-A; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT1 Receptor Agonists; Sigma-1 Receptor; Synaptic Transmission; Ventral Tegmental Area