Osemozotan Hydrochloride

Prefrontal dopamine release by the combined activation of 5-HT_1A and sigma-1 (σ₁ ) receptors is enhanced by the GABA_A receptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes.

Male mice were treated with picrotoxin to decrease GABA_A receptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c-Fos was determined immunohistochemically.

Picrotoxin caused an anxiogenic effect on three behavioural tests, but it did not affect the immobility time in the forced swim test. Picrotoxin decreased female preference in the female encounter test and attenuated the female encounter-induced increase in c-Fos expression in the nucleus accumbens. Picrotoxin-induced anhedonia was ameliorated by fluvoxamine and S-(+)-fluoxetine, selective serotonin reuptake inhibitors with high affinity for the σ₁ receptor. The effect of fluvoxamine was blocked by a 5-HT_1A or a σ₁ receptor antagonist, and co-administration of the σ₁ receptor agonist (+)-SKF-10047 and the 5-HT_1A receptor agonist osemozotan mimicked the effect of fluvoxamine. By contrast, desipramine, duloxetine and paroxetine, which have little affinity for the σ₁ receptor, did not affect picrotoxin-induced anhedonia. The effect of fluvoxamine was blocked by a dopamine D_2/3 receptor antagonist. Methylphenidate, an activator of the prefrontal dopamine system, ameliorated picrotoxin-induced anhedonia.

Picrotoxin-treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5-HT_1A and σ₁ receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti-anhedonic effect observed in picrotoxin-treated mice.

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.