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.

We have found that fluvoxamine-induced increases in prefrontal dopamine release are enhanced by adrenalectomy/castration and 5-HT1A receptors are involved in the enhancement. This study examined which 5-HT1A autoreceptors or postsynaptic receptor play a key role in the enhancement in mice. Adrenalectomy/castration-induced enhancement of fluvoxamine-induced increase in the dopamine release was not blocked by local perfusion with the 5-HT1A receptor antagonist WAY100635 (10 μM), while it was blocked by systemic administration of WAY100635 at low dose (0.1 mg/kg) which blocked preferentially autoreceptor-mediated responses. These finding suggests that 5-HT1A autoreceptors play a key role in the enhancement of prefrontal dopamine release.

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. KEY RESULTSPicrotoxin 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 σ 1 receptor. The effect of fluvoxamine was blocked by a 5-HT 1A or a σ 1 receptor antagonist, and co-administration of the σ 1 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 σ 1 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. CONCLUSION AND IMPLICATIONSPicrotoxin-treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5-HT 1A and σ 1 receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti-anhedonic effect observed in picrotoxin-treated mice.Abbreviations SSRI, selective serotonin reuptake inhibitor