Involvement of GABA.sub.A receptors in 5-HT.sub.1A and [sigma].sub.1 receptor synergism on prefrontal dopaminergic transmission under circulating neurosteroid deficiency

• Published in: Psychopharmacology Vol. 233; no. 17; p. 3125
• Main Authors: Ago, Yukio, Hasebe, Shigeru, Hiramatsu, Naoki, Mori, Kazuya, Watabe, Yuji, Onaka, Yusuke, Hashimoto, Hitoshi, Takuma, Kazuhiro, Matsuda, Toshio
• Format: Journal Article
• Language: English
• Published: Springer 01.09.2016
• Subjects: Dopamine; GABA; Health aspects; Prefrontal cortex; Synaptic transmission
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4353-3

Rationale 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 serotonin.sub.1A (5-HT.sub.1A) and [sigma].sub.1 receptors. However, the mechanistic details of the interaction between 5-HT.sub.1A and [sigma].sub.1 receptors are unknown. Objectives Because most neurosteroids have affinity for [gamma]-aminobutyric acid (GABA).sub.A receptors, in the present study, we examined the involvement of GABA.sub.A receptors in this process. Results Adrenalectomy/castration decreased pentobarbital-induced sleeping time in mice, suggesting that it reduced GABA.sub.A receptor function. The GABA.sub.A 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-HT.sub.1A receptor agonist osemozotan and the [sigma].sub.1 receptor agonist (+)-SKF-10,047, while it did not affect the co-administration-induced changes in noradrenaline and serotonin levels. Conversely, the GABA.sub.A 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. Conclusions These results suggest that the GABA.sub.A receptor plays a key role in mediating the synergistic effects of 5-HT.sub.1A and [sigma].sub.1 receptor activation on prefrontal dopamine neurotransmission.