Involvement of GABA receptors in 5-HT and σ receptor synergism on prefrontal dopaminergic transmission under circulating neurosteroid deficiency.

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Title:	Involvement of GABA receptors in 5-HT and σ receptor synergism on prefrontal dopaminergic transmission under circulating neurosteroid deficiency.
Authors:	Ago, Yukio, Hasebe, Shigeru, Hiramatsu, Naoki, Mori, Kazuya, Watabe, Yuji, Onaka, Yusuke, Hashimoto, Hitoshi, Takuma, Kazuhiro, Matsuda, Toshio
Source:	Psychopharmacology. Sep2016, Vol. 233 Issue 17, p3125-3134. 10p. 3 Diagrams, 5 Graphs.
Subjects:	GABA receptors, Dopaminergic mechanisms, Fluvoxamine, Adrenalectomy, Serotonin, Psychology
Abstract:	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 (5-HT) and σ receptors. However, the mechanistic details of the interaction between 5-HT and σ receptors are unknown. Objectives: Because most neurosteroids have affinity for γ-aminobutyric acid (GABA) receptors, in the present study, we examined the involvement of GABA receptors in this process. Results: Adrenalectomy/castration decreased pentobarbital-induced sleeping time in mice, suggesting that it reduced GABA receptor function. The GABA 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 receptor agonist osemozotan and the σ receptor agonist (+)-SKF-10,047, while it did not affect the co-administration-induced changes in noradrenaline and serotonin levels. Conversely, the GABA 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 receptor plays a key role in mediating the synergistic effects of 5-HT and σ receptor activation on prefrontal dopamine neurotransmission. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	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 (5-HT) and σ receptors. However, the mechanistic details of the interaction between 5-HT and σ receptors are unknown. Objectives: Because most neurosteroids have affinity for γ-aminobutyric acid (GABA) receptors, in the present study, we examined the involvement of GABA receptors in this process. Results: Adrenalectomy/castration decreased pentobarbital-induced sleeping time in mice, suggesting that it reduced GABA receptor function. The GABA 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 receptor agonist osemozotan and the σ receptor agonist (+)-SKF-10,047, while it did not affect the co-administration-induced changes in noradrenaline and serotonin levels. Conversely, the GABA 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 receptor plays a key role in mediating the synergistic effects of 5-HT and σ receptor activation on prefrontal dopamine neurotransmission. [ABSTRACT FROM AUTHOR]
ISSN:	00333158
DOI:	10.1007/s00213-016-4353-3