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Chronic antidepressant potentiates spontaneous activity of dorsal raphe serotonergic neurons by decreasing GABAB receptor-mediated inhibition of L-type calcium channels.

ABSTRACT: Spontaneous activity of serotonergic neurons of the dorsal raphe nucleus (DRN) regulates mood and motivational state. Potentiation of serotonergic function is one of the therapeutic strategies for treatment of various psychiatric disorders, such as major depression, panic disorder and obsessive-compulsive disorder. However, the control mechanisms of the serotonergic firing activity are still unknown. In this study, we examined the control mechanisms for serotonergic spontaneous activity and effects of chronic antidepressant administration on these mechanisms by using modified ex vivo electrophysiological recording methods. Serotonergic neurons remained firing even in the absence of glutamatergic and GABAergic ionotropic inputs, while blockade of L-type voltage dependent Ca2+ channels (VDCCs) in serotonergic neurons decreased spontaneous firing activity. L-type VDCCs in serotonergic neurons received gamma-aminobutyric acid B (GABAB) receptor-mediated inhibition, which maintained serotonergic slow spontaneous firing activity. Chronic administration of an antidepressant, citalopram, disinhibited the serotonergic spontaneous firing activity by weakening the GABAB receptor-mediated inhibition of L-type VDCCs in serotonergic neurons. Our results provide a new mechanism underlying the spontaneous serotonergic activity and new insights into the mechanism of action of antidepressants.

SUBMITTER: Asaoka N

PROVIDER: S-EPMC5648823 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Chronic antidepressant potentiates spontaneous activity of dorsal raphe serotonergic neurons by decreasing GABA<sub>B</sub> receptor-mediated inhibition of L-type calcium channels.

Asaoka Nozomi N Nishitani Naoya N Kinoshita Haruko H Kawai Hiroyuki H Shibui Norihiro N Nagayasu Kazuki K Shirakawa Hisashi H Nakagawa Takayuki T Kaneko Shuji S

Scientific reports 20171019 1

Spontaneous activity of serotonergic neurons of the dorsal raphe nucleus (DRN) regulates mood and motivational state. Potentiation of serotonergic function is one of the therapeutic strategies for treatment of various psychiatric disorders, such as major depression, panic disorder and obsessive-compulsive disorder. However, the control mechanisms of the serotonergic firing activity are still unknown. In this study, we examined the control mechanisms for serotonergic spontaneous activity and effe ...[more]

PMID: 29051549

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Project description:Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.

Dataset Information

Chronic antidepressant potentiates spontaneous activity of dorsal raphe serotonergic neurons by decreasing GABAB receptor-mediated inhibition of L-type calcium channels.

Publications

Chronic antidepressant potentiates spontaneous activity of dorsal raphe serotonergic neurons by decreasing GABA<sub>B</sub> receptor-mediated inhibition of L-type calcium channels.

Similar Datasets

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