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.
Highlights
The serotonergic system plays an important role in regulating a wide variety of brain functions, such as mood and cognition[1]
While most of previous researches pointed out that serotonergic neurons are silent in ex vivo recordings[2,6], recent study suggests that part of serotonergic neurons (~50%) showed spontaneous firing activity in “high quality” brain slices[7]
As L-type voltage dependent Ca2+ channels (VDCCs) are widely expressed in the brain, we examined whether L-type VDCCs on serotonergic neurons or other neurons are critical for the spontaneous serotonergic activity
Summary
The serotonergic system plays an important role in regulating a wide variety of brain functions, such as mood and cognition[1]. Despite the fact that serotonergic neurons are tonically active when recorded in vivo, most of the previous ex vivo electrophysiological analyses used pharmacological and/or electrical stimulations to generate continuous firing because of the difficulty in maintaining the spontaneous activity of serotonergic neurons in acute brain slices[2,6,7]. In this context, it was widely believed that the excitatory inputs from another brain area, such as the prefrontal cortex and locus coeruleus, are necessary for the tonic firing activity of serotonergic neurons, while www.nature.com/scientificreports/. These findings suggest the possibility that chronic treatment with antidepressant potentiates serotonergic activity
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