5-HT7 receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin

Abstract

The 5-HT7 receptor is one of the several serotonin (5-HT) receptor subtypes that are expressed in the dorsal raphe nucleus (DRN). Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-HT in the target structure. Male Wistar rats with microdialysis probes implanted in the prefrontal cortex (PFC) received injections of the 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB 269970), which induced an increase in the levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the PFC. In another set of experiments whole-cell recordings from presumed projection neurons were carried out using DRN slices. SB 269970 application resulted in depolarization and in an increase in the firing frequency of the cells. In order to activate 5-HT7 receptors, 5-carboxamidotryptamine (5-CT) was applied in the presence of N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635). Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Blockade of 5-HT7 receptors caused a decrease in the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), while its activation induced an increase. The mechanism of these effects appears to involve tonically-active 5-HT7 receptors modulating firing and/or GABA release from inhibitory interneurons which regulate the activity of DRN serotonergic projection neurons.

The 5-HT7 receptor antagonist SB 269970 ameliorates corticosterone-induced alterations in 5-HT7 receptor-mediated modulation of GABAergic transmission in the rat dorsal raphe nucleus

“…2), characteristic of putative 5-HT projection neurons (see also: Galindo-Charles et al 2008; Kusek et al 2015). The resting membrane potential and input resistance of recorded DRN neurons did not differ significantly between groups (Table 1).…”

“…These receptors appear to be located on DRN GABA interneurons, but not projection neurons, and their activation has earlier been shown to increase the frequency of sIPSCs recorded from DRN 5-HT projection neurons (Mnie-Filali et al 2011; Kusek et al 2015), consistent with the fact that 5-HT 7 receptors’ agonists raise the excitability of the neuron that expresses these receptors (Bacon and Beck 2000; Bickmeyer et al 2002; Tokarski et al 2003). Thus, another consequence of prolonged corticosterone exposure is a lack of 5-HT 7 receptor-mediated indirect inhibitory effect on DRN projection cells.…”

Lurasidone inhibits NMDA receptor antagonist‐induced functional abnormality of thalamocortical glutamatergic transmission via 5‐HT7 receptor blockade

“…Neither the expression nor the electrophysiological function of 5‐HT 7 receptors in the RTN has been clarified. However, 5‐HT 7 receptor agonist activates GABAergic neuronal activity in raphe nucleus (Kusek et al, ). Further studies are warranted to clarify detailed mechanisms underlying lurasidone‐induced inhibition of RTN–MDTN GABAergic transmission.…”

“…Drug doses and sample size were selected according to previous studies (Bonaventure et al, ; Fukuyama et al, ; Kusek et al, ; Nakano, Hasegawa, Suzuki, Motomura, & Okada, ; Okada, Fukuyama, Kawano, Shiroyama, Suzuki, & Ueda, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ). According to previous studies, all experiments in this study were designed with equally sized animal groups ( N = 6) without carrying out a formal power analysis (Fukuyama et al, ; Nakano et al, ; Okada, Fukuyama, Kawano, Shiroyama, Suzuki, & Ueda, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ), and all values were expressed as mean ± SD .…”

Of rodents and humans: A comparative review of the neurobehavioral effects of early life SSRI exposure in preclinical and clinical research

“…These GABAergic neurons function to regulate input onto 5-HT neurons. Local 5-HT release activates 5-HT receptors, including 5-HT1A, 5-HT2A/C, and 5-HT7 subtypes, generally resulting in activation of GABAergic neurons (Gocho et al, 2013;Liu et al, 2000;Roberts et al, 2004;Kusek et al, 2015), and reduced firing frequency of 5-HT neurons in the dorsal raphe and 5-HT release in the mPFC (Kusek et al, 2015). Activating these GABAergic interneurons may increase inhibitory postsynaptic currents in 5-HTergic neurons, thereby forming an indirect, local inhibitory feedback loop on 5-HTergic neurons (Gocho et al, 2013;Liu et al, 2000;Roberts et al, 2004), and regulate 5-HTergic firing patterns during various sleep-wake states (Gervasoni et al, 2000).…”