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.
Highlights
The dorsal raphe nucleus (DRN) is the main source of widespread serotonin (5-hydroxytryptamine, 5-HT) projections to the forebrain, which regulate the activity of neuronal circuits involved in a spectrum of functions including emotional states, sleep, motivation and aggression
DRN contains numerous nonserotonergic neurons which release glutamate, GABA, as well as dopamine and peptide transmitters (Kirby et al, 2003; reviewed in Liu et al, 2000; Commons, 2009; Soiza-Reilly and Commons, 2014). Some of these cells are local interneurons (Commons, 2009; Calizo et al, 2011); recent work has demonstrated that many DRN projection neurons are glutamatergic or GABAergic (Jackson et al, 2009; Bang and Commons, 2012)
The results of the present study indicate that blockade of the 5-HT7 receptor enhances the release and metabolism of 5-HT in the PFC
Summary
The dorsal raphe nucleus (DRN) is the main source of widespread serotonin (5-hydroxytryptamine, 5-HT) projections to the forebrain, which regulate the activity of neuronal circuits involved in a spectrum of functions including emotional states, sleep, motivation and aggression (reviewed in Celada et al, 2013; Paul and Lowry, 2013). DRN 5-HT projection neurons have been thoroughly studied (reviewed in Aghajanian et al, 1990; Gaspar and Lillesaar, 2012; Andrade and Haj-Dahmane, 2013). These cells exhibit in vivo a regular, slow activity pattern and fire broad (2–3 ms) action potentials which are generated by a combination of voltage-dependent sodium and calcium conductances (Penington et al, 1991; Beck et al, 2004). DRN contains numerous nonserotonergic neurons which release glutamate, GABA, as well as dopamine and peptide transmitters (Kirby et al, 2003; reviewed in Liu et al, 2000; Commons, 2009; Soiza-Reilly and Commons, 2014). Subsets of DRN 5HT neurons coexpress glutamate or GABA (Commons, 2009; Shikanai et al, 2012)
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