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Abstract

Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain in order to study serotonergic-GABAergic interaction. The slices were loaded with either [3H] serotonin or [3H]GABA, superfused and the electrically induced efflux of radioactivity was determined. The GABA(A) receptor agonist muscimol (3 to 30 microM) and the GABA(B) receptor agonist baclofen (30 and 100 microM) inhibited [3H]serotonin and [3H]GABA release. These effects of muscimol were reversed by the GABA(A) antagonists bicuculline (100 microM). The GABA(B) antagonist phaclofen (100 microM) also antagonized the baclofen-induced inhibition of [3H]serotonin and [3H]GABA release. Phaclofen by itself increased [3H]serotonin release but it did not alter [3H]GABA overflow. Muscimol (10 microM) and baclofen (100 microM) also inhibited [3H]serotonin release after depletion of GABAergic neurons by isoniazid pretreatment. These findings indicate the presence of postsynaptic GABA(A) and GABA(B) receptors located on serotonergic neurons. The 5-HT1A receptor agonist 8-OH-DPAT (0.01 to 1 microM) and the 5-HT1B receptor agonist CGS-12066A (0.01 to 1 microM) inhibited the electrically stimulated [3H]serotonin and [3H]GABA release. The 5-HT1A antagonist WAY-100135 (1 microM) was without effect on [3H]serotonin and [3H]GABA efflux by itself but it reversed the 8-OH-DPAT-induced transmitter release inhibition. During KCl (22 mM)-induced depolarization, tetrodotoxin (1 microM) did not alter the inhibitory effect of CGS-12066A (1 microM) on [3H]GABA release, it did blocked, however, the ability of 8-OH-DPAT (1 microM) to reduce [3H]GABA efflux. After depletion of raphe serotonin neurons by p-chlorophenylalanine pretreatment, CGS-12066A (1 microM) still inhibited [3H]GABA release whereas in serotonin-depleted slices, 8-OH-DPAT (1 microM) was without effect on the release. We conclude that reciprocal influence exists between serotonergic projection neurons and the GABAergic interneurons or afferents in the raphe nuclei and these interactions may be mediated by 5-HT1A/B and GABA(A/B) receptors. Both synaptic and non-synaptic neurotransmission may be operative in the 5-HTergic-GABAergic reciprocal interaction which may serve as a local tuning in the neural connection between cerebral cortex and midbrain raphe nuclei.

A group of non-serotonergic cells is CO2-stimulated in the medullary raphé

“…Raphé 5-HT neurons express GABA A and GABA B receptors, and are tonically inhibited by their activation (Gallager and Aghajanian, 1976; Bowery et al, 1987; Tao et al, 1996; Abellán et al, 2000; Bagdy et al, 2000; Boothman et al, 2006; Templin et al, 2012). Inhibitory postsynaptic currents in raphé 5-HT cells are mediated by GABA A receptors (Inyushkin et al, 2010).…”

“…Thus, both anatomic and functional data illustrate that raphé GABAergic neurons inhibit 5-HT neurons. Raphé 5-HT and GABA neurons also share a reciprocal connection, which would provide a negative feedback loop to inhibit 5-HT release (Bagdy et al, 2000; Richardson-Jones et al, 2011). When the CO 2 response of raphé neurons was tested in culture, recordings were made with antagonists for NMDA, AMPA, and GABA A receptors.…”

CO2-inhibited neurons in the medullary raphé are GABAergic

“…GABAergic raphé neurons tonically inhibit neighboring raphé 5-HT neurons (Boothman et al, 2006; Challis et al, 2014) through both GABA A and GABA B receptors (Abellan et al, 2000; Gallager and Aghajanian, 1976; Tao et al, 1996), and interconnected raphé 5-HT and GABAergic neurons have been proposed to reciprocally influence each other (Bagdy et al, 2000; Richardson-Jones et al, 2011). Therefore, inhibition of the GABAergic raphé neurons by CO 2 could attenuate GABA release, resulting in disinhibition of postsynaptic targets, including 5-HT cells.…”

5-HT1A receptor blockade reverses GABAA receptor α3 subunit-mediated anxiolytic effects on stress-induced hyperthermia

“…Electrophysiological studies show that WAY-100635 increases serotonergic neuronal activity probably by blocking 5-HT 1A autoreceptors (Corradetti et al 1996; Fornal et al 1996; Mundey et al 1996). In support, serotonergic raphe nuclei receive a prominent GABAergic input via distant sources as well as interneurons (Bagdy et al 2000; Gervasoni et al 2000; Harandi et al 1987; Varga et al 2001). However, this can only provide a partial explanation as WAY-100635 also augmented the benzodiazepine-induced hypothermia, putatively via an activation of α 1 -subunits (Vinkers et al 2009).…”