Dual control of dorsal raphe serotonergic neurons by GABAB receptors. Electrophysiological and microdialysis studies

Abstract

We assessed the role of GABA(B) receptors in the control of serotonergic (5-HT) neurons of the dorsal raphe nucleus (DRN) by using microdialysis in vivo and intra- and extracellular recording in vitro in the rat. The GABA(B) agonist R(+)baclofen (but not the inactive S(-)enantiomer) enhanced the 5-HT output in the DRN (4. 7-fold at 15 mg/kg s.c.) and, to a much lesser extent, striatum of unanesthetized rats. Phaclofen (2 mg/kg s.c.) antagonized the effects of 6 mg/kg R(+)baclofen in dorsal striatum. Using dual-probe microdialysis, R(+)baclofen (0.1-100 microM) applied in the DRN enhanced the local 5-HT output (4.5-fold at 100 microM) but decreased that in striatum at 100 microM. At concentrations higher than 100 microM there was a moderate decrement in the elevation of 5-HT in the DRN. In midbrain slices, bath R(+)baclofen exerted a biphasic effect on DRN 5-HT neurons. Consistent with a reduced striatal 5-HT release when infused in the DRN, R(+)baclofen (0.1-30 microM) induced an outward current in 5-HT neurons (IC(50) = 1.4 microM). Lower R(+)baclofen concentrations (0.01-1 microM) preferentially reduced GABAergic inhibitory postsynaptic currents induced by N-methyl-D-aspartate (20 microM) in 5-HT neurons (IC(50) = 72 nM). Using extracellular recordings, R(+)baclofen (300 nM) enhanced the ability of NMDA to induce firing in a subpopulation of serotonergic neurons. These results are consistent with a preferential activation by a low concentration of R(+)baclofen of presynaptic GABA(B) receptors on GABAergic afferents that could disinhibit 5-HT neurons and increase 5-HT release.

Early life adversity programs changes in central 5‐HT neuronal function in adulthood

“…These data perhaps suggest that EMS causes an increase in the spontaneous in vivo activity of a sub-population of classical (nonbursting) DRN 5-HT neurons. Increased ®ring rate would be consistent with increased a 1adrenoceptor-mediated excitation or decreased 5-HT 1A receptor inhibition and/or changes in tonic regulation of these neurons by other neurotransmitters (Baraban & Aghajanian, 1980;Pin Äeyro & Blier, 1999;Abellan et al, 2000). However, in spite of any possible increased activity of a proportion of 5-HT neurons, it is of note that in our in vivo microdialysis study we found no increase in basal 5-HT levels in the frontal cortex.…”

GABAB receptor mRNA in the raphe nuclei: co‐expression with serotonin transporter and glutamic acid decarboxylase

“…In accordance with that, microdialysis studies have shown that under lights-off conditions the infusion of the GABA B agonist baclofen in the DR diminishes the release of 5-HT (Tao et al 1996). However, during the lights-on period baclofen infusion in the DR and MnR increases 5-HT release, indicating a disinhibitory action (Abellán et al 2000b). This view is also supported by intracellular recordings of dorsal raphe nucleus (DR) 5-HT neurones in midbrain slices, showing that baclofen at low concentrations (IC 50 ¼ 72 nM) counteracts GABA A -mediated inhibitory post-synaptic currents in 5-HT neurones, whereas higher concentrations (IC 50 ¼ 1.4 lM) are required to elicit a direct inhibitory effect (Abellán et al 2000b).…”

“…This observation together with the present data showing the occurrence of GABA B receptor mRNA in both or 5-HTT mRNA-positive and GAD-containing cells in the raphe nuclei provides anatomical support to the hypothesis expressed by Abellán et al (2000b) to explain the dual effect of the GABA B agonist baclofen on 5-HT cells. Thus, post-synaptic GABA B receptors located on serotonergic neurones could mediate the inhibition of 5-HT release caused by baclofen (Tao et al 1996), whereas the activation of pre-synaptic GABA B receptors located in GABAergic cells would result in a final disinhibitory action on serotonergic neurones (Abellán et al 2000a(Abellán et al , 2000b. It should be pointed out that, according to our observations, GAD/ GABA B receptor mRNA-containing cells in the raphe nuclei are not abundant.…”

“…However, during the lights-on period baclofen infusion in the DR and MnR increases 5-HT release, indicating a disinhibitory action (Abellán et al 2000b). This view is also supported by intracellular recordings of dorsal raphe nucleus (DR) 5-HT neurones in midbrain slices, showing that baclofen at low concentrations (IC 50 ¼ 72 nM) counteracts GABA A -mediated inhibitory post-synaptic currents in 5-HT neurones, whereas higher concentrations (IC 50 ¼ 1.4 lM) are required to elicit a direct inhibitory effect (Abellán et al 2000b). These data have been interpreted as resulting from a dual action of baclofen, including an indirect (disinhibitory) effect mediated through GABA B pre-synaptic autoreceptors located on GABAergic terminals projecting to serotonergic neurones, and a direct (inhibitory) effect mediated through postsynaptic GABA B receptors located on 5-HT neurones.…”

Modulation of serotonergic neurotransmission by short‐ and long‐term treatments with sigma ligands

“…), a g-aminobutyric acid B (GABA) agonist, which also, did not restore the number of spontaneously ®ring neurons suggesting that the silent neurons were not depolarized. However, a lack of repolarizing eect of the GABA B agonist could not be totally excluded based on recent ®ndings suggesting that, under some circumstances, (+)baclofen might disinhibit DRN 5-HT neurons by preferentially activating GABA B autoreceptors (Abellan et al, 2000). Therefore, at present the possibility of a depolarization blockade cannot be completely ruled out and we will be further investigating this phenomenon as this would be the ®rst report of such a phenomenon occurring in 5-HT neurons.…”