Dual control of dorsal raphe serotonergic neurons by GABA(B) receptors. Electrophysiological and microdialysis studies.
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.
Abellán
M T
MT
Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona (IDIBAPS), CSIC, Barcelona, Spain.
Jolas
T
T
Aghajanian
G K
GK
Artigas
F
F
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004594:Electrophysiology; D005110:Extracellular Space / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D001418:Baclofen