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

We assessed the role of GABAB receptors in the control of serotonergic (5-H T) 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) ag onist 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 microd ialysis, R(+)baclofen (0.1-100 mu M) applied in the DRN enhanced the local 5-HT output (4.5-fold at 100 mu M) but decreased that in striatum at 100 mu M. At concentrations higher than 100 mu M there was a moderate decrement i n the elevation of 5-HT in the DRN. In midbrain slices, bath R(+)baclofen e xerted a biphasic effect on DRN 5-HT neurons. Consistent with a reduced str iatal 5-HT release when infused in the DRN, R(+)baclofen (0.1-30 mu M) indu ced an outward current in 5-HT neurons (IC50 = 1.4 mu M). Lower R(+)baclofe n concentrations (0.01-1 mu M) preferentially reduced GABAergic inhibitory postsynaptic currents induced by N-methyl-D-aspartate (20 mu M) in 5-HT neu rons (IC50 = 72 nM). Using extracellular recordings, R(+)baclofen (300 nM) enhanced the ability of NMDA to induce firing in a subpopulation of seroton ergic neurons. These results are consistent with a preferential activation by a low concentration of R(+)baclofen of presynaptic GABAB receptors on GA BAergic afferents that could disinhibit 5-HT neurons and increase 5-HT rele ase. (C) 2000 Wiley-Liss, Inc.