Inhibitory influence of GABA on central serotonergic transmission. Raphe´nuclei as the neuroanatomical site of the GABAergic inhibition of cerebral serotonergic neurons

Abstract

Acute injection of the γ-aminobutyric acid (GABA) mimetics progabide, aminooxyacetic acid, γ-acetylenic GABA and dipropylacetamide reduced 5-hydroxytryptophan (5-HTP) accumulation in serotonergic nerve terminal (prefrontal cortex, olfactory tubercle, septum, striatum, hypothalamus, hippocampus, substantia nigra, cerebellum and spinal cord) as well as in corresponding cell body areas (raphe´dorsalis, medianus, pontis and magnus). This effect was antagonized by bicuculline. The inhibition of serotonin (5-HT) synthesis induced by a single progabide administration was accentuated on repeated treatment in the striatum, prefrontal cortex and cerebellum but was similar to that seen after acute treatment in the other areas. Local infusion of high concentrations of GABA or GABA mimetics into the striatum, septum or substantia nigra failed to modify 5-HTP accumulation in these areas. Cerebral hemitransection antagonized the ability of progabide (1200 mg/kg i.p.) to diminish 5-HTP accumulation in the striatum, hippocampus and prefrontal cortex. Intra-raphe´dorsalis infusion of muscimol (0.1–100 ng) or GABA (1–100 μg) decreased 5-HT synthesis in the corresponding projection areas (e.g. striatum, substantia nigra, cortex) but not in the hippocampus or cerebellum. Conversely, intra-raphe´medianus infusion of these drugs diminished 5-HTP accumulation in the corresponding projection areas (e.g. hippocampus, septum, cortex) but not in the striatum or cerebellum. Intra-raphe´dorsalis or medianus injection of GABA antagonists (bicuculline, picrotoxinin, RU-5135) was without effect on cerebral 5-HT synthesis but antagonized the diminution of the amine synthesis observed in corresponding projection areas after intra-raphe´dorsalis or medianus infusion of muscimol or GABA. These results suggest that GABA exerts an inhibitory (non-tonic) control over central serotonergic neurons which is mediated via GABA receptors located in the raphe´nuclei.