Inhibitory influence of GABA on central serotonergic transmission. Involvement of the habenulo-raphé pathways in the GABAergic inhibition of ascending cerebral serotonergic neurons.

In order to explore the anatomical nature of the inhibitory GABAergic control of cerebral serotonergic neurons exerted at the level of the anterior raphé cells in the rat, we have studied the effect of GABA agonist agents (given systemically or infused locally into the raphé dorsalis or medianus) on cerebral 5-hydroxytryptophan (5-HTP) accumulation after lesion or pharmacological manipulation of various raphé inputs. Destruction of noradrenergic pathways by local injection of 6-hydroxydopamine in the pedunculus cerebellaris superior or by systemic injection of DSP-4 (50 mg/kg i.p.), or alteration of central dopaminergic transmission (by systemic administration of apomorphine or haloperidol) failed to modify the ability of progabide (400 mg/kg i.p.) or dipropylacetamide (150 mg/kg i.p.) to diminish 5-HTP accumulation in the striatum, hippocampus and substantia nigra. In contrast, electrolytic lesion of the habenular nuclei blocked the ability of these compounds (given systemically) to reduce 5-HTP accumulation both in serotonergic nerve terminal and cell body (raphé dorsalis and medianus) areas. A similar blockade of the effects of GABA mimetics was seen after ibotenate-induced lesion of the habenula but not after electrolytic lesion of the stria medullaris (which conveys most of the afferents to the habenula). Acute cessation of impulse flow in the habenulo-raphé tract also prevented the depamide-induced diminution of cerebral 5-HTP accumulation. Finally, interruption of nerve transmission in the habenulo-raphé pathways (by means of electrolytic lesion of the habenula or fasciculus retroflexus) blocked the ability of GABA (100 micrograms) or muscimol (50 ng) injected into the raphé dorsalis or medianus to reduce 5-HTP accumulation in the corresponding serotonergic nerve terminal areas. It is concluded that the GABAergic inhibition of ascending serotonergic neurons exerted in the raphé dorsalis and medianus depends upon an ongoing neuronal activity in the habenulo-raphé pathways; GABA may exert its inhibitory control over serotonergic neurons by tuning down a facilitatory influence on these cells exerted by the habenula.