Further evidence for, and nature of, the facilitatory GABAergic influence on central noradrenergic transmission

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Abstract
In order to explore the nature of the facilitatory GABAergic control of cerebral noradrenergic neurons, we have studied the effect of a variety of GABA mimetics (given systemically or injected locally into brain areas containing noradrenergic cell bodies or terminals) on several indices of noradrenaline turnover in the rat brain. Systemic administration of both direct and indirect acting GABA mimetics enhanced; 1) the pargyline induced accumulation of normetanephrine in the hypothalamus; 2) total DOPEG levels in a number of brain regions innervated by noradrenergic neurons; 3) both DOPAC and MOPEG levels in noradrenergic cell body areas (A1, A2 and A6). These effects are probably mediated by GABAA receptors as specific GABAA or mixed GABAA/GABAB agonists but not the GABAB agonist baclofen enhanced noradrenaline turnover. Interruption of noradrenergic impulse flow (by local injection of tetrodotoxin or by hemitransection) blocked the ability of progabide to increase DOPEG concentrations in the hypothalamus and cerebral cortex. Similarly, the coadministration of clonidine with progabide antagonized the progabide-induced increase in hypothalamic total DOPEG levels. Co-administration of yohimbine with progabide provoked an additive effect on hypothalamic DOPEG levels at moderate but not at high doses of yohimbine. Thus, the acceleration of noradrenaline turnover induced by GABA mimetics appears to depend on ongoing activity in noradrenergic neurons and occurs via an increase in neuronal discharges. Local injection of muscimol into the nucleus accumbens or hypothalamus failed to affect DOPEG levels in these structures; similarly, local injection of muscimol into the locus coeruleus failed to modify DOPEG levels in corresponding noradrenergic projection areas. These data indicate that the GABAergic influence is not exerted via GABA receptors located on noradrenergic cell bodies or nerve endings. Furthermore, since systemically administered progabide still increased hypothalamic DOPEG levels after ibotenate-induced destruction of the hypothalamic neuronal cell bodies, a presynaptic modulation of noradrenergic neurons by local GABAergic interneurons is excluded. Chemical desctruction of serotoninergic pathways or enhancement of 5-HT transmission by quipazine failed to alter the ability of progabide to increase cerebral DOPEG levels. Moreover, seopolamine or naloxone also failed to affect the progabide-induced increase in cerebral DOPEG levels. These results exclude the implication of serotoninergic, cholinergic and opioid systems in the mediation of the facilitatory influence of GABA on noradrenergic neurons. It is concluded that the facilitatory GABAergic influence on cerebral noradrenergic transmission is probably indirect and mediated via GABAergic synapses involved in transsynaptic neuronal circuits (the nature of which remains to be defined) regulating noradrenergic cell activity.