D₁ Receptor Mediated Trophic Action of Dopamine on the Synthesis of GABA at the Terminals of Striatal Projections

Abstract

There is no doubt that degeneration of the dopaminergic innervation of the basal ganglia affects GABAergic activity in these structures. Among the parameters of GABAergic activity affected is the activity of the enzyme in charge of the synthesis of GABA, glutamic acid decarboxylase. Several approaches have been followed to test the effect of the degeneration on the activity of the enzyme. One approach has been to see whether the activity of the enzyme is affected by Parkinson’s disease (McGeer et al., 1971; Lloyd and Hornykiewicz, 1973; McGeer and McGeer, 1976; Javoy-Agid et al., 1981). There is consensus that Parkinson’s disease markedly reduces GAD activity in internal globus pallidus and substantia nigra (most probably in pars reticulata). However conflicting results have been found in the striatum. Here some authors (Lloyd and Hornykiewicz, 1973) have found a significant decrease in GAD activity, but others (McGeer and McGeer, 1976; Perry et al., 1983) have not found any effect of the disease on the activity of the enzyme. Another approach has been to see whether experimentally induced degeneration of the dopaminergic nigrostriatal system affects GAD activity. Without exception, it has been found that the degeneration of the dopaminergic nigrostriatal system (induced by 6-hydroxydopamine) increases GAD activity in the rat neostriatum (Vincent et al., 1978; Segovia and Garcia-Muñoz, 1987; Vernier et al, 1988; Segovia et al., 1989, 1990, 1991). Degeneration of the dopaminergic input to neostriatum not only increases GAD activity but GAD mRNA as well (Segovia et al., 1990). From this, these authors have proposed that dopaminergic neurons down regulate the gene expression for GAD in neostriatal GABAergic neurons. In other words, the dopaminergic innervation appears to exert a tonic inhibitory action on GAD activity mediated by a down regulation in the synthesis of GAD due to a decrease in GAD mRNA. This proposition is the opposite of that of Lloyd and Hornykiewicz, who based on the observation that levodopa partially recovered the GAD activity in the basal ganglia of parkinsonian brains (Lloyd and Hornykiewicz, 1973) proposed that “GAD-containing neurons could be under a continuous “trophic” influence of the dopaminergic system”, adding that “degeneration of the dopaminergic pathway might result in a biochemical “atrophy” of the GAD neurones”. How to reconcile these two propositions? The conflicting results may arise, in part, from the conditions in which GAD activity was measured, that is, in the presence of saturating concentrations of substrate (glutamic acid) and cofactor (pyridoxal phosphate). It appears that these conditions do not reflect the true functional GAD activity of the GABAergic neurons (Miller et al., 1978; Itoh and Uchimura, 1981).