Interactions of dopaminergic and GABAergic neurotransmission: Impact of 6- hydroxydopamine lesions into the substantia nigra of rats

We have evaluated (a) the effects of dopamine (DA) denervation on χ- aminobutyric acid (GABA) turnover in terms of in vive rate of GABA synthesis; (b) effects of DAD₁ and D₂ receptor agonists and antagonists on the in vivo GABA synthesis rate; and (c) the effects of GABA(A) and GABA(B) receptor agonists and antagonists on the intracellular accumulation of cAMP in the ipsi- and contralateral striatum and substantia nigra of rats after unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal DA system (DA depletion >90%). We observed that the in vive rate of GABA synthesis remained unaffected when the DA levels were depleted by 95% and 50% in the ipsilateral striatum and substantia nigra, respectively, compared with the contralateral intact side. Basal cAMP levels were increased significantly (92%) in the ipsilateral striatum only, compared with the contralateral intact side. The DA D₂ agonist quinpirole (1.0 mg/kg) significantly decreased the rate of GABA formation in the ipsi- and contralateral striatum and substantia nigra. In contrast, the D₂ antagonist (±)-sulpiride (25.0 mg/kg) augmented the rate of GABA formation in the DA-denervated and intact striatum and substantia nigra. On the other hand, D₁ agonist SKF 38393 (10.0 mg/kg) did not affect the GABA synthesis rate. The in vivo rate of GABA synthesis also remained unaffected after administration of D₁ antagonist SCH 23390 (1.0 mg/kg) except in the ipsilateral striatum. The GABA(B) receptor agonist (-)-baclofen (100 μM) significantly decreased the forskolin-induced increase in intracellular accumulation of cAMP in slices from both the lesioned and intact striatum and substantia nigra which were attenuated by the GABA(B) antagonist 2-hydroxysaclofen (100 μM). In addition, GABA (300 μM) also decreased the cAMP accumulation in both sides of striatum and substantia nigra. The GABA(A) receptor antagonist bicuculline (100 μM) failed to block the (-)-baclofen- or GABA-mediated response on cAMP accumulation. Taken together our results suggest that DA denervation does not affect the GABA synthesis rate in vivo, and it is the DA D₂ receptor subtype, not the D₁ receptor, involved in regulating the GABA synthesis in the striatonigral system. On the other hand, the GABA(B) subtype of receptor, not GABA(A) subtype, is possibly involved in controlling the activity of nigrostriatal dopaminergic neurons by regulating the cAMP-generating system.