FUNCTIONAL-CHANGES IN RAT NIGRAL GABA(A) RECEPTORS INDUCED BY DEGENERATION OF THE STRIATONIGRAL GABAERGIC PATHWAY - AN ELECTROPHYSIOLOGICALSTUDY OF RECEPTORS INCORPORATED INTO XENOPUS OOCYTES

Expression of rat brain gamma-aminobutyric acid type A (GABA(A)) recep tors in Xenopus laevis oocytes can be achieved by injection of the ooc ytes with synaptosomes, This approach has now been applied to evaluate changes in the function of nigral GABA(A) receptors after degeneratio n of the striatonigral GABAergic pathway induced by the unilateral inf usion of kainic acid into the rat striatum, Ten days after striatal in jection, synaptosomal membranes were prepared from the substantia nigr a and introduced into oocytes, Nigral GABA(A) receptors incorporated i nto the oocyte cell membrane were then characterized electrophysiologi cally under voltage-clamp conditions. The maximal amplitude of GABA-in duced Cl- currents in oocytes injected with synaptosomes from denervat ed substantia nigra was twice that observed in oocytes injected with s ynaptosomes from control substantia nigra. The concentration of GABA r equired for the half-maximal response did not differ between the two g roups of oocytes. In addition, the potentiation of GABA-induced curren ts by the benzodiazepine diazepam (1 mu M) and the steroid derivative allopregnanolone (3 mu M) was increased by similar to 65 and 60%, resp ectively, in oocytes injected with synaptosomes from denervated substa ntia nigra compared with those injected with control synaptosomes. The concentrations of diazepam and allopregnanolone giving half-maximal r esponses were not affected by denervation. In contrast, the inhibitory effects of the benzodiazepine receptor inverse agonists FG 7142 (10 m u M) and 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid ethyl ester (1 mu M) were reduced by 48 and 38%, respectively, after denerva tion. These results indicate that the up-regulation of nigral GABA(A) receptors induced by degeneration of the striatonigral GABAergic pathw ay is associated with an increased efficacy of positive allosteric mod ulators, such as benzodiazepines and steroids, and with a reduced effi cacy of negative allosteric modulators such as beta-carbolines.