ALPHA-2-ADRENOCEPTOR POTENTIATES GLYCINE RECEPTOR-MEDIATED TAURINE RESPONSE THROUGH PROTEIN-KINASE-A IN RAT SUBSTANTIA-NIGRA NEURONS

1. The modulatory effect of alpha 2 adrenoceptor on the taurine respon se was investigated in substantia nigra (SN) neurons acutely dissociat ed from the rat using a nystatin perforated-patch recording mode under voltage-clamp conditions. 2. Complete cross-desensitization was obser ved between 10(-3) M glycine and 3 x 10(-3) M taurine-induced currents . Both currents were antagonized by 10(-6) M strychnine, thus indicati ng that taurine acts on strychnine-sensitive glycine receptor on the S N neurons. 3. The simultaneous application of norepinephrine (NE) with prazosin (10(-5) M) and propranolol (10(-5) M) potentiated the taurin e response (I-tau) in an NE concentration-dependent manner at a holdin g potential (V-H) of -40 mV. Clonidine mimicked the NE effect on the I -tau, thus indicating the involvement of alpha 2 adrenoceptor activati on in the potentiation of I-tau. 4. Alpha 2 adrenoceptor activation by NE with prazosin and propranolol significantly potentiated the peak a mplitude of I-tau without shifting the taurine concentration-response relationships either to left or right side. The respective concentrati ons of taurine for the threshold, half maximal and maximal responses i n the presence of 10(-4) M NE with prazosin (10(-5) M) and propranolol (10(-5) M) were 3 x 10(-5) M, 3.1 x 10(-4) M, and 3 x 10(-3) M. The s ame concentrations in the absence of NE were 3 x 10(-5) M, 3.2 x 10(-4 ) M, and 3 x 10(-3) M, respectively. 5. The reversal potentials of I-t au with and without NE were very close to the theoretical Cl- equilibr ium potential, thus indicating that the potentiation of I-tau by alpha 2 adrenoceptor activation was due to an increase in the taurine-induc ed Cl- currents. 6. Forskolin (3 x 10(-5) M) and isobutylmethylxanthin e (3 x 10(-5) M) suppressed the peak amplitude of I-tau. In the presen ce of dibutyryl cyclic AMP (10(-4) M), which also suppressed I-tau, al pha 2 adrenoceptor activation failed to potentiate I-tau. 7. N-[2(meth ylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride (H-89) mimic ked the effect of alpha 2 adrenoceptor activation on I-tau. In additio n, the potentiation of I-tau by alpha 2 adrenoceptor was not observed in the presence of 10(-6) M H-89. 8. The treatment of SN neurons with pertussis toxin (500 ng/ml) for 18 h completely abolished the facilita tory effect of alpha 2 adrenoceptor on I-tau. 9. These results suggest that the activation of alpha 2 adrenoceptor coupled with IAP-sensitiv e GTP binding protein decreases the intracellular cyclic AMP and cycli c AMP-dependent protein kinase activity, thus resulting in the potenti ation of glycine receptor-mediated taurine response in rat SN neurons.