Pertussis toxin lesions of the rat substantia nigra block the inhibitory effects of the gamma-hydroxybutyrate agent S(-)HA-966 without affecting the basal firing properties of dopamine neurons

S(-)3-amino-1-hydroxypyrrolidone-2 (S(-)HA-966), a potent gamma-hydroxybuty rate-like drug, inhibits spontaneous firing and induces a pacemaker-like di scharge pattern in nigral dopamine (DA)-containing neurons. Recent evidence has suggested that these effects could be mediated by GABA(B) receptors an d, thus, is likely to involve G protein intermediaries. To test this hypoth esis, extracellular single-unit recording techniques were used to assess th e effects of S(-)HA-966 in animals that had received an intranigral injecti on of pertussis toxin (PT). Failure to respond to the inhibitory effects of apomorphine was taken as presumptive evidence that PT-sensitive G protein- coupled receptors had been inactivated. No significant differences were obs erved in the basal firing properties of DA cells recorded in control and PT -lesioned animals. However, in marked contrast to the inhibitory effects ob served in uninjected and sham-lesioned animals, S(-)HA-966 significantly in creased the firing rate of apomorphine-insensitive DA neurons in PT-lesione d mts, The excitatory effects of S(-)HA-966 were accompanied by a significa nt reduction in bursting activity and an increase in the regularity of firi ng. These data indicate that the inhibitory effects of S(-)HA-966 are media ted locally within the substantia nigra by a PT-sensitive substrate, presum ably a G protein-coupled receptor. [Neuropsychopharmacology 21:650-661, 199 9] (C) 1999 American College of Neuropsychopharmacology. Published by Elsev ier Science Inc.