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-hydroxybutyrate-like drug, inhibits spontaneous firing and induces a pacemaker-like discharge pattern in nigral dopamine (DA)-containing neurons. Recent evidence has suggested that these effects could be mediated by GABAB receptors and, thus, is likely to involve G protein intermediaries. To test this hypothesis, extracellular single-unit recording techniques were used to assess the effects of S(-)HA-966 in animals that had received an intranigral injection 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 observed in the basal firing properties of DA cells recorded in control and PT-lesioned animals. However, in marked contrast to the inhibitory effects observed in uninjected and sham-lesioned animals, S(-)HA-966 significantly increased the firing rate of apomorphine-insensitive DA neurons in PT-lesioned rats. The excitatory effects of S(-)HA-966 were accompanied by a significant reduction in bursting activity and an increase in the regularity of firing. These data indicate that the inhibitory effects of S(-)HA-966 are mediated locally within the substantia nigra by a PT-sensitive substrate, presumably a G protein-coupled receptor.
Shepard
P D
PD
Maryland Psychiatric Research Center, Baltimore 21228, USA.
Connelly
S T
ST
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003714:Denervation; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D037342:Pertussis Toxin; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D058788:GABA-B Receptor Antagonists; D011760:Pyrrolidinones; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; C001369:1-hydroxy-3-amino-2-pyrrolidone; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine