GABA-mimetic drugs enhance apomorphine-induced contralateral turning in rats with unilateral nigrostriatal dopamine denervation: implications for the therapy of Parkinson's disease.
The underlying mechanisms responsible for advanced Parkinson's disease's becoming refractory to dopamimetic therapies are unclear. Postmortem brain studies indicate that patients with Parkinson's disease have decreased basal ganglia gamma-aminobutyric acid (GABA) function in addition to profound striatal dopamine (DA) deficiencies. In experimental animals, GABA-utilizing striatal and nigral projection neurons appear to mediate motor behaviors arising from the stimulation of striatal DA receptors by agonists. We have examined the ability of directly and indirectly acting GABA-mimetic drugs to alter turning behavior elicited by administering apomorphine, a DA agonist, to rats with unilateral lesions of dopaminergic nigrostriatal neurons. Low doses of directly acting postsynaptic GABA agonists (progabide, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin--3-01) or a neuronal GABA transport inhibitor (SKF 100330-A) potentiate apomorphine-induced turning. Higher doses of these agents or acute inhibition of GABA catabolism inhibits turning. Our results suggest that low doses of certain GABA mimetics will improve the responses of patients with Parkinson's disease to concurrent DA receptor agonist therapy.
D000480:Alkynes; D000614:Aminocaproates / Q000627:therapeutic use; D000818:Animals; D000978:Antiparkinson Agents; D001058:Apomorphine / Q000008:administration & dosage; D004357:Drug Synergism; D007555:Isoxazoles / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009539:Nicotinic Acids / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000627:therapeutic use*
D000480:Alkynes; D000614:Aminocaproates; D000978:Antiparkinson Agents; D007555:Isoxazoles; D009539:Nicotinic Acids; C017985:progabide; D005680:gamma-Aminobutyric Acid; C013785:4-amino-5-hexynoic acid; C045597:SK&F 100330-A; C015542:gaboxadol; D001058:Apomorphine