Subchronic administration of GABAergic agonists elevates [3H]GABA binding and produces tolerance in striatal dopamine catabolism.
Directly and indirectly acting GABAergic agonists were assessed for their ability to alter striatal dopamine catabolism after subchronic administration (7-14 days) via subcutaneously implanted osmotic minipumps. THIP, kojic amine and baclofen failed to alter striatal DOPAC and HVA concentrations, but THIP and kojic amine were effective after a single acute dose. Striatal GABA levels proved difficult to elevate when inhibitors of GABA transaminase were released from minipumps, but a high dose of gamma-vinyl GABA increased GABA by 44% of control, although striatal dopamine and DOPAC levels were unaltered. [3H]GABA binding studies revealed that THIP and kojic amine, but not baclofen or gamma-acetylenic GABA, produced large increases in [3H]GABA 'A' binding (150 and 228% of control respectively) which were attributable to altered densities of binding sites without changes in affinity. Despite alterations in GABAergic function, nigrostriatal dopaminergic neurones seem to develop tolerance to the effects of GABAergic drugs.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000480:Alkynes; D000614:Aminocaproates / Q000494:pharmacology; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000480:Alkynes; D000614:Aminocaproates; D007555:Isoxazoles; D011753:Pyrones; D015102:3,4-Dihydroxyphenylacetic Acid; D000625:Aminooxyacetic Acid; D005680:gamma-Aminobutyric Acid; C013785:4-amino-5-hexynoic acid; C018990:kojic amine; D020888:Vigabatrin; D001418:Baclofen; C015542:gaboxadol; D004298:Dopamine