Effect of the new gamma-aminobutyric acid agonist SL 76 002 on striatal acetylcholine: relation to neuroleptic-induced extrapyramidal alterations.
A single injection of the new GABA receptor agonist SL 76 002 reduces the activity of striatal cholinergic neurons. Behaviorally, SL 76 002 (in large dose) potentiates haloperidol-induced catalepsy and antagonizes apomorphine-induced stereotypies. Repeated coadministration of haloperidol and SL 76 002 for 10 days does not affect the tolerance of the cholinergic system which is observed after haloperidol alone. In contrast, coadministration of the two drugs results in a marked prevention of the tolerance to the cataleptogenic action of haloperidol and of the increased sensitivity to apomorphine. It is suggested that (a) GABA mimetic medication inhibits striatal cholinergic transmission by a direct action on ACh cells; (b) behavioral effects resulting from alteration of dopaminergic transmission are--in contrast to the current view--not exclusively mediated by changes of cholinergic activity; (c) GABA affects striatal function via at least two mechanisms: by a direct input on, and independently from, both dopaminergic and cholinergic neurons; and (d) SL 76 002 possibly exerts a beneficial action in L-DOPA-induced abnormal movements in parkinsonian patients and neuroleptic-induced tardive dyskinesias.
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000502:physiology; D005116:Extrapyramidal Tracts / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*
D014150:Antipsychotic Agents; C017985:progabide; D005680:gamma-Aminobutyric Acid; D006220:Haloperidol; D000109:Acetylcholine; D004298:Dopamine