Neuroleptics cause stimulation of dopamine D1 receptors and their desensitization after chronic treatment.
Recent evidence indicates that the neuroleptic-induced increase of in vivo acetylcholine output in the striatum does not depend on the relief of cholinergic neurons from the inhibitory control by dopamine, but on increased dopamine output onto dopamine D1 receptors. The present microdialysis study was aimed at finding if the neuroleptic-induced increase in striatal acetylcholine release persists after chronic treatment, and how it is correlated with dopamine output. Rats were chronically treated with the dopamine D2 receptor antagonists, haloperidol and (-)-sulpiride (0.5 mg/kg and 50 mg/kg i.p., respectively, daily, for 30 days). The stimulant effect of both neuroleptics on striatal dopamine release persisted unaltered throughout the chronic treatment (by about 100% over basal values). In contrast, the enhancing effects of haloperidol and (-)-sulpiride on striatal acetylcholine release remained unchanged up to day 12 of treatment. Thereafter, tolerance developed, so that both neuroleptics became totally ineffective on day 30 of treatment. Both on day 1 and 30, the neuroleptic-induced dopamine release was reversed by gamma-butyrolactone (gamma-hydroxybutyric acid lactone), suggesting that this effect is mediated by enhanced neuronal activity. On day 1 and day 10, the neuroleptic-induced acetylcholine release was antagonized by the blockade of dopamine D1 receptors with SCH 39166 (trans-(-)-(6aS,13bR)-11-chloro-6,6a,7,8,9,13b- hexahydro-7-methyl-5H-benzo[d]napht[2,1-b]azepine-12-ol, hydrochloride) (0.5 mg/kg i.p.). SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride) (5 mg/kg i.p.) increased acetylcholine release by about 50% in control rats and in rats treated with (-)-sulpiride or haloperidol for up to 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)
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G.M. Everett' Laboratory of Neuropsychopharmacology, Bernard B. Brodie Department of Neuroscience, University of Cagliari, Italy.
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D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004361:Drug Tolerance; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000502:physiology; D013469:Sulpiride / Q000494:pharmacology*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D013469:Sulpiride; D006220:Haloperidol; D000109:Acetylcholine; D004298:Dopamine