Decreased striatal release of acetylcholine following withdrawal from long-term treatment with haloperidol: modulation by cholinergic, dopamine-D1 and -D2 mechanisms.
The effect of chronic treatment with haloperidol (2.7-5.3 mumol/kg/day) on K(+)-evoked release of [3H]acetylcholine (ACh) from superfused slices of the striatum was assessed. Acute injections of haloperidol (0.7-13.3 mumol/kg) produced 5-54% increases in the release of [3H]ACh in the striatum. Chronic treatment with haloperidol for 2.5 and 5 months also resulted in enhanced release of [3H]ACh in the striatum (28-35%). However, withdrawal from 2.5 and 5 months of treatment produced 34 and 38% decreases in K(+)-evoked release of [3H]ACh in the striatum, respectively. The drug SKF 38393 (D1-agonist), produced concentration-dependent (0.1-10 microM) increases (24-59%) in the release of [3H]ACh in the striatum which were blocked by the selective D1-antagonist, SCH 23390. The effect of stimulation of D1-receptors was significantly reduced after 2.5 or 5 months of chronic treatment with haloperidol. Both LY171555 (D2-agonist) and carbachol (muscarinic agonist) produced concentration-dependent (0.1-10 microM) inhibitions of the release of [3H]ACh in the striatum (LY171555: 28-62%; carbachol: 23-63%). Long-term treatment with haloperidol (2.5 and 5 months) elicited increases in sensitivity to the effect of LY171555, while the effect of carbachol was diminished only after the 5-month treatment period. These findings demonstrate that withdrawal from chronic exposure to haloperidol in the rat results in a reduction in the release of acetylcholine in the striatum. This effect is accompanied by (1) attenuated dopaminergic D1 mechanisms which ordinarily facilitate evoked release of ACh, (2) enhanced D2 mechanism which elicits inhibition of the release of ACh in the striatum, and (3) diminished muscarinic inhibitory influence which regulates the release of ACh.
Department of Psychiatry, Medical College of Pennsylvania/EPPI, Philadelphia 19129.
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Butkerait
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013469:Sulpiride / Q000494:pharmacology
D001552:Benzazepines; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D013469:Sulpiride; D006220:Haloperidol; D000109:Acetylcholine