Haloperidol-mediated phosphoinositide hydrolysis via direct activation of alpha1-adrenoceptors in frontal cerebral rat cortex.
In addition to its effect on D2 dopamine receptor blockades, haloperidol is able to interact with multiple neurotransmitters (NTs). Its action on phosphoinositide (PI) turnover was studied on cerebral cortex preparations. It induces an increase in inositol phosphate (IP) accumulation, which was only blunted by the alpha1-adrenoceptor blocker prazosin. Haloperidol maximal effect (Emax) was less than the effect of the full agonist norepinephrine (NE), and dose-response curves for both NE in the presence of submaximal doses of haloperidol and haloperidol in the presence of Emax doses of NE showed that haloperidol behaves as a partial agonist of cerebral alpha1-adrenoceptors. Its effect on PI hydrolysis is mediated through phospholipase C activation, as 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC) and 1-[6-([(17beta)-3-methoxyestra- 1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione) (U-73122) were able to abrogate both haloperidol and NE actions. Further, the typical neuroleptic exerts a direct activation of alpha1-adrenoceptors as its actions were not modified by cocaine and persisted in spite of chemical rat cerebral denervation with 6-hydroxydopamine (6-OHDA). The possibility that this agonistic action on alpha1-adrenoceptors would be involved in haloperidol side effects is also discussed.
Borda
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TG
Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas de la República Argentina (CONICET) y Universidad de Buenos Aires.
Cremaschi
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G
Sterin-Borda
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L
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology*; D006868:Hydrolysis; D009638:Norepinephrine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D010738:Type C Phospholipases / Q000378:metabolism
D014150:Antipsychotic Agents; D010716:Phosphatidylinositols; D018340:Receptors, Adrenergic, alpha-1; D010738:Type C Phospholipases; D006220:Haloperidol; D009638:Norepinephrine