Haloperidol downregulates phospholipase A(2) signaling in rat basal ganglia circuits.
Our laboratory has developed an in vivo method to quantitatively evaluate phospholipase A(2) (PLA(2))-mediated signal transduction in brain regions of rodents. In this method, quantitative autoradiography is used to identify brain uptake of intravenously injected, radiolabeled arachidonic acid ([3H]AA). Dopamine D(2) receptors are coupled to G-proteins that activate PLA(2), releasing AA from the stereospecifically numbered (sn) 2 position of phospholipids, and regional [3H]AA uptake is proportional to the rate of release. In the present experiment, the D(2) antagonist haloperidol (1.0 mg/kg i.p.) or the drug vehicle was administered to male adult rats for 21 days. Rats were infused 3 days later with 1.75 mCi/kg [3H]AA (i.v.), anesthetized and decapitated 20 min after infusion onset, and brains were processed for quantitative autoradiography. Chronic haloperidol significantly decreased [3H]AA incorporation in two primary dopaminergic basal ganglia-frontal cortex circuits, the mesocorticolimbic and nigrostriatal systems, while insignificant changes in AA incorporation were noted in other brain regions. These results suggest that one mechanism by which haloperidol exerts its effect is by downregulating D(2)-mediated PLA(2) signaling involving AA release in basal ganglia-frontal cortex circuitry.
Section on Brain Physiology and Metabolism, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. cmyers@mprc.umaryland.edu
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Myers
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Contreras
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Chang
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Rapoport
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Appel
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000493:pharmacokinetics; D001345:Autoradiography; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D010741:Phospholipases A / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014316:Tritium
D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D014316:Tritium; D016718:Arachidonic Acid; D010741:Phospholipases A; D006220:Haloperidol; D004298:Dopamine