Chronic lithium chloride administration to unanesthetized rats attenuates brain dopamine D2-like receptor-initiated signaling via arachidonic acid.
We studied the effect of lithium chloride on dopaminergic neurotransmission via D2-like receptors coupled to phospholipase A2 (PLA2). In unanesthetized rats injected i.v. with radiolabeled arachidonic acid (AA, 20:4 n-6), regional PLA2 activation was imaged by measuring regional incorporation coefficients k* of AA (brain radioactivity divided by integrated plasma radioactivity) using quantitative autoradiography, following administration of the D2-like receptor agonist, quinpirole. In rats fed a control diet, quinpirole at 1 mg/kg i.v. increased k* for AA significantly in 17 regions with high densities of D2-like receptors, of 61 regions examined. Increases in k* were found in the prefrontal cortex, frontal cortex, accumbens nucleus, caudate-putamen, substantia nigra, and ventral tegmental area. Quinpirole, 0.25 mg/kg i.v. enhanced k* significantly only in the caudate-putamen. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, neither 0.25 mg/kg nor 1 mg/kg quinpirole increased k* significantly in any region. Orofacial movements following quinpirole were modified but not abolished by LiCl feeding. The results suggest that downregulation by lithium of D2-like receptor signaling involving PLA2 and AA may contribute to lithium's therapeutic efficacy in bipolar disorder.
Basselin
Mireille
M
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. mirvasln@mail.nih.gov
Chang
Lisa
L
Bell
Jane M
JM
Rapoport
Stanley I
SI
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000502:physiology*; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects*; D004032:Diet; D018491:Dopamine Agonists / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D018692:Antimanic Agents; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D018021:Lithium Chloride