title: Chronic valproate treatment blocks D2-like receptor-mediated brain signaling via arachidonic acid in rats.
abstract: OBJECTIVE
  Hyperdopaminergic signaling and an upregulated brain arachidonic acid (AA) cascade may contribute to bipolar disorder (BD). Lithium and carbamazepine, FDA-approved for the treatment of BD, attenuate brain dopaminergic D(2)-like (D(2), D(3), and D(4)) receptor signaling involving AA when given chronically to awake rats. We hypothesized that valproate (VPA), with mood-stabilizing properties, would also reduce D(2)-like-mediated signaling via AA.
  
  
  METHODS
  An acute dose of quinpirole (1 mg/kg) or saline was administered to unanesthetized rats that had been treated for 30 days with a therapeutically relevant dose of VPA (200 mg/kg/day) or vehicle. Regional brain AA incorporation coefficients, k*, and incorporation rates, J(in), markers of AA signaling and metabolism, were measured by quantitative autoradiography after intravenous [1-(14)C]AA infusion. Whole brain concentrations of prostaglandin (PG)E(2) and thromboxane (TX)B(2) also were measured.
  
  
  RESULTS
  Quinpirole compared to saline significantly increased k* in 40 of 83 brain regions, and increased brain concentrations of PGE(2) in chronic vehicle-treated rats. VPA treatment by itself reduced concentrations of plasma unesterified AA and whole brain PGE(2) and TXB(2), and blocked the quinpirole-induced increments in k* and PGE(2).
  
  
  CONCLUSIONS
  These results further provide evidence that mood stabilizers downregulate brain dopaminergic D(2)-like receptor signaling involving AA.
authors.affiliation: Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. ramadanir@mail.nih.gov
authors.forename: Epolia
authors.initials: E
authors.lastname: Ramadan
authors.forename: Mireille
authors.initials: M
authors.lastname: Basselin
authors.forename: Ameer Y
authors.initials: AY
authors.lastname: Taha
authors.forename: Yewon
authors.initials: Y
authors.lastname: Cheon
authors.forename: Lisa
authors.initials: L
authors.lastname: Chang
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000097:blood / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D015232:Dinoprostone / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013929:Thromboxane B2 / Q000378:metabolism; D014635:Valproic Acid / Q000097:blood / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D016718:Arachidonic Acid; D013929:Thromboxane B2; D014635:Valproic Acid; D015232:Dinoprostone