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Chronic valproate treatment blocks D2-like receptor-mediated brain signaling via arachidonic acid in rats.

AbstractBACKGROUND AND 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).
CONCLUSION:
These results further provide evidence that mood stabilizers downregulate brain dopaminergic D(2)-like receptor signaling involving AA.
AuthorsEpolia Ramadan, Mireille Basselin, Ameer Y Taha, Yewon Cheon, Lisa Chang, Mei Chen, Stanley I Rapoport
JournalNeuropharmacology (Neuropharmacology) Vol. 61 Issue 8 Pg. 1256-64 (Dec 2011) ISSN: 1873-7064 [Electronic] England
PMID21839100 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
CopyrightPublished by Elsevier Ltd.
Chemical References
  • Antimanic Agents
  • Carbon Radioisotopes
  • Dopamine Agonists
  • Dopamine Antagonists
  • Receptors, Dopamine D2
  • Arachidonic Acid
  • Thromboxane B2
  • Valproic Acid
  • Dinoprostone
Topics
  • Analysis of Variance
  • Animals
  • Antimanic Agents (blood, pharmacology)
  • Arachidonic Acid (metabolism, pharmacokinetics)
  • Autoradiography
  • Brain (drug effects, metabolism)
  • Carbon Radioisotopes (pharmacokinetics)
  • Dinoprostone (metabolism)
  • Dopamine Agonists (pharmacology)
  • Dopamine Antagonists (pharmacology)
  • Male
  • Rats
  • Rats, Inbred F344
  • Receptors, Dopamine D2 (metabolism)
  • Signal Transduction (drug effects)
  • Thromboxane B2 (metabolism)
  • Valproic Acid (blood, pharmacology)

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