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

Neuropharmacology. 2011 Dec;61(8):1256-64. doi: 10.1016/j.neuropharm.2011.07.025. Epub 2011 Aug 3.


Background 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Antimanic Agents / blood
  • Antimanic Agents / pharmacology*
  • Arachidonic Acid / metabolism*
  • Arachidonic Acid / pharmacokinetics
  • Autoradiography
  • Brain / drug effects*
  • Brain / 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
  • Valproic Acid / pharmacology*


  • Antimanic Agents
  • Carbon Radioisotopes
  • Dopamine Agonists
  • Dopamine Antagonists
  • Receptors, Dopamine D2
  • Arachidonic Acid
  • Thromboxane B2
  • Valproic Acid
  • Dinoprostone