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

Abstract

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 D2-like (D2, D3, and D4) receptor signaling involving AA when given chronically to awake rats. We hypothesized that valproate (VPA), with mood-stabilizing properties, would also reduce the D2-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, Jin, markers of AA signaling and metabolism, were measured by quantitative autoradiography after intravenous [1-14C]AA infusion. Whole brain concentrations of prostaglandin (PG)E2 and thromboxane (TX)B2 also were measured. Results Quinpirole compared to saline significantly increased k* in 40 of 83 brain regions, and increased brain concentrations of PGE2 in chronic vehicle-treated rats. VPA treatment by itself reduced concentrations of plasma unesterified AA and whole brain PGE2 and TXB2, and blocked the quinpirole-induced increments in k* and PGE2. Conclusion These results further support our hypothesis that similar to lithium and carbamazepine, VPA downregulates brain dopaminergic D2-like receptor-signaling involving AA.

Imaging brain signal transduction and metabolism via arachidonic and docosahexaenoic acid in animals and humans

“…Each of the agents reduced brain COX-2 expression, whereas VPA also reduced COX-1 expression. Each agent also reduced brain PGE 2 concentration, and VPA like CBZ decreased the brain TXB 2 concentration (Basselin et al, 2007a; Basselin et al, 2008a; Basselin et al, 2008b; Bosetti et al, 2002; Bosetti et al, 2003; Ghelardoni et al, 2004; Ramadan et al, 2011b). Lithium and CBZ each reduced expression and DNA binding of activator protein 2 (AP-2), a cPLA 2 transcription factor (Rao et al, 2005; Rao et al, 2007).…”

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

“…Hyperdopaminergic signalling (via upregulation of GSK-3 ) and an upregulated brain arachidonic acid cascade may contribute to bipolar disorder (Ramadan et al, 2011;Bazinet, 2009) as well as to food and drug addiction (Zhuang et al, 2001;Baik, 2013). The endocannabinoid-arachidonic acid pathway may be an important part in the neural machinery underlying relapse which is the resumption of drug taking following a period of abstinence (Yamamoto et al, 2005).…”

“…The endocannabinoid-arachidonic acid pathway may be an important part in the neural machinery underlying relapse which is the resumption of drug taking following a period of abstinence (Yamamoto et al, 2005). Lithium and valproate attenuated brain dopaminergic D2, D3 and D4 receptor signalling involving arachidonic acid when given chronically (Ramadan et al, 2011). Chronic lithium and valproate decrease arachidonic acid turn-over and downregulate brain cyclooxygenase 2 (COX 2) and prostaglandin E 2), thereby decreasing the phospholipase A2-arachidonic acid dependent metabolites and reducing excitotoxicity / neuro-inflammation-induced upregulation of the markers Bosetti et al, 2002.…”

“…Cocaine increases expression of SIRTI which probably increases NF-kappa β to maintain the addiction state (Russo et al, 2009) and resveratrol-induced activation of SIRTI enhances the motivational properties of cocaine (Kenny, 2011). Chronic valproate (Ramadan et al, 2011) and metformin Hristova, 2011) may block D2-like receptor-mediated brain signalling via arachidonic acid. Cannabinoid CB2 agonists modulate midbrain dopamine neuronal activity and dopamine-related behaviour in mice Oriaifo et al, 2015).…”

Does Chronic Administration of Sodium Valproate to Juvenile Rats Induce Movement Disorder and Cognitive Dysfunction during Adulthood?

“…Patients can also develop bradykinesia, rigidity, hyperreflexia, dysphagia, anarthria and aphonia, which constitute Parkinsonism plus Syndrome [9]. The movement disorder after chronic SV treatment is attributed to its ability to reduce D2 signalling in the brain [10].…”