Chronic Carbamazepine Administration Attenuates Dopamine D2-like Receptor-Initiated Signaling via Arachidonic Acid in Rat Brain

Abstract

Observations that dopaminergic antagonists are beneficial in bipolar disorder and that dopaminergic agonists can produce mania suggest that bipolar disorder involves excessive dopaminergic transmission. Thus, mood stabilizers used to treat the disease might act in part by downregulating dopaminergic transmission. In agreement, we reported that dopamine D 2 -like receptor mediated signaling involving arachidonic acid (AA, 20:4n-6) was downregulated in rats chronically treated with lithium. To see whether chronic carbamazepine, another mood stabilizer, did this as well, we injected i.p. saline or the D 2 -like receptor agonist, quinpirole (1 mg/kg), into unanesthetized rats that had been pretreated for 30 days with i.p. carbamazepine (25 mg/kg/day) or vehicle, and used quantitative autoradiography to measure regional brain incorporation coefficients (k*) for AA, markers of signaling. We also measured brain prostaglandin E 2 (PGE 2 ), an AA metabolite. In vehicle-treated rats, quinpirole compared with saline significantly increased k* for AA in 35 of 82 brain regions examined, as well as brain PGE 2 concentration. Affected regions belong to dopaminergic circuits and have high D 2 -like receptor densities. Chronic carbamazepine pretreatment prevented the quinpirole-induced increments in k* and in PGE 2 . These findings are consistent with the hypothesis that effective mood stabilizers generally downregulate brain AA signaling via D 2 -like receptors, and that this signaling is upregulated in bipolar disorder.

Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder

“…Rat brains were prepared, microwaved and used as reported previously (Basselin et al , 2008; Basselin et al , 2007a). Eicosanoid concentrations were measured with polyclonal PGE 2 and TXB 2 ELISA assay kits (Oxford Biochemical Research, USA).…”

“…In the present study, we hypothesized that LTG, like lithium, valproate and carbamazepine, when given chronically to rats (Basselin et al , 2006a; Basselin et al , 2008; Basselin et al , 2007a), would block NMDAR-initiated AA signaling in rat brain, and dampen other parameters of the AA metabolic cascade stimulated by NMDA. Confirming this would support our hypothesis that a common mechanism for the action of FDA-approved mood stabilizers in BD is down-regulation of the brain AA cascade that involves inhibition of NMDAR-mediated AA signaling (Rapoport et al , 2009; Rapoport and Bosetti, 2002).…”

“…When glutamate or NMDA binds to an NMDAR, extracellular Ca 2+ enters the cell and activates, among other enzymes, Ca 2+ -dependent-cytosolic phospholipase A 2 type IV (cPLA 2 -IV), which selectively releases arachidonic acid (AA, 20:4n-6) from cell membrane phospholipids (Basselin et al , 2006a; Basselin et al , 2008; Basselin et al , 2007a; Clark et al , 1991; Dumuis et al , 1988; Ramadan et al , 2010). Consistent with a hyperglutamatergic state, the postmortem BD brain shows up-regulated markers of AA metabolism, including cPLA 2 , cyclooxygenase (COX)-2, and membrane prostaglandin E synthase, which converts AA to pro-inflammatory prostaglandin (PG)E 2 (Kim et al , 2011).…”

“…increased k* and J in for AA in many brain regions. The increases could be blocked by pretreatment with the specific NMDAR antagonist, MK-801, or with each of three mood stabilizers effective against BD, namely lithium, valproate or carbamazepine (Basselin et al , 2006a; Basselin et al , 2008; Basselin et al , 2007a). We have also found that lithium and carbamazepine, when administered chronically at therapeutically relevant concentrations, reduced mRNA, protein, and activity levels of cPLA 2 -IV, and each of the three drugs, as well as lamotrigine (LTG), another FDA-approved mood stabilizer (Bowden, 2005; FDA, 2009), decreased protein and mRNA of COX-2 in rat brain (Lee et al , 2008; Rao et al , 2007b; Rao et al , 2007c; Rao et al , 2005; Rapoport et al , 2009).…”

Chronic Administration of Valproic Acid Reduces Brain NMDA Signaling via Arachidonic Acid in Unanesthetized Rats

“…In chronic vehicle-treated rats, acute NMDA (25 mg/kg) produced repeated cycles of activity (head weaving and body movements) lasting on average 4 s, following by a ''calm'' period averaging 9 s, with the net cycling period lasting a mean of 95 s ( Table 1). The mean durations of the Values are the means ± SD (n = 4-6) measured before [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]AA infusion. * P \ 0.05; ** P \ 0.001 effect of 25 mg/kg, i.p.…”