Chronic carbamazepine administration attenuates dopamine D2-like receptor-initiated signaling via arachidonic acid in rat brain

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.