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 D2-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 D2-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 E2 (PGE2), 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 PGE2 concentration. Affected regions belong to dopaminergic circuits and have high D2-like receptor densities. Chronic carbamazepine pretreatment prevented the quinpirole-induced increments in k* and in PGE2. These findings are consistent with the hypothesis that effective mood stabilizers generally downregulate brain AA signaling via D2-like receptors, and that this signaling is upregulated in bipolar disorder.
Basselin
Mireille
M
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bldg. 9, Room 1S126, Bethesda, MD 20892, USA. mirvasln@mail.nih.gov
Chang
Lisa
L
Chen
Mei
M
Bell
Jane M
JM
Rapoport
Stanley I
SI
D000465:Algorithms; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000502:physiology*; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D001923:Brain Chemistry / Q000187:drug effects; D002220:Carbamazepine / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013929:Thromboxane B2 / Q000378:metabolism
D018692:Antimanic Agents; D018491:Dopamine Agonists; D005231:Fatty Acids, Unsaturated; D010743:Phospholipids; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D016718:Arachidonic Acid; D002220:Carbamazepine; D013929:Thromboxane B2; D015232:Dinoprostone