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 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.

Fig. 1

Coronal autoradiographs of brains showing effects of quinpirole and carbamazepine on regional AA incorporation coefficients k* in rats. Values of k* (ml/s/g brain × 10⁻⁴) are given on a color scale from 4 (blue) to 8 (yellow-orange). Abbreviations: Acb, nucleus accumbens; Acg, anterior cingulate cortex; CPu, caudate-putamen; DB, diagonal band; Fr 8, frontal cortex area 8; Fr 10, frontal cortex area 10; Mot, motor cortex. Note: For interpretation of the references to color in this figure legend, the reader is referred to the online version of this article

Fig. 2

Difference patterns of k* responses to quinpirole and carbamazepine in sagittal representation of rat brain. Regions in which k* was increased significantly (P < 0.05) compared with chronic vehicle + saline are solid black, regions in which k* was decreased significantly are hatched. List of regions: A, amygdala; Acb, nucleus accumbens; Aud, auditory cortex; av, anteroventral thalamic nucleus; CbG, cerebellar gray matter; CbW, crebellar white matter; CPu, caudate putamen; DLG, dorsal lateral geniculate nucleus; Fr, frontal cortex; GP, globus pallidus; HB, habenular nuclei; HIP, hippocampus; HYP, hypothalamus; IC, inferior colliculus; IPC, interpeduncular nucleus; MM, mammillary nucleus; mG, medial geniculate nucleus; MolCBG, molecular layer of cerebellar gray matter; Mot, motor cortex; OT, olfactory tubercle; PF, prefrontal cortex; pt, paratenial thalamic nucleus; SN, substantia nigra; S, septum; SS, somatosensory cortex; SC, superior colliculus; SCgl, gray layer of superior colliculus; STH, subthalamic nucleus; THa, thalamus; Vis, visual cortex