Chronic lithium chloride administration to unanesthetized rats attenuates brain dopamine D2-like receptor-initiated signaling via arachidonic acid

We studied the effect of lithium chloride on dopaminergic neurotransmission via D-2-like receptors coupled to phospholipase A(2) (PLA(2)). In unanesthetized rats injected i.v. with radiolabeled arachidonic acid ( AA, 20: 4 n-6), regional PLA(2) activation was imaged by measuring regional incorporation coefficients k* of AA ( brain radioactivity divided by integrated plasma radioactivity) using quantitative autoradiography, following administration of the D-2-like receptor agonist, quinpirole. In rats fed a control diet, quinpirole at 1 mg/kg i.v. increased k* for AA significantly in 17 regions with high densities of D-2-like receptors, of 61 regions examined. Increases in k* were found in the prefrontal cortex, frontal cortex, accumbens nucleus, caudate - putamen, substantia nigra, and ventral tegmental area. Quinpirole, 0.25 mg/kg i.v. enhanced k* significantly only in the caudate - putamen. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, neither 0.25 mg/kg nor 1 mg/kg quinpirole increased k* significantly in any region. Orofacial movements following quinpirole were modified but not abolished by LiCl feeding. The results suggest that downregulation by lithium of D-2-like receptor signaling involving PLA(2) and AA may contribute to lithium's therapeutic efficacy in bipolar disorder.