D-Amphetamine Stimulates D2 Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

Abstract

In rat brain, dopaminergic D2-like but not D1-like receptors can be coupled to phospholipase A2 (PLA2) activation, to release the second messenger, arachidonic acid (AA, 20:4n-6), from membrane phospholipids. In this study, we hypothesized that D-amphetamine, a dopamine-releasing agent, could initiate such AA signaling. The incorporation coefficient, k∗ (brain radioactivity/integrated plasma radioactivity) for AA, a marker of the signal, was determined in 62 brain regions of unanesthetized rats that were administered i.p. saline, D-amphetamine (2.5 or 0.5 mg/kg i.p.), or the D2-like receptor antagonist raclopride (6 mg/kg, i.v.) before saline or 2.5 mg/kg D-amphetamine. After injecting [1-14C]AA intravenously, k∗ was measured by quantitative autoradiography. Compared to saline-treated controls, D-amphetamine 2.5 mg/kg i.p. increased k∗ significantly in 27 brain areas rich in D2-like receptors. Significant increases were evident in neocortical, extrapyramidal, and limbic regions. Pretreatment with raclopride blocked the increments, but raclopride alone did not alter baseline values of k∗. In independent experiments, D-amphetamine 0.5 mg/kg i.p. increased k∗ significantly in only seven regions, including the nucleus accumbens and layer IV neocortical regions. These results indicate that D-amphetamine can indirectly activate brain PLA2 in the unanesthetized rat, and that activation is initiated entirely at D2-like receptors. D-Amphetamine's low-dose effects are consistent with other evidence that the nucleus accumbens, considered a reward center, is particularly sensitive to the drug.