ABSTRACT
Background. Dopamine transporter (DAT) homozygous knockout (DAT−/−) mice have a 10-fold higher extracellular (DA) concentration in the caudate-putamen and nucleus accumbens than do wildtype (DAT+/+) mice, but show reduced presynaptic DA synthesis and fewer postsynaptic D2 receptors. One aspect of neurotransmission involves DA binding to postsynaptic D2-like receptors coupled to cytosolic phospholipase A2 (cPLA2), which releases the second messenger, arachidonic acid (AA), from synaptic membrane phospholipid. We hypothesized that tonic overactivation of D2-like receptors in DAT−/− mice due to the excess DA would not increase brain AA signaling, because of compensatory downregulation of postsynaptic DA signaling mechanisms. Methods: [1–14C]AA was infused intravenously for 3 min in unanesthetized DAT+/+, heterozygous (DAT+/−), and DAT−/− mice. AA incorporation coefficients k* and rates Jin, markers of AA metabolism and signaling, were imaged in 83 brain regions using quantitative autoradiography; brain cPLA2-IV activity also was measured. Results: Neither k* nor Jin for AA in any brain region, or brain cPLA2-IV activity, differed significantly among DAT−/−, DAT+/–, and DAT+/+ mice. Conclusions: These results differ from reported increases in k* and Jin for AA, and in brain cPLA2 expression, in serotonin reuptake transporter (5-HTT) knockout mice, and suggest that postsynaptic dopaminergic neurotransmission mechanisms involving AA are downregulated despite elevated DA in DAT–/– mice.