Knocking out the dopamine reuptake transporter (DAT) does not change the baseline brain arachidonic acid signal in the mouse

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 D ₂ receptors. One aspect of neurotransmission involves DA binding to postsynaptic D ₂-like receptors coupled to cytosolic phospholipase A ₂ (cPLA ₂), which releases the second messenger, arachidonic acid (AA), from synaptic membrane phospholipid. We hypothesized that tonic overactivation of D ₂-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 J _in, markers of AA metabolism and signaling, were imaged in 83 brain regions using quantitative autoradiography; brain cPLA ₂-IV activity also was measured. Results: Neither k* nor J _in for AA in any brain region, or brain cPLA ₂-IV activity, differed significantly among DAT ^-/-, DAT ^+/-, and DAT ^+/+ mice. Conclusions: These results differ from reported increases in k* and J _in for AA, and in brain cPLA ₂ 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.