Knocking Out the Dopamine Reuptake Transporter (DAT) Does not Change the Baseline Brain Arachidonic Acid Signal in the Mouse

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 J_in, 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 J_in 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 J_in 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.

KEYWORDS: :

• arachidonic acid
• dopamine
• dopamine transporter
• knockout
• mouse
• phospholipase A₂