Imaging Elevated Brain Arachidonic Acid Signaling in Unanesthetized Serotonin Transporter (5-HTT)-Deficient Mice

Certain polymorphisms reduce serotonin (5-HT) reuptake transporter (5-HTT) function and increase susceptibility to psychiatric disorders. Heterozygous (5-HTT+/-)-deficient mice, models for humans with these polymorphisms, have elevated brain 5-HT concentrations and behavioral abnormalities. As postsynaptic 5-HT2A/2C receptors are coupled to cytosolic phospholipase A(2) (cPLA(2)), which releases arachidonic acid (AA) from membrane phospholipid, 5-HTT-deficient mice may have altered brain AA signaling and metabolism. To test this hypothesis, signaling was imaged as an AA incorporation coefficient k* in unanesthetized homozygous knockout (5-HTT-/-), 5-HTT+/- and wild-type (5-HTT+/+), mice following saline (baseline) or 1.5 mg/kg s.c. DOI, a partial 5-HT2A/2C receptor agonist. Enzyme activities, metabolite concentrations, and head-twitch responses to DOI were also measured. Baseline k* was widely elevated by 20-70% in brains of 5-HTT+/- and 5-HTT-/- compared to 5-HTT+/+ mice. DOI increased k* in 5-HTT+/+ mice, but decreased k* in 5-HTT-deficient mice. Brain cPLA(2) activity was elevated in 5-HTT-deficient mice; cyclooxygenase activity and prostaglandin E-2 and F-2 alpha and thromboxane B-2 concentrations were reduced. Head-twitch responses to DOI, although robust in 5-HTT+/+ and 5-HTT+/- mice, were markedly fewer in 5-HTT-/- mice. Pretreatment with para-chlorophenylalanine, a 5-HT synthesis inhibitor, restored head twitches in 5-HTT-/- mice to levels in 5-HTT+/+ mice. We propose that increased baseline values of k* in 5-HTT-deficient mice reflect tonic cPLA(2) stimulation through 5-HT2A/2C receptors occupied by excess 5-HT, and that reduced k* and head-twitch responses to DOI reflected displacement of receptor-bound 5-HT by DOI with a lower affinity. Increased baseline AA signaling in humans having polymorphisms with reduced 5-HTT function might be identified using positron emission tomography. Neuropsychopharmacology (2009) 34, 1695-1709; doi:10.1038/npp.2008.227; published online 14 January 2009