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-HT(2A/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-HT(2A/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(2alpha) 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-HT(2A/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.
Basselin
Mireille
M
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. mirvasln@mail.nih.gov
Fox
Meredith A
MA
Chang
Lisa
L
Bell
Jane M
JM
Greenstein
Dede
D
Chen
Mei
M
Murphy
Dennis L
DL
Rapoport
Stanley I
SI
D000662:Amphetamines / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001345:Autoradiography / Q000379:methods; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000378:metabolism; D002849:Chromatography, Gas; D015237:Dinoprost; D015232:Dinoprostone; D005227:Fatty Acids / Q000097:blood; D010134:Fenclonine / Q000494:pharmacology; D019416:Head Movements / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013929:Thromboxane B2 / Q000378:metabolism; D014851:Wakefulness
D000662:Amphetamines; D002247:Carbon Isotopes; D005227:Fatty Acids; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C493231:Slc6a4 protein, mouse; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases; D054510:Phospholipases A2, Cytosolic; D015232:Dinoprostone; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D010134:Fenclonine