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

Overview

Journal Neuropsychopharmacology

Date 2009 Jan 16

PMID 19145225

Citations 21

Authors

Mireille Basselin

Meredith A Fox

Lisa Chang

Jane M Bell

Dede Greenstein

Mei Chen

Dennis L Murphy

Stanley I Rapoport

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Radiosynthesis of 20-[F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.

Van Valkenburgh J, Duro M, Burnham E, Chen Q, Wang S, Tran J Prostaglandins Leukot Essent Fatty Acids. 2022; 186:102510.

PMID: 36341886 PMC: 9888757. DOI: 10.1016/j.plefa.2022.102510.

Tissue pretreatment for LC-MS/MS analysis of PUFA and eicosanoid distribution in mouse brain and liver.

Reinicke M, Dorow J, Bischof K, Leyh J, Bechmann I, Ceglarek U Anal Bioanal Chem. 2019; 412(10):2211-2223.

PMID: 31865417 PMC: 7118053. DOI: 10.1007/s00216-019-02170-w.

Brain serotonin transporter binding, plasma arachidonic acid and depression severity: A positron emission tomography study of major depression.

Gopaldas M, Zanderigo F, Zhan S, Ogden R, Miller J, Rubin-Falcone H J Affect Disord. 2019; 257:495-503.

PMID: 31319341 PMC: 6886679. DOI: 10.1016/j.jad.2019.07.035.

Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders.

Rebholz H, Friedman E, Castello J Int J Mol Sci. 2018; 19(11).

PMID: 30428567 PMC: 6274737. DOI: 10.3390/ijms19113581.

Receptor binding profiles and behavioral pharmacology of ring-substituted N,N-diallyltryptamine analogs.

Klein L, Cozzi N, Daley P, Brandt S, Halberstadt A Neuropharmacology. 2018; 142:231-239.

PMID: 29499272 PMC: 6230509. DOI: 10.1016/j.neuropharm.2018.02.028.

References

Folch J, Lees M, SLOANE STANLEY G . A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957; 226(1):497-509. View

Baca-Garcia E, Vaquero-Lorenzo C, Diaz-Hernandez M, Rodriguez-Salgado B, Dolengevich-Segal H, Arrojo-Romero M . Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 31(2):416-20. DOI: 10.1016/j.pnpbp.2006.10.016. View

Fox M, Andrews A, Wendland J, Lesch K, Holmes A, Murphy D . A pharmacological analysis of mice with a targeted disruption of the serotonin transporter. Psychopharmacology (Berl). 2007; 195(2):147-66. DOI: 10.1007/s00213-007-0910-0. View

Zhang J, Goorha S, Raghow R, Ballou L . The tissue-specific, compensatory expression of cyclooxygenase-1 and -2 in transgenic mice. Prostaglandins Other Lipid Mediat. 2002; 67(2):121-35. DOI: 10.1016/s0090-6980(01)00177-0. View

Bosetti F . Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models. J Neurochem. 2007; 102(3):577-86. PMC: 2084377. DOI: 10.1111/j.1471-4159.2007.04558.x. View

Anton R, Wallis C, Randall C . In vivo regional levels of PGE and thromboxane in mouse brain: effect of decapitation, focused microwave fixation, and indomethacin. Prostaglandins. 1983; 26(3):421-9. DOI: 10.1016/0090-6980(83)90177-6. View

Sokoloff L . Energetics of functional activation in neural tissues. Neurochem Res. 1999; 24(2):321-9. DOI: 10.1023/a:1022534709672. View

Kaufmann W, Worley P, Pegg J, Bremer M, Isakson P . COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A. 1996; 93(6):2317-21. PMC: 39793. DOI: 10.1073/pnas.93.6.2317. View

Basselin M, Villacreses N, Chen M, Bell J, Rapoport S . Chronic carbamazepine administration reduces N-methyl-D-aspartate receptor-initiated signaling via arachidonic acid in rat brain. Biol Psychiatry. 2007; 62(8):934-43. PMC: 2131715. DOI: 10.1016/j.biopsych.2007.04.021. View

10.

Hu X, Lipsky R, Zhu G, Akhtar L, Taubman J, Greenberg B . Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet. 2006; 78(5):815-826. PMC: 1474042. DOI: 10.1086/503850. View

11.

Basselin M, Villacreses N, Langenbach R, Ma K, Bell J, Rapoport S . Resting and arecoline-stimulated brain metabolism and signaling involving arachidonic acid are altered in the cyclooxygenase-2 knockout mouse. J Neurochem. 2006; 96(3):669-79. DOI: 10.1111/j.1471-4159.2005.03612.x. View

12.

Pardue S, Rapoport S, Bosetti F . Co-localization of cytosolic phospholipase A2 and cyclooxygenase-2 in Rhesus monkey cerebellum. Brain Res Mol Brain Res. 2003; 116(1-2):106-14. DOI: 10.1016/s0169-328x(03)00262-6. View

13.

Rapoport S . In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling. J Mol Neurosci. 2001; 16(2-3):243-61; discussion 279-84. DOI: 10.1385/JMN:16:2-3:243. View

14.

Gottschalk L, Stone W, GLESER G, Iacono J . Anxiety and plasma free fatty acids (FFA). Life Sci. 1969; 8(2):61-8. DOI: 10.1016/0024-3205(69)90118-0. View

15.

Rao J, Ertley R, Rapoport S, Bazinet R, Lee H . Chronic NMDA administration to rats up-regulates frontal cortex cytosolic phospholipase A2 and its transcription factor, activator protein-2. J Neurochem. 2007; 102(6):1918-1927. DOI: 10.1111/j.1471-4159.2007.04648.x. View

16.

Marques F, Hutz M, Bau C . Influence of the serotonin transporter gene on comorbid disorders among alcohol-dependent individuals. Psychiatr Genet. 2006; 16(3):125-31. DOI: 10.1097/01.ypg.0000199449.07786.7d. View

17.

Toborek M, Malecki A, Garrido R, Mattson M, Hennig B, Young B . Arachidonic acid-induced oxidative injury to cultured spinal cord neurons. J Neurochem. 1999; 73(2):684-92. DOI: 10.1046/j.1471-4159.1999.0730684.x. View

18.

Mathews T, Fedele D, Coppelli F, Avila A, Murphy D, Andrews A . Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J Neurosci Methods. 2004; 140(1-2):169-81. DOI: 10.1016/j.jneumeth.2004.05.017. View

19.

Berg K, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke W . Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol. 1998; 54(1):94-104. View

20.

Qu Y, Villacreses N, Murphy D, Rapoport S . 5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter. Psychopharmacology (Berl). 2005; 180(1):12-20. DOI: 10.1007/s00213-005-2231-5. View