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Effect of S-COMT deficiency on behavior and extracellular brain dopamine concentrations in mice

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Abstract

Introduction

Catechol-O-methyltransferase (COMT) has soluble (S-COMT) and membrane bound (MB-COMT) isoforms. Our aims were to assess the behavioral phenotype of S-COMT mutant mice and to clarify the role of MB-COMT in dopamine metabolism in different brain areas.

Methods

Behavioral phenotype of the S-COMT mutant mice was assessed using a test battery designed to describe anxiety phenotype, spontaneous locomotor activity, sensorymotor gating, social behavior, and pain sensitivity. Microdialysis was used to explore the effect of S-COMT deficiency on extracellular dopamine under an L-dopa load (carbidopa /L-dopa 30/10 mg/kg i.p.).

Results

In behavioral tests, mature adult S-COMT mutants that only possessed MB-COMT exhibited enhanced acoustic startle without alterations in sensorimotor gating. They also showed barbering of vibrissae and nonaggressive social dominance, suggesting a change in their social interactions. In addition, S-COMT deficiency slightly and sex-dependently affected spinal pain reflex and the effect of morphine on hot-plate latency. In microdialysis studies under L-dopa load, S-COMT mutants of both sexes had higher accumbal dopamine levels, but male S-COMT mutant mice showed paradoxically lower prefrontal cortical dopamine concentrations than wild-type animals. S-COMT deficiency induced the accumulation of 3,4-dihydroxyphenylacetic acid in all brain areas, which was accentuated after L-dopa loading. The lack of S-COMT decreased extracellular homovanillic acid levels. However, after L-dopa loading, homovanillic acid concentrations in the prefrontal cortex of S-COMT mutants were similar to those of wild-type mice.

Conclusion

A lack of S-COMT has a notable, albeit small, brain-area and sex-dependent effect on the O-methylation of dopamine and 3,4-dihydroxyphenylacetic acid in the mouse brain. It also induces subtle changes in mouse social interaction behaviors and nociception.

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References

  • Ahl AS (1986) The role of vibrissae in behaviour: a status review. Vet Res Comm 10:245–268

    Article  CAS  Google Scholar 

  • Akil M, Kolachana BS, Rothmond DA, Hyde TM, Weinberger DR, Kleinman JE (2003) Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 23:2008–2013

    CAS  PubMed  Google Scholar 

  • Babovic D, O’Tuathaigh CM, O’Connor AM, O’Sullivan GJ, Clifford JJ, Tighe O, Croke DT, Karayiorgou M, Gogos JA, Cotter D, Waddington JL (2008) Phenotypic characterization of cognition and social behavior in mice with heterozygous versus homozygous deletion of catechol-O-methyltransferase. Neuroscience 155:1021–1029

    Article  CAS  PubMed  Google Scholar 

  • Crawley JN (2006) What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. Wiley, Hoboken

    Google Scholar 

  • Du X, Schwander M, Moresco EMY, Viviani P, Haller C, Hildebrand MS, Pak K, Tarantino L, Roberts A, Richardson H, Koob G, Najmabadi H, Ryan AF, Smith RJH, Müller U, Beutler B (2008) A catechol-O-methyltransferase that is essential for auditory function in mice and humans. Proc Natl Acad Sci USA 105:14609–14614

    Article  CAS  PubMed  Google Scholar 

  • Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, Karayiorgou M (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 95:9991–9996

    Article  CAS  PubMed  Google Scholar 

  • Guldberg HC, Marsden CA (1975) Catechol-O-methyltransferase: pharmacological aspects and physiological role. Pharmacol Rev 27:135–206

    CAS  PubMed  Google Scholar 

  • Haasio K, Huotari M, Nissinen E, Männistö PT (2003) Tissue histopathology, clinical chemistry and behaviour of adult Comt-gene-disrupted mice. J Appl Toxicol 23:213–219

    Article  CAS  PubMed  Google Scholar 

  • Hong J, Shu-Leong H, Tao X, Lap-Ping Y (1998) Distribution of catechol-O-methyltransferase expression in human central nervous system. Neuroreport 9:2861–2864

    Article  CAS  PubMed  Google Scholar 

  • Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A, Hyttinen J, Männistö PT (2002) Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 15:246–256

    Article  PubMed  Google Scholar 

  • Kaakkola S, Wurtman RJ (1992) Effects of COMT inhibitors on striatal dopamine metabolism: A microdialysis study. Brain Res 587:241–249

    Article  CAS  PubMed  Google Scholar 

  • Kaakkola S, Männistö PT, Nissinen E (1987) Striatal membrane-bound and soluble catechol-O-methyltransferase after selective neural lesions in the rat. J Neural Transm 69:221–228

    Article  CAS  PubMed  Google Scholar 

  • Käenmäki M, Tammimäki A, Garcia-Horsman JA, Myöhänen T, Schendzielorz N, Karayiorgou M, Gogos JA, Männistö PT (2009) Importance of the two forms of catechol-O-methyltransferase (COMT) in L-dopa metabolism: a pharmacokinetic study in two types of Comt gene modified mice. Brit J Pharmacol 158:1884–1894

    Article  Google Scholar 

  • Kalueff AV, Minasyan A, Keisala T, Shah TZ, Tuohimaa P (2006) Hair barbering in mice: Implications for neurobehavioral research. Behav Processes 71:8–15

    Article  CAS  PubMed  Google Scholar 

  • Kambur O, Männistö PT, Viljakka K, Reenilä I, Lemberg K, Kontinen VK, Karayiorgou M, Gogos JA, Kalso E (2008) Stress-induced analgesia and morphine responses are changed in catechol-O-methyltransferase-deficient male mice. Basic Clin Pharmacol Toxicol 103:367–373

    Article  CAS  PubMed  Google Scholar 

  • Karhunen T, Tilgmann C, Ulmanen I, Panula P (1995a) Neuronal and non-neuronal catechol-O-methyltransferase in primary cultures of rat brain cells. Int J Dev Neurosci 13:825–834

    Article  CAS  PubMed  Google Scholar 

  • Karhunen T, Tilgmann C, Ulmanen I, Panula P (1995b) Catechol-O-methyltransferase (COMT) in rat brain: Immunoelectron microscopic study with an antiserum against rat recombinant COMT protein. Neurosci Lett 187:57–60

    Article  CAS  PubMed  Google Scholar 

  • Koch M (1999) The neurobiology of startle. Prog Neurobiol 59:107–128

    Article  CAS  PubMed  Google Scholar 

  • Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34:202–4210

    Article  Google Scholar 

  • Lundström K, Salminen M, Jalanko A, Savolainen R, Ulmanen I (1991) Cloning and characterization of human placental catechol-O-methyltransferase cDNA. DNA Cell Biol 10:181–189

    Article  PubMed  Google Scholar 

  • Männistö PT, Kaakkola S (1999) Catechol-O-methyltransferase (COMT): Biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51:593–628

    PubMed  Google Scholar 

  • Mazei MS, Pluto CP, Kirkbride B, Pehek EA (2002) Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat. Brain Res 936:58–67

    Article  CAS  PubMed  Google Scholar 

  • Morón JA, Brockington A, Wise RA, Rocha BA, Hope BT (2002) Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: Evidence from knock-out mouse lines. J Neurosci 22:389–395

    PubMed  Google Scholar 

  • Nackley-Neely AG, Tan KS, Fecho K, Flood P, Diatchenko L, Maixner W (2007) Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2 and beta3 adrenergic receptors. Pain 128:199–208

    Article  Google Scholar 

  • Napolitano A, Bellini G, Borroni E, Zurcher G, Bonuccelli U (2003) Effects of peripheral and central catechol-O-methyltransferase inhibition on striatal extracellular levels of dopamine: a microdialysis study in freely moving rats. Parkinsonism Relat Disord 9:145–150

    Article  PubMed  Google Scholar 

  • Negredo P, Martin YB, Lagares A, Castro J, Villacorta JA, Avendano C (2009) Trigeminothalamic barrelette neurons: natural structural side asymmetries and sensory input-dependent plasticity in adult rats. Neuroscience 163:1242–1254

    Article  CAS  PubMed  Google Scholar 

  • Odlind C, Reenilä I, Männistö PT, Juvonen R, Uhlen S, Gogos JA, Karayiorgou M, Hansell P (2002) Reduced natriuretic response to acute sodium loading in COMT gene deleted mice. BMC Physiol 2:14

    Article  PubMed  Google Scholar 

  • Papaleo F, Crawley JN, Song J, Lipska BK, Pickel J, Weinberger DR, Chen J (2008) Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci 28:8709–8723

    Article  CAS  PubMed  Google Scholar 

  • Rakvåg TT, Klepstad P, Baar C, Kvam TM, Dale O, Kaasa S, Krokan HE, Skorpen F (2005) The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 116:73–78

    Article  PubMed  Google Scholar 

  • Rivett A, Francis A, Roth JA (1983) Distinct cellular localization of membrane-bound and soluble forms of catechol-O-methyltransferase in brain. J Neurochem 40:215–219

    Article  CAS  PubMed  Google Scholar 

  • Roth JA (1992) Membrane-bound catechol-O-methyltransferase: a reevaluation of its role in the O-methylation of the catecholamine neurotransmitters. Rev Physiol Biochem Pharmacol 120:1–29

    Article  CAS  PubMed  Google Scholar 

  • Roussos P, Giakoumaki SG, Bitsios P (2009) Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818C/G polymorphism. Biol Psychiatry 66:997–1004

    Article  CAS  PubMed  Google Scholar 

  • Salminen M, Lundström K, Tilgmann C, Savolainen R, Kalkkinen N, Ulmanen I (1990) Molecular cloning and characterization of rat liver catechol-O-methyltransferase. Gene 93:241–247

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Andrade G, Kendrick KM (2009) The main olfactory system and social learning in mammals. Behav Brain Res 200:323–335

    Article  PubMed  Google Scholar 

  • Sellien H, Ebner FF (2007) Rapid plasticity follows whisker pairing in barrel cortex of the awake rat. Exp Brain Res 177:1–14

    Article  PubMed  Google Scholar 

  • Sesack SR, Hawrylack VA, Matus C, Guido MA, Levey AI (1998) Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J Neurosci 18:2697–2708

    CAS  PubMed  Google Scholar 

  • Staiger JF, Bisler S, Schleicher A, Gass P, Stehle JH, Zilles K (2000) Exploration of a novel environment leads to the expression of inducible transduction factors in barrel-related columns. Neuroscience 99:7–16

    Article  CAS  PubMed  Google Scholar 

  • Tenhunen J, Ulmanen I (1993) Production of rat soluble and membrane-bound catechol O-methyltransferase forms from bifunctional mRNAs. Biochem J 296:595–600

    CAS  PubMed  Google Scholar 

  • Tenhunen J, Salminen M, Lundström K, Kiviluoto T, Savolainen R, Ulmanen I (1994) Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 223:1049–1059

    Article  CAS  PubMed  Google Scholar 

  • Tillerson JL, Caudle WM, Parent JM, Gong C, Schallert T, Miller GW (2006) Olfactory discrimination deficits in mice lacking the dopamine transporter or the D2 dopamine receptor. Behav Brain Res 172:97–105

    Article  CAS  PubMed  Google Scholar 

  • Törnwall M, Kaakkola S, Tuomainen P, Kask A, Männistö PT (1994) Comparison of two new inhibitors of catechol O-methylation on striatal dopamine metabolism: a microdialysis study in rats. Br J Pharmacol 112:13–18

    PubMed  Google Scholar 

  • Yavich L, Forsberg M, Gogos JA, Karayiorgou M, Männistö PT (2007) Site specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum. J Neurosci 27:10196–10202

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Ms Anna Niemi and Mrs Kati Rautio for excellent technical assistance. These studies were supported by a grant from the Academy of Finland (No. 1131915/2008 and No. 117881/2006) and Sigrid Juselius Foundation to PTM.

Conflict of interest

The authors do not have a financial relationship with the organizations that sponsored the research. The authors have full control of all primary data, and the journal is allowed to review the data upon request.

Ethical standards

All procedures with animals were performed according to European Community Guidelines for the use of experimental animals (European Communities Council Directive 86/609/EEC), EU Commission recommendation on guidelines for the accommodation and care of animals used for experimental and other scientific purposes (2007/526/EC), and Finnish Act on the Use of Animals for Experimental Purposes. Research plan was reviewed and approved by the Animal Experiment Board of the Provincial Office in Southern Finland.

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Authors and Affiliations

  1. Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland

    Anne Tammimäki, Mikko Käenmäki, Oleg Kambur, Tiina Keisala, Eeva Karvonen, J. Arturo García-Horsman & Pekka T. Männistö

  2. Neuroscience Center, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland

    Natalia Kulesskaya & Heikki Rauvala

  3. Institute of Behavioral Genetics, University of Colorado at Boulder, UCB 447, Boulder, CO, 80309-0447, USA

    Anne Tammimäki

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  1. Anne Tammimäki
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Correspondence to Anne Tammimäki.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1

COMT activities in the female and male kidney membrane fractions of S-COMT mutant and wild-type mice (DOC 530 kb)

Online Resource 2

Behavioral test battery (DOC 33 kb)

Online Resource 3

Quantification of dopamine and dopamine metabolites in brain dialysates (DOC 28 kb)

Online Resource 4

Motor activity of S-COMT mutant and wild-type mice (DOC 32 kb)

Online Resource 5

The effect of S-COMT deficiency on stress-induced analgesia in the tail flick test, in the hot plate test, mechanic nociceptive thresholds as well as in inflammatory pain in male and female mice (DOC 1641 kb)

Online Resource 6

The area under the concentration curve values in the dorsal striatum, nucleus accumbens, and prefrontal cortex after carbidopa/l-dopa treatment (DOC 40 kb)

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Tammimäki, A., Käenmäki, M., Kambur, O. et al. Effect of S-COMT deficiency on behavior and extracellular brain dopamine concentrations in mice. Psychopharmacology 211, 389–401 (2010). https://doi.org/10.1007/s00213-010-1944-2

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  • DOI: https://doi.org/10.1007/s00213-010-1944-2

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