PNMT Transgenic Mice Have an Aggressive Phenotype

Abstract

PNMT (phenylethanolamine-N-methyl-transferase) is the enzyme that catalyzes the formation of epinephrine from norepinephrine. In transgenic mice over-expressing PNMT, observations revealed a very high level of aggression compared to their background strain, C57BL/6J. To evaluate the influence of PNMT on aggression and emotionality in this transgenic line, single-sex male and female groups were independently established that consisted of either four wild-type mice or four transgenic mice overexpressing PNMT. The members of each group were littermates. Mixed single-sex groups consisting of two transgenic mice and two wild-type mice were also established. Almost no fights were observed within the female groups. In males, the transgenic line showed a significantly higher level of fighting than controls (p = 0.007) and mixed male groups (p = 0.02). Housing mice from the transgenic line in mixed groups with wild-type mice seems to decrease the level of aggression in the transgenic line. In conclusion, this is the first study to demonstrate a clear, significant increase in aggression arising from PNMT overexpression. This suggests an important role for central epinephrine levels in aggressive behavior.

Keywords

Epinephrine - Mice - Open field - Behavior - C57Bl/6

References

• 1 Snyder S H. Drugs and the brain. Scientific American Library New York; 1996
• 2 Haller J. Adrenomedullar Catecholamine Liberation and Carbohydrate-Metabolism During the 1St 30 Min of An Aggressive Encounter in Rats.  Physiol Behav. 1993;  54 195-197
• 3 Haller J, Makara G, Kruk M R. Catecholaminergic involvement in the control of aggression: Hormones, the peripheral sympathetic, and central noradrenergic systems.  Neurosci Biobehav R. 1998;  22 85-97
• 4 Mefford I N. Epinephrine in mammalian brain.  Prog Neuro-psychoph. 1988;  12 365-388
• 5 Cooper J R, Bloom F E, Roth R T. Norepinephrine and epinephrine. In: Cooper J, Bloom FE, and Roth R (eds) The biochemical basis of neuropharmacology. Oxford University Press Oxford; 1996: 226-292
• 6 Haller J, Makara G B, Kruk M R. Catecholaminergic involvement in the control of aggression: Hormones, the peripheral sympathetic, and central noradrenergic systems.  Neurosci Biobehav R. 1998;  22 85-97
• 7 Böttner A, Haidan A, Eisenhofer G, Kristensen K, Castle A L, Scherbaum W A, Schneider H, Chrousos G P, Bornstein S R. Increased body fat mass and suppression of circulating leptin levels in response to hypersecretion of epinephrine in phenylethanolamine-N-methyltransferase (PNMT)-overexpressing mice.  Endocrinology. 2000;  141 4239-4246
• 8 Nicklas W, Baneux P, Boot R, Decelle T, Deeny AA, Fumanelli M, Illgen-Wilcke B. Recommendations for the health monitoring of rodent and rabbit colonies in breeding and experimental units.  Lab Anim. 2002;  36 20-42
• 9 Hurst J L, Fang J, Barnard C J. The role of substrate odours in maintaining social tolerance between male house mice, Mus musculus domesticus.  Anim Behav. 1993;  45 997-1006
• 10 Hurst J L, Fang J, Barnard C. The role of substrate odours in maintaining social tolerance between male house mice, Mus musculus domesticus: relatedness, incidental kinship effects and the establishment of social status.  Anim Behav. 1994;  48 157-167
• 11 Gray S J, Hurst J L. The effects of cage cleaning on aggression within groups of male laboratory mice.  Anim Behav. 1995;  49 821-826
• 12 Jennings M, Batchelor G R, Brain P F, Dick A, Elliott H, Francis R J, Hubrecht R C, Hurst J L, Morton D B, Peters A G, Raymond R, Sales G D, Sherwin C M, West C D. Refining rodent husbandry: The mouse.  Lab Anim. 1998;  32 233-259
• 13 Van Loo P LP, Kruitwagen C LJJ, Van Zutphen L FM, Koolhaas J M, Baumans V. Modulation of aggression in male mice: Influence of cage cleaning regime and scent marks.  Anim Welfare. 2000;  9 281-295
• 14 Eisenhofer G, Goldstein D S, Stull R, Keiser H R, Sunderland T, Murphy D L, Kopin I J. Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase.  Clinical Chemistry. 1986;  32 2030-2033
• 15 Latham N, Mason G. From house mouse to mouse house: the behavioural biology of free-living Mus musculus and its implications in the laboratory.  Appl Anim Behav Sci. 2004;  86 261-289
• 16 Latham N, Mason G. From house mouse to mouse house: the behavioural biology of free-living Mus musculus and its implications in the laboratory.  Appl Anim Behav Sci. 2004;  86 261-289
• 17 Haemisch A, Voss T, Gärtner K. Effects of environmental enrichment on aggressive behaviour, dominance hierarchies, and endocrine states in male DBA/2J mice.  Physiol Behav. 1994;  56 1041-1048
• 18 Ely D L, Henry J P. Neuroendocrine response patterns in dominant and subordinate mice.  Horm Behav. 1978;  10 156-169
• 19 Maengwyn-Davies G D, Johnson D G, Thoa N B, Weise V K, Kopin I J. Influence of isolation and of fighting on adrenal Tyrosine hydroxylase and Phenylethanolamine-N-Methyltransferase activities in three strains of mice.  Psychopharmacologia. 1973;  28 339-350
• 20 Hucklebridge F H, Gamal-El-Din L, Brain P F. Social status and the adrenal medulla in the house mouse (Mus musculus, L.).  Behav Neural Biol. 1981;  33 345-363
• 21 Haemisch A, Gärtner K. Dissociation between adrenal tyrosinehydroxylase and phenylethanolamine N-methyltransferase activities following repeated experience of defeats in individually housed male DBA/2J mice.  Physiol Behav. 1996;  59 1117-1122
• 22 Butler R G. Population size, social behaviour, and dispersal in house mice: A quantitative investigation.  Anim Behav. 1980;  28 78-85
• 23 Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Müller U, Aguet M, Babinet C, Chen S hih , De Maeyer E. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA.  Science. 1995;  268 1763-1766
• 24 Abelson J L, Weg J G, Nesse R M, Curtis G C. Neuroendocrine responses to laboratory panic: Cognitive intervention in the doxapram model.  Psychoneuroendocrinology. 1996;  21 375-390
• 25 Cooper J, Bloom F E, Roth R T. Serotonin (5-hydroxytryptamine) and histamine. In: Cooper J, Bloom FE, Roth RT (Eds) The biochemical basis of neuropharmacology. Oxford University Press Oxford; 1996: 352-409
• 26 Nelson R J, Chiavegatto S. Molecular basis of aggression.  Trends Neurosci. 2001;  24 713-719
• 27 Miczek K A, Maxson S C, Fish E W, Faccidomo S. Aggressive behavioral phenotypes in mice.  Behav Brain Res. 2001;  125 167-181