Characterization of a dopamine transporter polymorphism and behavior in Belgian Malinois

BMC Genetics

Anita M Oberbauer¹  Claire Diederich²  Anouck Haverbeke²  Nathan Lybarger⁴  Debby Boehm³  Janelle M Belanger¹  Lisa Lit¹ 

[1] Department of Animal Science, University of California Davis, One Shields Ave, Davis, CA 95616, USA;Department of Veterinary Medicine, IVRU-NARILIS, University of Namur, 61 rue de Bruxelles, Namur 5000, Belgium;Precision Canine, Phoenix, Arizona, USA;Left Coast Canine, Marysville, CA, USA

关键词: Seizure;    Behavior;    Dopamine transporter;    Belgian Malinois;    Dog;   

Others  :  1087044
DOI  :  10.1186/1471-2156-14-45

 received in 2012-12-11, accepted in 2013-05-22,  发布年份 2013

【 摘 要 】

Background

The Belgian Malinois dog breed (MAL) is frequently used in law enforcement and military environments. Owners have reported seizures and unpredictable behavioral changes including dogs’ eyes “glazing over,” dogs’ lack of response to environmental stimuli, and loss of behavioral inhibition including owner-directed biting behavior. Dogs with severe behavioral changes may be euthanized as they can represent a danger to humans and other dogs. In the dog, the dopamine transporter gene (DAT) contains a 38-base pair variable number tandem repeat (DAT-VNTR); alleles have either one or two copies of the 38-base pair sequence. The objective of this study was to assess frequency of DAT-VNTR alleles, and characterize the association between DAT-VNTR alleles and behavior in MAL and other breeds.

Results

In an American sample of 280 dogs comprising 26 breeds, most breeds are predominantly homozygous for the DAT-VNTR two-tandem-repeat allele (2/2). The one-tandem-repeat allele is over-represented in American MAL (AM-MAL) (n = 144), both as heterozygotes (1/2) and homozygotes (1/1). All AM-MAL with reported seizures (n = 5) were 1/1 genotype. For AM-MAL with at least one “1” allele (1/1 or 1/2 genotype, n = 121), owners reported higher levels of attention, increased frequency of episodic aggression, and increased frequency of loss of responsiveness to environmental stimuli. In behavior observations, Belgian Military Working Dogs (MWD) with 1/1 or 1/2 genotypes displayed fewer distracted behaviors and more stress-related behaviors such as lower posture and increased yawning. Handlers’ treatment of MWD varied with DAT-VNTR genotype as did dogs’ responses to handlers’ behavior. For 1/1 or 1/2 genotype MWD, 1) lower posture after the first aversive stimulus given by handlers was associated with poorer obedience performance; 2) increased aversive stimuli during protection exercises were associated with decreased performance; 3) more aversive stimuli during obedience were associated with more aversive stimuli during protection; and 4) handlers used more aversive stimuli in protection compared with obedience exercises.

Conclusions

The single copy allele of DAT-VNTR is associated with owner-reported seizures, loss of responsiveness to environmental stimuli, episodic aggression, and hyper-vigilance in MAL. Behavioral changes are associated with differential treatment by handlers. Findings should be considered preliminary until replicated in a larger sample.

【 授权许可】

   
2013 Lit et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

Figure 3.

【 参考文献 】

• [1]Gainetdinov RR, Jones SR, Caron MG: Functional hyperdopaminergia in dopamine transporter knock-out mice. Biol Psychiatry 1999, 46(3):303-311.
• [2]Schultz W: Getting formal with dopamine and reward. Neuron 2002, 36(2):241-263.
• [3]Haddad PM, Dursun SM: Neurological complications of psychiatric drugs: clinical features and management. Hum Psychopharmacol 2008, 23(Suppl 1):15-26.
• [4]White DM, Van Cott AC: Clozapine (Clozaril), seizures, and EEG abnormalities. Am J Electroneurodiagnostic Technol 2007, 47(3):190-197.
• [5]Center for Disease Control and Prevention: Dog Bite Fact Sheet (2009). http://www.cdc.gov/HomeandRecreationalSafety/Dog-Bites/dogbite-factsheet.html webcite
• [6]Haverbeke A, De Smet A, Depiereux E, Giffroy J-M, Diederich C: Assessing undesired aggression in military working dogs. Appl Anim Behav Sci 2009, 117(1–2):55-62.
• [7]Chandler K: Canine epilepsy: what can we learn from human seizure disorders? Vet J 2006, 172(2):207-217.
• [8]Berg AT: Epilepsy, cognition, and behavior: the clinical picture. Epilepsia 2011, 52(Suppl 1):7-12.
• [9]Gerard ME, Spitz MC, Towbin JA, Shantz D: Subacute postictal aggression. Neurology 1998, 50(2):384-388.
• [10]Pontius AA: Violence in schizophrenia versus limbic psychotic trigger reaction: Prefrontal aspects of volitional action. Aggr Violent Behav 2004, 9(5):503-521.
• [11]Delgado-Escueta AV, Mattson RH, King L, Goldensohn ES, Spiegel H, Madsen J, Crandall P, Dreifuss F, Porter RJ: The nature of aggression during epileptic seizures (Reprinted from New England Journal of Medicine, vol 305, pg 711–716, 1981). Epilepsy Behav 2002, 3(6):550-556.
• [12]Ito M, Okazaki M, Takahashi S, Muramatsu R, Kato M, Onuma T: Subacute postictal aggression in patients with epilepsy. Epilepsy Behav 2007, 10(4):611-614.
• [13]Yankovsky AE, Veilleux M, Dubeau F, Andermann F: Post-ictal rage and aggression: a video-EEG study. Epileptic Disord 2005, 7(2):143-147.
• [14]Jochle W: Abnormal behavior and adaptation problems and their pharmacological control in dogs and cats. Tierarztliche Praxis Ausgabe Kleintiere Heimtiere 1998, 26(6):410-421.
• [15]Kanner AM: Psychosis of epilepsy: a Neurologist’s perspective. Epilepsy Behav 2000, 1(4):219-227.
• [16]Kanner AM: Recognition of the various expressions of anxiety, psychosis, and aggression in epilepsy. Epilepsia 2004, 45:22-27.
• [17]Tassinari CA, Tassi L, Calandra-Buonaura G, Stanzani-Maserati M, Fini N, Pizza F, Sartori I, Michelucci R, Lo Russo G, Meletti S: Biting behavior, aggression, and seizures. Epilepsia 2005, 46(5):654-663.
• [18]Goiz-Marquez G, Chacon SC, Ortiz HS, Lopez HS: Canine epilepsy. Vet Mex 2008, 39(3):279-321.
• [19]Dodman NH, Bronson R, Gliatto J: Tail chasing in a bull terrier. J Am Vet Med Assoc 1993, 202(5):758-760.
• [20]Dodman NH, Miczek KA, Knowles K, Thalhammer JG, Shuster L: Phenobarbital-responsive episodic dyscontrol (rage) in dogs. J Am Vet Med Assoc 1992, 201(10):1580-1583.
• [21]Dodman NH, Knowles KE, Shuster L, Moon-Fanelli AA, Tidwell AS, Keen CL: Behavioral changes associated with suspected complex partial seizures in bull terriers. J Am Vet Med Assoc 1996, 208(5):688-091.
• [22]Cornelissen JM, Hopster H: Dog bites in the Netherlands: a study of victims, injuries, circumstances and aggressors to support evaluation of breed specific legislation. Vet J 2010, 186(3):292-298.
• [23]Shihab N, Bowen J, Volk HA: Behavioral changes in dogs associated with the development of idiopathic epilepsy. Epilepsy & Behavior 2011, 21(2):160-167.
• [24]Mortensen OV, Amara SG: Dynamic regulation of the dopamine transporter. Eur J Pharmacol 2003, 479(1–3):159-170.
• [25]Le Strat Y, Ramoz N, Pickering P, Burger V, Boni C, Aubin HJ, Ades J, Batel P, Gorwood P: The 3’ part of the dopamine transporter gene DAT1/SLC6A3 is associated with withdrawal seizures in patients with alcohol dependence. Alcohol Clin Exp Res 2008, 32(1):27-35.
• [26]Tiihonen J, Kuikka J, Bergstrom K, Hakola P, Karhu J, Ryynanen OP, Fohr J: Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics. Nat Med 1995, 1(7):654-657.
• [27]Starr MS: The role of dopamine in epilepsy. Synapse 1996, 22(2):159-194.
• [28]Jones NC, Martin S, Megatia I, Hakami T, Salzberg MR, Pinault D, Morris MJ, O’Brien TJ, van den Buuse M: A genetic epilepsy rat model displays endophenotypes of psychosis. Neurobiol Dis 2010, 39(1):116-125.
• [29]UCSC Genome Browser. http://genome.ucsc.edu webcite
• [30]Arata S, Ogata N, Shimozuru M, Takeuchi Y, Mori Y: Sequences and polymorphisms of the canine monoamine transporter genes SLC6A2, SLC6A3, and SLC6A4 among five dog breeds. J Vet Med Sci 2008, 70(9):971-975.
• [31]Vage J, Lingaas F: Single nucleotide polymorphisms (SNPs) in coding regions of canine dopamine- and serotonin-related genes. BMC Genet 2008, 9:8.
• [32]Vage J, Bonsdorff TB, Arnet E, Tverdal A, Lingaas F: Differential gene expression in brain tissues of aggressive and non-aggressive dogs. BMC Vet Res 2010, 6:34. BioMed Central Full Text
• [33]Hejjas K, Vas J, Kubinyi E, Sasvari-Szekely M, Miklosi A, Ronai Z: Novel repeat polymorphisms of the dopaminergic neurotransmitter genes among dogs and wolves. Mamm Genome 2007, 18(12):871-879.
• [34]Parker HG, Kim LV, Sutter NB, Carlson S, Lorentzen TD, Malek TB, Johnson GS, DeFrance HB, Ostrander EA, Kruglyak L: Genetic structure of the purebred domestic Dog. Science 2004, 304(5674):1160-1164.
• [35]Raad van Beheer Association: Dutch Breeds. Netherlands: Raad van Beheer; 2002.
• [36]Lit L, Schweitzer JB, Iosif AM, Oberbauer AM: Owner reports of attention, activity, and impulsivity in dogs: a replication study. Behav Brain Funct 2010, 6(1):1. BioMed Central Full Text
• [37]Haverbeke A, Messaoudi F, Depiereux E, Stevens M, Giffroy JM, Diederich C: Efficiency of working dogs undergoing a new human familiarization and training program. J Vet Behav-Clin Appl Res 2010, 5(2):112-119.
• [38]Haverbeke A, Rzepa C, Depiereux E, Deroo J, Giffroy J-M, Diederich C: Assessing efficiency of a human familiarisation and training programme on fearfulness and aggressiveness of military dogs. Appl Anim Behav Sci 2010, 123(3–4):143-149.
• [39]Haverbeke A, Laporte B, Depiereux E, Giffroy JM, Diederich C: Training methods of military dog handlers and their effects on the team’s performances. Appl Anim Behav Sci 2008, 113(1–3):110-122.
• [40]Grillon C: Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology. Biol Psychiatry 2002, 52(10):958-975.
• [41]Armbruster D, Mueller A, Strobel A, Lesch K-P, Kirschbaum C, Brocke B: Variation in genes involved in dopamine clearance influence the startle response in older adults. J Neural Transm 2011, 118(9):1281-1292.
• [42]Hunnerkopf R, Strobel A, Gutknecht L, Brocke B, Lesch KP: Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits. Neuropsychopharmacology 2007, 32(12):2552-2560.
• [43]A.P.A: Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th edition. Washington, DC: American Psychiatric Association; 2000.
• [44]Hoexter M, Fadel G, Felício A, Calzavara M, Batista I, Reis M, Shih M, Pitman R, Andreoli S, Mello M, et al.: Higher striatal dopamine transporter density in PTSD: an in vivo SPECT study with [(99m)Tc] TRODAT-1. Psychopharmacology1-9.
• [45]Drury SS, Theall KP, Keats BJB, Scheeringa M: The role of the dopamine transporter (DAT) in the development of PTSD in preschool children. J Traum Stress 2009, 22(6):534-539.
• [46]Segman RH, Cooper-Kazaz R, Macciardi F, Goltser T, Halfon Y, Dobroborski T, Shalev AY: Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry 2002, 7(8):903-907.
• [47]Valente N, Vallada H, Cordeiro Q, Miguita K, Bressan R, Andreoli S, Mari J, Mello M: Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF. J Mol Neurosci 2011, 44(1):59-67.
• [48]Lefebvre D, Diederich C, Delcourt M, Giffroy J-M: The quality of the relation between handler and military dogs influences efficiency and welfare of dogs. Appl Anim Behav Sci 2007, 104(1–2):49-60.
• [49]Vermeire S, Audenaert K, De Meester R, Vandermeulen E, Waelbers T, De Spiegeleer B, Eersels J, Dobbeleir A, Peremans K: Serotonin 2A receptor, serotonin transporter and dopamine transporter alterations in dogs with compulsive behaviour as a promising model for human obsessive-compulsive disorder. Psychiatr Res Neuroimaging 2012, 201(1):78-87.
• [50]Pagel AA: The Berger Belge Anthology: History, Genetics & Varieties. Pasadena: Pacific Book and Printing; 1981.
• [51]Oberbauer AM, Grossman DI, Eggleston ML, Irion DN, Schaffer AL, Pedersen NC, Belanger JM: Alternatives to blood as a source of DNA for large-scale scanning studies of canine genome linkages. Vet Res Commun 2003, 27(1):27-38.
• [52]Vas J, Topal J, Pech E, Miklosi A: Measuring attention deficit and activity in dogs: a new application and validation of a human ADHD questionnaire. Appl Anim Behav Sci 2007, 103(1–2):105-117.
• [53]Wan M, Kubinyi E, Miklósi Á, Champagne F: A cross-cultural comparison of reports by German shepherd owners in Hungary and the united states of America. Appl Anim Behav Sci 2009, 121(3–4):206-213.
• [54]Planta DJU: Testing dogs for aggressive biting behaviour: the MAG-test (sociable acceptable behaviour test) as an alternative for the aggression-test. In Proceedings of the Third International Congress on Animal Behaviour Medicine. Edited by Overall KL, Mills DS, Heath SE, Horwitz D. Vancouver: UFAW Herts, UK; 2001:142-144.
• [55]Netto WJ, Planta DJU: Behavioural testing for aggression in the domestic dog. Appl Anim Behav Sci 1997, 52(3–4):243-263.
• [56]Beerda B, Schilder MBH, van Hooff J, de Vries HW, Mol JA: Behavioural, saliva cortisol and heart rate responses to different types of stimuli in dogs. Appl Anim Behav Sci 1998, 58(3–4):365-381.
• [57]Schilder MBH, van der Borg JAM: Training dogs with help of the shock collar: short and long term behavioural effects. Appl Anim Behav Sci 2004, 85(3–4):319-334.
• [58]IBM SPSS Statistics Version 20. http://www-01.ibm.com/software/analytics/spss/ webcite
• [59]Dunn OJ: Multiple comparisons using rank sums. Technometrics 1964, 6:241-252.