Motor and associative deficits in D2 dopamine receptor knockout mice.
Behavioral abnormalities produced by D2 dopamine receptor gene deletion in mice have been attributed either to resulting Parkinson-like features (i.e. response slowing and response initiation difficulties) or to behavioral deficits contributed by alleles of the originating 129Sv strain. Three strategies were used to address these conflicting hypotheses: (1) we used mice congenic at n10 backcross into the C57BL/6 line to minimize the 129Sv contribution; (2) we compared mice that were wild-type (+/+), heterozygous (+/-), or homozygous (-/-) for the D2 gene with the two most relevant inbred lines (129Sv and C57BL/6) and (3) we used both conventional and novel behavioral assessment methods. Behavioral attributes were expressed in terms of locomotor activity, wall rearing, rotarod performance, operant response acquisition, operant response performance, lick dynamics (force, rhythm), grip strength, and tremor in response to harmaline challenge. Results showed that, compared to controls, the -/- mice exhibited longer duration wall rears, retarded operant response acquisition, increased latencies to move from the operandum to the reward well, and exaggerated response to harmaline. Age was investigated as a variable (10-11 weeks versus 41-44 weeks of age) in the locomotor activity and wall rear assessments. A gene dosage effect (deficits in the +/- mice) on these two variables became apparent in the older mice. Taken together, the results showed that mice without the D2 gene exhibited Parkinson-like behavioral features that were not easily attributed to alleles contributed by the 129Sv strain, but were consistent with basal ganglia dysfunction.
Fowler
S C
SC
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045, USA. scfowler@ukans.edu
Zarcone
T J
TJ
Vorontsova
E
E
Chen
R
R
D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D018737:Hand Strength / Q000502:physiology; D006246:Harmaline / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics
D017448:Receptors, Dopamine D2; D006246:Harmaline; D004298:Dopamine