Asymmetric elevation of striatal dopamine D2 receptors in the chakragati mouse: neurobehavioral dysfunction in a transgenic insertional mutant.
We have previously reported the discovery of a transgenic insertional mutant, recently named the chakragati (ckr) mouse, which displays lateralized circling, locomotor hyperactivity, hyperreactivity, as well as body weight deficits. Since lateralized dopamine function is associated with circling behavior we sought to determine whether dopamine (DA) D1 and D2 receptors were asymmetrically distributed in the striata of adolescent and adult ckr mice using receptor autoradiography. Stereotypic and rotational responses to quinpirole served as behavioral indices of D2 receptor function. The ckr mice showed hemispherically asymmetric elevations in DA D2 receptors in the lateral subregions of the striatum whereas medial regions of the striatum were symmetrically and bilaterally elevated (overall elevation = 30%). As a group, ckr mice had higher D2 receptor levels on the side which was contralateral to the preferred direction of spontaneous nocturnal rotation. Striatal D1 receptors and mesolimbic D2 and D1 receptors of ckr mice were neither elevated nor differentially asymmetric. Young adult ckr mice showed dose-dependent increases in net rotations in response to quinpirole whereas normal mice showed no change from baseline levels. Both groups showed similar stereotypic responses. Older adult ckr mice, however, showed dose-dependent reductions in rotation after quinpirole whereas normal mice turned at baseline levels. Older ckr mice also displayed significantly greater stereotyped sniffing behavior. This unique mutant provides a novel genetic model of basal ganglia dysfunction, and may be useful in studying aspects of neuropsychiatric disorders associated with dopaminergic abnormalities.
Fitzgerald
L W
LW
Department of Pharmacology and Toxicology, Albany Medical College 12208.
Miller
K J
KJ
Ratty
A K
AK
Glick
S D
SD
Teitler
M
M
Gross
K W
KW
D000818:Animals; D001921:Brain / Q000033:anatomy & histology; D003342:Corpus Striatum / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D019257:Quinpirole; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects
D015259:Dopamine Agents; D004873:Ergolines; D009419:Nerve Tissue Proteins; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole