Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice.
Expression of dopamine ([DA] D1 and D2) and glutamate ([Glu], (N-methyl-d-aspartic acid [NMDA], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D4 receptor knockout mice and their wild-type controls. Selective radioligand binding to D4 receptors was virtually absent in D4 receptor knockout mouse brain in contrast to significant specific D4 binding in forebrain tissue of wild-type controls. Labeling of D1 receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D4-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA1 (21%) and CA3 (25%) regions of D4 knockouts vs wild-type controls. No changes in D2, AMPA or KA receptors were found. The findings suggest that D1, D4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.
Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, MA 02478, USA.
Lu
L
Gan
Tomas L
TL
Falzone
Kehong
K
Zhang
Marcelo
M
Rubinstein
Ross J
RJ
Baldessarini
Frank I
FI
Tarazi
D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000235:genetics; D015259:Dopamine Agents / Q000493:pharmacokinetics; D018683:Excitatory Amino Acid Agents / Q000493:pharmacokinetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics*; D050638:Receptors, Dopamine D4; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*
D015259:Dopamine Agents; D018683:Excitatory Amino Acid Agents; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C493600:Drd4 protein, mouse