These DRD3 knockout mice are devoid of D3 receptors in homozygotes and display enhanced cocaine seeking and self-administration behavior. They may be useful for studying dopamine autoreceptor inhibitory control in dopaminergic neurotransmission.
IMR Colony, The Jackson Laboratory
D3 receptors are G-protein coupled receptors localized to the limbic areas of the brain, which are associated with cognitive, emotional, and endocrine functions by inhibition of adenylyl cyclase activity. Dopamine (DA) stimulation of presynaptic D3 receptors induces a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. Defects in DA neurons have been associated with Parkinson's disease, schizophrenia, attention-deficit and hyperactivity disorder, and compulsive drug abuse. D3 receptors are also expressed in renal proximal tubules and juxtaglomerular cells and may be responsible for the dopamine-mediated decrease in renin secretion in these cells. Homozygous are viable and fertile. Dopamine antagonist binding studies indicate the absence of D3 receptors in homozygotes and a greatly reduced number in heterozygotes. These DRD3 KO mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. They also exhibit an increase in locomotor activity, increase in exploratory behavior, and decrease in grooming. Behavioral alterations were less pronounced in heterozygotes. When treated with cocaine they exhibit reduced hyperactivity and increased head bobbing. Both systolic and diastolic blood pressures were approximately 20 mmHg higher in heterozygotes and homozygotes compared to wild-type mice.
A targeting vector was designed to insert a neomycin resistance (neo) cassette and 30 non-endogenous residues (STOP) into exon 2 of the dopamine receptor D3 (Drd3) gene. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric males were bred to C57BL/6 females. These mice were imported on a mixed B6 x 129S4 background as Stock No. 002425. Upon arrival at The Jackson Laboratory, these mice were backcrossed to C57BL/6J mice (Stock No. 000664) to establish a congenic colony.
|Allele Name||targeted mutation 1, Domenico Accili|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||D3-; delta148(+30)|
|Gene Symbol and Name||Drd3, dopamine receptor D3|
|Strain of Origin||129S4/SvJae|
|Molecular Note||A neomycin selection cassette and sequence encoding 30 non-endogenous residues was inserted into exon 2. RT-PCR analysis on RNA derived from brain of homozygous mice demonstrated the absence of normal transcript. Mutant transcript was detected in both heterozygous and homozygous mutant mice. Binding assays on brain sections derived from homozygous mice confirmed that no functional protein was expressed. Notably, heterozygotes displayed a nearly complete loss of D3-specific binding, to a greater extent than expected for a mutation affecting expression of one allele of the Drd3 gene, raising the possibility that this mutation acts in a dominant-negative fashion.|
|Mutations Made By|| |
Prof. Sara Fuchs, National Institutes of Health
When maintaining a live colony, homozygous mice may be bred together.
When using the D3- mouse strain in a publication, please cite the originating article(s) and include JAX stock #002958 in your Materials and Methods section.