title: Dopamine D2 receptor overexpression alters behavior and physiology in Drd2-EGFP mice.
abstract: Bacteria artificial chromosome (BAC) transgenic mice expressing the reporter protein enhanced green fluorescent protein (EGFP) under the control of the D1 and D2 dopamine receptor promoters (Drd1-EGFP and Drd2-EGFP) have been widely used to study striatal function and have contributed to our understanding of the physiological and pathological functions of the basal ganglia. These tools were produced and promptly made available to address questions in a cell-specific manner that has transformed the way we frame hypotheses in neuroscience. However, these mice have not been fully characterized until now. We found that Drd2-EGFP mice display an ∼40% increase in membrane expression of the dopamine D2 receptor (D2R) and a twofold increase in D2R mRNA levels in the striatum when compared with wild-type and Drd1-EGFP mice. D2R overexpression was accompanied by behavioral hypersensitivity to D2R-like agonists, as well as enhanced electrophysiological responses to D2R activation in midbrain dopaminergic neurons. Dopamine (DA) transients evoked by stimulation in the nucleus accumbens showed slower clearance in Drd2-EGFP mice, and cocaine actions on DA clearance were impaired in these mice. Thus, it was not surprising to find that Drd2-EGFP mice were hyperactive when exposed to a novel environment and locomotion was suppressed by acute cocaine administration. All together, this study demonstrates that Drd2-EGFP mice overexpress D2R and have altered dopaminergic signaling that fundamentally differentiates them from wild-type and Drd1-EGFP mice.
authors.affiliation: Sections on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, and Molecular Neuropharmacology Section, National Institute on Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Kramer
authors.forename: Christine H
authors.initials: CH
authors.lastname: Christensen
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hazelwood
authors.forename: Alice
authors.initials: A
authors.lastname: Dobi
authors.forename: Roland
authors.initials: R
authors.lastname: Bock
authors.forename: David R
authors.initials: DR
authors.lastname: Sibley
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Mateo
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D017089:Ankyrin Repeat / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D017447:Receptors, Dopamine D1 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018709:Statistics, Nonparametric; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology
chemical_list: D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019257:Quinpirole; D003042:Cocaine