title: Ablation of kappa-opioid receptors from brain dopamine neurons has anxiolytic-like effects and enhances cocaine-induced plasticity.
abstract: Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites. By breeding these mice with lines that express Cre-recombinase (Cre) in early embryogenesis (EIIa-Cre) or only in DA neurons (dopamine transporter (DAT)-Cre), we developed constitutive KOR knockouts (KOR(-/-)) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KOR(lox/lox)). Autoradiography demonstrated complete ablation of KOR binding in the KOR(-/-) mutants, and reduced binding in the DAT-KOR(lox/lox) mutants. Quantitative reverse transcription PCR (qPCR) studies confirmed that KOR mRNA is undetectable in the constitutive mutants and reduced in the midbrain DA systems of the conditional mutants. Behavioral characterization demonstrated that these mutant lines do not differ from controls in metrics, including hearing, vision, weight, and locomotor activity. Whereas KOR(-/-) mice appeared normal in the open field and light/dark box tests, DAT-KOR(lox/lox) mice showed reduced anxiety-like behavior, an effect that is broadly consistent with previously reported effects of KOR antagonists. Sensitization to the locomotor-stimulating effects of cocaine appeared normal in KOR(-/-) mutants, but was exaggerated in DAT-KOR(lox/lox) mutants. Increased sensitivity to cocaine in the DAT-KOR(lox/lox) mutants is consistent with a role for KORs in negative regulation of DA function, whereas the lack of differences in the KOR(-/-) mutants suggests compensatory adaptations after constitutive receptor ablation. These mouse lines may be useful in future studies of KOR function.
authors: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
authors: Ashlee
authors: A
authors: Van't Veer
authors: Anita J
authors: AJ
authors: Bechtholt
authors: Sara
authors: S
authors: Onvani
authors: David
authors: D
authors: Potter
authors: Yujun
authors: Y
authors: Wang
authors: Lee-Yuan
authors: LY
authors: Liu-Chen
authors: Günther
authors: G
authors: Schütz
authors: Elena H
authors: EH
authors: Chartoff
authors: Uwe
authors: U
authors: Rudolph
authors: Bruce M
authors: BM
authors: Cohen
authors: William A
authors: WA
authors: Carlezon
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D044482:Benzeneacetamides / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000172:deficiency*
chemical_list: D014151:Anti-Anxiety Agents; D044482:Benzeneacetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D003042:Cocaine; C045444:U 69593