title: Effects of genetic deletion of endogenous opioid system components on the reinstatement of cocaine-seeking behavior in mice.
abstract: The repeated cycles of cessation of consumption and relapse remain the major clinical concern in treating drug addiction. The endogenous opioid system is a crucial component of the reward circuit that participates in the adaptive changes leading to relapse in the addictive processes. We have used genetically modified mice to evaluate the involvement of μ-opioid receptor (MOR) and δ-opioid receptor (DOR) and their main endogenous ligands, the enkephalins derived from proenkephalin (PENK) and prodynorphin (PDYN), in the reinstatement of cocaine-seeking behavior. Constitutive knockout mice of MOR, DOR, PENK, and PDYN, and their wild-type littermates were trained to self-administer cocaine or to seek for palatable food, followed by a period of extinction and finally tested on a cue-induced reinstatement of seeking behavior. The four lines of knockout mice acquired operant cocaine self-administration behavior, although DOR and PENK knockout mice showed less motivation for cocaine than wild-type littermates. Moreover, cue-induced relapse was significantly decreased in MOR and DOR knockout mice. In contrast, PDYN knockout mice showed a slower extinction and increased relapse than wild-type littermates. C-Fos expression analysis revealed differential activation in brain areas related with memory and reward in these knockout mice. No differences were found in any of the four genotypes in operant responding to obtain palatable food, indicating that the changes revealed in knockout mice were not due to unspecific deficit in operant performance. Our results indicate that MOR, DOR, and PDYN have a differential role in cue-induced reinstatement of cocaine-seeking behavior.
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutiérrez-Cuesta
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Aurelijus
authors.initials: A
authors.lastname: Burokas
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Samantha
authors.initials: S
authors.lastname: Mancino
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Sami
authors.initials: S
authors.lastname: Kummer
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-García
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
mesh_terms: D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000008:administration & dosage; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D003463:Cues; D058999:Drug-Seeking Behavior / Q000502:physiology*; D004745:Enkephalins / Q000172:deficiency* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011498:Protein Precursors / Q000172:deficiency* / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000172:deficiency / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000172:deficiency* / Q000235:genetics; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D000779:Anesthetics, Local; D004745:Enkephalins; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C029992:proenkephalin; C033660:preproenkephalin; D003042:Cocaine