Original Article

Neuropsychopharmacology (2014) 39, 2974–2988; doi:10.1038/npp.2014.149; published online 23 July 2014

Effects of Genetic Deletion of Endogenous Opioid System Components on the Reinstatement of Cocaine-Seeking Behavior in Mice

Javier Gutiérrez-Cuesta1,2, Aurelijus Burokas1,2,4, Samantha Mancino1,3, Sami Kummer1,3, Elena Martín-García1 and Rafael Maldonado1

1Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

Correspondence: Professor R Maldonado, Laboratory of Neuropharmacology, Pompeu Fabra University, Dr Aiguader 88, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain, Tel: +1 34 93 3160824, Fax: +1 34 93 3160901, E-mail: rafael.maldonado@upf.edu

2These authors contributed equally to this work.

3These authors contributed equally to this work.

4Present address: Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.

Received 12 December 2013; Revised 30 May 2014; Accepted 10 June 2014
Accepted article preview online 19 June 2014; Advance online publication 23 July 2014



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.

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