Michael K Bird1, Peter Lohmann2, Billy West1, Robyn M Brown3, Jeppe Kirchhoff1, Clarke R Raymond2, Andrew J Lawrence4. 1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia. 2. The John Curtin School of Medical Research & Eccles Institute of Neuroscience, Australian National University, Canberra, Australia. 3. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia; Medical University of South Carolina, Charleston, SC, USA. 4. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia. Electronic address: andrew.lawrence@florey.edu.au.
Abstract
BACKGROUND: There is extensive evidence implicating the metabotropic glutamate 5 (mGlu5) receptor in aspects of addiction-related behaviours. METHODS: Here, we used a well-characterized line of mGlu5-deficient mice to further examine the role of this receptor in cocaine-driven behaviours. We confirmed the previously reported deficit in hippocampal long-term potentiation and associated spatial learning impairment. RESULTS: Despite a spatial learning deficit, mGlu5-deficient mice developed and maintained a conditioned place preference to cocaine, suggesting cocaine reward and Pavlovian conditioning are intact in these animals. Notably, however, mGlu5-deficient mice exhibited a marked deficit in the extinction of a cocaine-conditioned place preference compared to wild type littermates. Moreover, in a fixed ratio operant intravenous self-administration paradigm, both genotypes showed similar responding for cocaine over two different doses, while mGlu5-deficient mice displayed enhanced responding on a progressive ratio schedule. In addition, cue-induced drug-seeking after abstinence was exaggerated in mGlu5-deficient mice. CONCLUSION: Collectively, these findings suggest that while the mGlu5 receptor may be involved in mediating the rewarding effects of cocaine, it appears necessary for the extinction of cocaine-driven behaviours.
BACKGROUND: There is extensive evidence implicating the metabotropic glutamate 5 (mGlu5) receptor in aspects of addiction-related behaviours. METHODS: Here, we used a well-characterized line of mGlu5-deficient mice to further examine the role of this receptor in cocaine-driven behaviours. We confirmed the previously reported deficit in hippocampal long-term potentiation and associated spatial learning impairment. RESULTS: Despite a spatial learning deficit, mGlu5-deficient mice developed and maintained a conditioned place preference to cocaine, suggesting cocaine reward and Pavlovian conditioning are intact in these animals. Notably, however, mGlu5-deficient mice exhibited a marked deficit in the extinction of a cocaine-conditioned place preference compared to wild type littermates. Moreover, in a fixed ratio operant intravenous self-administration paradigm, both genotypes showed similar responding for cocaine over two different doses, while mGlu5-deficient mice displayed enhanced responding on a progressive ratio schedule. In addition, cue-induced drug-seeking after abstinence was exaggerated in mGlu5-deficient mice. CONCLUSION: Collectively, these findings suggest that while the mGlu5 receptor may be involved in mediating the rewarding effects of cocaine, it appears necessary for the extinction of cocaine-driven behaviours.
Authors: Shawn Zheng Kai Tan; Despina E Ganella; Alec Lindsay Ward Dick; Jhodie R Duncan; Emma Ong-Palsson; Ross A D Bathgate; Jee Hyun Kim; Andrew J Lawrence Journal: Neurochem Res Date: 2015-05-10 Impact factor: 3.996
Authors: Michael T Stefanik; Mike Milovanovic; Craig T Werner; John C G Spainhour; Marina E Wolf Journal: Biol Psychiatry Date: 2018-02-23 Impact factor: 13.382
Authors: E J Young; A M Blouin; S B Briggs; S E Sillivan; L Lin; M D Cameron; G Rumbaugh; C A Miller Journal: Mol Psychiatry Date: 2015-08-04 Impact factor: 15.992
Authors: Stephanie M Groman; Ansel T Hillmer; Heather Liu; Krista Fowles; Daniel Holden; Evan D Morris; Daeyeol Lee; Jane R Taylor Journal: Biol Psychiatry Date: 2020-06-29 Impact factor: 13.382