Florey Department of Neuroscience and Mental Health - Research Publications

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Author: Lawrence, Andrew × End date: 2014 × Start date: 2012 × Type: Journal Article × Subject: Cocaine ×

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    The mGlu5 receptor regulates extinction of cocaine-driven behaviours
    Bird, MK ; Lohmann, P ; West, B ; Brown, RM ; Kirchhoff, J ; Raymond, CR ; Lawrence, AJ (ELSEVIER IRELAND LTD, 2014-04-01)
    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.
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    mGlu5 and adenosine A2A receptor interactions regulate the conditioned effects of cocaine
    Brown, RM ; Duncan, JR ; Stagnitti, MR ; Ledent, C ; Lawrence, AJ (OXFORD UNIV PRESS, 2012-08)
    Adenosine A2A receptors and metabotropic glutamate type 5 (mGlu5) receptors are co-localized in the striatum and can functionally interact to regulate drug-seeking. We further explored this interaction using antagonism of mGlu5 receptors with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) in combination with genetic deletion of A2A receptors. The conditioned rewarding and locomotor-activating properties of cocaine were evaluated via conditioned place preference (CPP). Vehicle-treated mice of both genotypes expressed a CPP to cocaine while MTEP abolished cocaine CPP in wild-type, but not A2A knockout, mice. These results were mirrored when conditioned hyperactivity was assessed. In contrast, MTEP attenuated the acute locomotor-activating properties of cocaine similarly in both genotypes. These data provide evidence for a functional interaction between adenosine A2A and mGlu5 receptors in mediating the conditioned effects of cocaine but not direct cocaine-induced hyperactivity. This functional interaction is supported by modulation of 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolol[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol ([125I]ZM241385) binding to the A2A receptor by MTEP.