Cellular and Molecular mechanisms of cocaine addiction
Dates:September 1, 2016 - December 31, 2016
Application deadline:September 1, 2016
~ Sep-Dec 2016 ~ Jan-March 2017 ~ Apr-June 2017
Long-lasting alterations of neuronal properties that occur in specific brain areas form the bases of drug addiction. They require changes in transcription and new protein synthesis. We showed that the ERK pathway plays a key role in molecular and behavioral adaptations to cocaine. ERK activation relies on the physical interaction (i.e. heteromerization) between Dopamine D1 and NMDA receptors1 and modulates gene expression and chromatin remodeling in response to cocaine. In this way, ERK controls cocaine-induced synaptic plasticity and behavioral alterations2,3. We propose herein to trace the cellular events that drive cocaine-induced ERK activation in specific brain areas and to decipher the molecular consequences of this activation. A combination of genetic tools and state-of the art genomic and epigenomic studies will be used to study the role of i) D1R/NMDAR heteromers in the neuronal circuitry of reward in long-lasting responses to cocaine; ii) ERK activation in the epigenetic signature (miRNA) to cocaine. To tackle the first issue, we propose to unravel the role of DAR/NMDAR heteromers by a using a viral-mediated approach that allows a time- controlled and brain region-specific disruption of heteromers. The impact of heteromer disruption will be studied on downstream nuclear event and behavioral adaptations such as cocaine-induced psychomotor sensitization and self-administration. The second specific aim is to establish a genome-wide landscape of the transcriptomic and miRNA signature of chronic cocaine administration in D1R- and D2R-MSNs, along with the role of ERK signaling in this signature. Candidate therapeutic targets will be tested at the behavioral level in the afford-mentioned non-operant and operant paradigms.
Completion of our project will to pave the way for new therapeutic approaches in addiction.
1-Cahill E, Pascoli V, Trifieff P, Lüscher C, Caboche J, Vanhoutte P (2014) D1R/GluN1 complexes in the striatum integrate dopamine and glutamate signalling to control synaptic plascity and cocaïne-induced responses. Mol Psychiatry 19: 1295-304.
2-Pascoli V, Cahill E, Bellivier F, Caboche J, Vanhoutte P (2014) Extracellular signal-Regulated kinases 1 and 2 activation by addictive drugs: A signal toward pathological adaptation. Biol. Psychiatry. doi: 10.1016/j.biopsych.2014.04.005.
3- Cahill E, Salery M, Vanhoutte P, Caboche J (2014) Convergence of Dopamine and Glutamate signalling onto striatal ERK activation in response to drugs of abuse. Front Pharmacol, 4: 172.
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