Contrasting forms of cocaine-evoked plasticity control components of relapse

Vincent Pascoli, Jean Terrier, Julie Espallergues, Emmanuel Valjent, Eoin Cornelius O’Connor and Christian Lüscher ()
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Vincent Pascoli: Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland
Jean Terrier: Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland
Julie Espallergues: INSERM, U661, Montpellier F-34094, France
Emmanuel Valjent: INSERM, U661, Montpellier F-34094, France
Eoin Cornelius O’Connor: Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland
Christian Lüscher: Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland

Nature, 2014, vol. 509, issue 7501, 459-464

Abstract: Abstract Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established. Here we use a mouse model of delayed cue-associated cocaine seeking with ex vivo electrophysiology in optogenetically delineated circuits. We find that seeking correlates with rectifying AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor transmission and a reduced AMPA/NMDA (N-methyl-d-aspartate) ratio at medial prefrontal cortex (mPFC) to nucleus accumbens shell D1-receptor medium-sized spiny neurons (D1R-MSNs). In contrast, the AMPA/NMDA ratio increases at ventral hippocampus to D1R-MSNs. Optogenetic reversal of cocaine-evoked plasticity at both inputs abolishes seeking, whereas selective reversal at mPFC or ventral hippocampus synapses impairs response discrimination or reduces response vigour during seeking, respectively. Taken together, we describe how information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Our approach holds promise for identifying synaptic causalities in other behavioural disorders.

Date: 2014
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DOI: 10.1038/nature13257

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