Journal Article

Contrasting forms of cocaine-evoked plasticity control components of relapse

Terrier, Jean, Lüscher, Christian, Valjent, Emmanuel, Pascoli, Vincent, Espallergues, Julie, O’Connor, Eoin Cornelius

2014

Overview

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. Information integration in the nucleus accumbens is commandeered by cocaine at discrete synapses to allow relapse. Cocaine-induced brain changes that lead to relapse Addictive drugs are thought to hijack the neural circuits in integrative brain centres, such as the nucleus accumbens, that send signals to various brain regions to control behavioural responses. Drug-associated cues can become powerful triggers of drug-seeking behaviour because of such manipulations, increasing the chance of relapse after the cessation of drug-taking. Here Christian Lüscher and colleagues identify cocaine-evoked alterations to specific neural pathways in projections from the prefrontal cortex or ventral hippocampus that interact with separate dopaminergic populations in the nucleus accumbens of mice. Manipulation of drug-induced plasticity within both these pathways abolishes drug-seeking behaviour, whereas disrupting plasticity in just one pathway impairs drug-response discrimination or the vigour of cue responses. These findings reveal the plasticity mechanisms underlying information integration at the nucleus accumbens and show how drugs like cocaine can alter this plasticity to permit relapse.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2591 / alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism / Animal behavior / Animals / Artificial chromosomes / Cocaine / Cocaine - pharmacology / Cocaine abuse / Cocaine-Related Disorders - pathology / Cocaine-Related Disorders - physiopathology / Cocaine-Related Disorders - psychology / Control (Psychology) / Development and progression / Disease Models, Animal / Diseases / Dopamine / Dopaminergic Neurons - drug effects / Drug abuse / Drug-Seeking Behavior - drug effects / Female / Health aspects / Hippocampus - cytology / Hippocampus - drug effects / Hippocampus - pathology / Humanities and Social Sciences / Life Sciences / Male / Mice / multidisciplinary / N-Methylaspartate - metabolism / Neural Pathways - drug effects / Neuronal Plasticity - drug effects / Neurons / Neuroplasticity / Nucleus accumbens / Nucleus Accumbens - cytology / Nucleus Accumbens - drug effects / Nucleus Accumbens - pathology / Optogenetics / Physiological aspects / Plasticity / Prefrontal Cortex - cytology / Prefrontal Cortex - drug effects / Prefrontal Cortex - pathology / Properties / Psychiatric research / Receptors, AMPA - metabolism / Receptors, Dopamine D1 - metabolism / Recurrence / Relapse / Rodents / Science / Synapses - drug effects / Synapses - metabolism