Contrasting forms of cocaine-evoked plasticity control components of relapse.
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.
1] Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland [2].
Vincent
V
Pascoli
1] Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland [2].
Jean
J
Terrier
1] INSERM, U661, Montpellier F-34094, France [2] CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France [3] Universités de Montpellier 1 & 2, UMR-5203, Montpellier F-34094, France.
Julie
J
Espallergues
1] INSERM, U661, Montpellier F-34094, France [2] CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France [3] Universités de Montpellier 1 & 2, UMR-5203, Montpellier F-34094, France.
Emmanuel
E
Valjent
Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.
Eoin Cornelius
EC
O'Connor
1] Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland [2] Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, CH-1211 Geneva, Switzerland.
Christian
C
Lüscher
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects; D058999:Drug-Seeking Behavior / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D062308:Optogenetics; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D018091:Receptors, AMPA / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D012008:Recurrence; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003042:Cocaine