Contrasting forms of cocaine-evoked plasticity control components of relapse
Résumé
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 (alpha-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.
Mots clés
Female
Male
Animals
Mice
Recurrence
Disease Models
Animal
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
Cocaine-Related Disorders/pathology/*physiopathology/psychology
Cocaine/*pharmacology
Dopaminergic Neurons/drug effects
Drug-Seeking Behavior/drug effects
Hippocampus/cytology/drug effects/pathology
N-Methylaspartate/metabolism
Neural Pathways/drug effects
Neuronal Plasticity/*drug effects
Nucleus Accumbens/cytology/*drug effects/pathology
Optogenetics
Prefrontal Cortex/cytology/drug effects/pathology
Receptors
AMPA/metabolism
Dopamine D1/metabolism
Synapses/drug effects/metabolism