Journal Article

Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour

Pascoli, Vincent, Turiault, Marc, Lüscher, Christian

2012

Overview

In mice, cocaine is found to potentiate excitatory transmission in medium-sized spiny neurons expressing the type-1 dopamine receptor; depotentiation reversed cocaine-induced locomotor sensitization, raising the possibility of novel treatments for addiction. Cocaine effects reversible Synaptic plasticity is known to occur in drug addiction, but there is little evidence to link drug-evoked plasticity to the behavioural adaptations seen in drug-addicted animals. Pascoli et al . report that specific potentiation in dopaminergic neurons expressing the type I dopamine receptor causes the locomotor sensitization often observed in animals exposed to cocaine. Specific depotentiation of this pathway using optogenetics both restores normal synaptic transmission and eliminates the behavioural phenotype. These data link synaptic potentiation of D1R-expressing neurons to drug-evoked behaviour, and suggest that therapeutic reversal of cocaine-induced adaptive synaptic changes could lead to behavioural corrections. Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction 1 . Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing 2 and early neuroadaptive effects 3 by inhibiting the dopamine transporter, thus causing a strong increase in mesolimbic dopamine. Among the many signalling pathways subsequently engaged, phosphorylation of the extracellular signal-regulated kinase (ERK) in the nucleus accumbens 4 is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (D1)-receptor-dependent synaptic potentiation 5 as well as in several behavioural adaptations 6 , 7 , 8 . A causal link between drug-evoked plasticity at identified synapses and behavioural adaptations, however, is missing, and the benefits of restoring baseline transmission have yet to be demonstrated. Here we find that cocaine potentiates excitatory transmission in D1-receptor-expressing medium-sized spiny neurons (D1R-MSNs) in mice via ERK signalling with a time course that parallels locomotor sensitization. Depotentiation of cortical nucleus accumbens inputs by optogenetic stimulation in vivo efficiently restored normal transmission and abolished cocaine-induced locomotor sensitization. These findings establish synaptic potentiation selectively in D1R-MSNs as a mechanism underlying a core component of addiction, probably by creating an imbalance between distinct populations of MSNs in the nucleus accumbens. Our data also provide proof of principle that reversal of cocaine-evoked synaptic plasticity can treat behavioural alterations caused by addictive drugs and may inspire novel therapeutic approaches involving deep brain stimulation or transcranial magnetic stimulation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1689/5 / 631/378/2591 / 631/443/376 / 631/477 / Action potentials (Electrophysiology) / Adaptability (Psychology) / Adaptation, Physiological - drug effects / Addictive behaviors / Animals / Artificial chromosomes / Behavior / Biological and medical sciences / Cocaine / Cocaine - administration & dosage / Cocaine - pharmacology / Cocaine-Related Disorders - metabolism / Cocaine-Related Disorders - pathology / Dopamine / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - metabolism / Drug abuse / Electric Stimulation / Enzyme Activation / Excitatory Postsynaptic Potentials - drug effects / Extracellular Signal-Regulated MAP Kinases - metabolism / Fundamental and applied biological sciences. Psychology / Gene expression / Health aspects / Humanities and Social Sciences / Injections / letter / Long-Term Potentiation - drug effects / MAP Kinase Signaling System - drug effects / Medical sciences / Mice / Mice, Inbred C57BL / Motor Activity - drug effects / multidisciplinary / Neurology / Neuronal Plasticity - drug effects / Neuropharmacology / Neuroplasticity / Nucleus Accumbens - cytology / Nucleus Accumbens - drug effects / Pharmacology. Drug treatments / Phenotype / Plasticity / Proteins / Protocol / Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer / Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) / Psychology. Psychoanalysis. Psychiatry / Psychopharmacology / Receptors, Dopamine D1 - metabolism / Rodents / Science / Science (multidisciplinary) / Substance abuse treatment / Synapses - drug effects / Synapses - metabolism / Synaptic Transmission - drug effects / Vertebrates: nervous system and sense organs