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

Abstract

Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction1. Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing2 and early neuroadaptive effects3 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 accumbens4 is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (D1)-receptor-dependent synaptic potentiation5 as well as in several behavioural adaptations6,7,8. 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.

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Figure 1: Cocaine disrupts HFS-induced LTP in D1R-MSNs of the nucleus accumbens by potentiation of excitatory afferents.
Figure 2: HFS LTP and cocaine-evoked potentiation both depend on ERK activation.
Figure 3: Reversal of cocaine-evoked potentiation abolishes locomotor sensitization to cocaine.
Figure 4: Optogenetic depotentiation resets behavioural sensitization induced by chronic cocaine injections.

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Acknowledgements

We thank P. Kalivas and the members of the Lüscher laboratory for suggestions on the manuscript. This work is supported by the Swiss National Science Foundation (C.L.) and “Synapsy”, a National Competence Center in Research (NCCR) of the Swiss Confederation on the synaptic basis of mental disorders.

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V.P. carried out all electrophysiology experiments and was helped by M.T. with the behavioural experiments. C.L. designed the study and wrote the manuscript together with V.P. and M.T.

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Correspondence to Christian Lüscher.

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The authors declare no competing financial interests.

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Pascoli, V., Turiault, M. & Lüscher, C. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour. Nature 481, 71–75 (2012). https://doi.org/10.1038/nature10709

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