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Scientific Understanding of Consciousness |
Synaptic Plasticity Reversal of Cocaine-Induced Adaptive Behaviour
Nature 481, 71–75 (05 January 2012) Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland Vincent Pascoli, Marc Turiault & Christian Lüscher Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, CH-1211 Geneva, Switzerland Christian Lüscher [paraphrase] Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction. Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing and early neuroadaptive effects 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 is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (D1)-receptor-dependent synaptic potentiation as well as in several behavioural adaptations. 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. We have explored and gained insight into the molecular mechanisms of synaptic adaptations to develop a strategy for reversal of cocaine-evoked potentiation with the goal of normalizing behaviour. We chose an optogenetic depotientiaton of inputs from the infralimbic cortex to the nucleus accumbens shell because of the strong anatomical connection and the functional implication of this projection in cocaine-seeking behaviour. It is an appealing idea that behavioural adaptation, which closely reflects the potentiation of excitatory transmission onto D1R-MSNs, is due to an imbalance of the two classes of MSNs. Several studies have already reported that pharmacological and molecular manipulations of key players in synaptic plasticity in the nucleus accumbens can affect adaptive behaviours associated with addictive drug exposure. For example, the inhibition of calcium-permeable AMPARs, a hallmark of late-stage cocaine-evoked synaptic plasticity in the nucleus accumbens and the viral expression of a peptide that impairs GluA1 trafficking, reduce cue-induced cocaine seeking and cocaine-primed reinstatement, respectively. We provide proof of principle that optogenetic manipulations can be used to reverse cocaine-evoked synaptic plasticity and thus abolish locomotor sensitization. Although light stimulation fully resets locomotor behaviour, sensitization begins to reappear after a few days, suggesting that several treatment sessions may be required to obtain long-lasting effects. This is not surprising, as chronic cocaine exposure also induces a number of additional adaptive changes including structural remodelling (for example, increase in spines) and alterations of gene expression. Sensitization to cocaine-associated stimuli has been linked with incentive saliency and may explain the exceptionally strong motivation of addicts to obtain the drug. With chronic use, early adaptive changes such as those described here may build up to enhance craving during cocaine withdrawal. Successful interventions that reverse these changes in animal models could inspire novel treatments for human addiction, a disease with a high social burden. Indeed, novel protocols of deep brain stimulation or transcranial magnetic stimulation may induce forms of synaptic plasticity that reverse drug-evoked adaptations, thus curbing the risk of relapse. [end of paraphrase]
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