Stochastic synaptic plasticity underlying compulsion in a model of addiction

Vincent Pascoli, Agnès Hiver, Ruud Zessen, Michaël Loureiro, Ridouane Achargui, Masaya Harada, Jérôme Flakowski and Christian Lüscher ()
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Vincent Pascoli: University of Geneva
Agnès Hiver: University of Geneva
Ruud Zessen: University of Geneva
Michaël Loureiro: University of Geneva
Ridouane Achargui: University of Geneva
Masaya Harada: University of Geneva
Jérôme Flakowski: University of Geneva
Christian Lüscher: University of Geneva

Nature, 2018, vol. 564, issue 7736, 366-371

Abstract: Abstract Activation of the mesolimbic dopamine system reinforces goal-directed behaviours. With repetitive stimulation—for example, by chronic drug abuse—the reinforcement may become compulsive and intake continues even in the face of major negative consequences. Here we gave mice the opportunity to optogenetically self-stimulate dopaminergic neurons and observed that only a fraction of mice persevered if they had to endure an electric shock. Compulsive lever pressing was associated with an activity peak in the projection terminals from the orbitofrontal cortex (OFC) to the dorsal striatum. Although brief inhibition of OFC neurons temporarily relieved compulsive reinforcement, we found that transmission from the OFC to the striatum was permanently potentiated in persevering mice. To establish causality, we potentiated these synapses in vivo in mice that stopped optogenetic self-stimulation of dopamine neurons because of punishment; this led to compulsive lever pressing, whereas depotentiation in persevering mice had the converse effect. In summary, synaptic potentiation of transmission from the OFC to the dorsal striatum drives compulsive reinforcement, a defining symptom of addiction.

Date: 2018
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DOI: 10.1038/s41586-018-0789-4

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