Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction

Vincent Pascoli; Jean Terrier; Agnès Hiver; Christian Lüscher

doi:10.1016/j.neuron.2015.10.017

Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction

Neuron. 2015 Dec 2;88(5):1054-1066. doi: 10.1016/j.neuron.2015.10.017. Epub 2015 Nov 12.

Authors

Vincent Pascoli¹, Jean Terrier¹, Agnès Hiver¹, Christian Lüscher²

Affiliations

¹ Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1211 Geneva, Switzerland.
² Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1211 Geneva, Switzerland; Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, 1211 Geneva, Switzerland. Electronic address: christian.luscher@unige.ch.

PMID: 26586182
DOI: 10.1016/j.neuron.2015.10.017

Abstract

The factors causing the transition from recreational drug consumption to addiction remain largely unknown. It has not been tested whether dopamine (DA) is sufficient to trigger this process. Here we use optogenetic self-stimulation of DA neurons of the ventral tegmental area (VTA) to selectively mimic the defining commonality of addictive drugs. All mice readily acquired self-stimulation. After weeks of abstinence, cue-induced relapse was observed in parallel with a potentiation of excitatory afferents onto D1 receptor-expressing neurons of the nucleus accumbens (NAc). When the mice had to endure a mild electric foot shock to obtain a stimulation, some stopped while others persevered. The resistance to punishment was associated with enhanced neural activity in the orbitofrontal cortex (OFC) while chemogenetic inhibition of the OFC reduced compulsivity. Together, these results show that stimulating VTA DA neurons induces behavioral and cellular hallmarks of addiction, indicating sufficiency for the induction and progression of the disease.

Publication types

Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Animals
Channelrhodopsins
Clozapine / analogs & derivatives
Clozapine / pharmacology
Cocaine / administration & dosage
Cocaine / pharmacology
Cocaine-Related Disorders / pathology*
Conditioning, Operant / drug effects
Conditioning, Operant / physiology
Disease Models, Animal
Dopamine Plasma Membrane Transport Proteins / genetics
Dopamine Plasma Membrane Transport Proteins / metabolism
Dopamine Uptake Inhibitors / administration & dosage
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / physiology*
Food Deprivation
GABA Antagonists / pharmacology
Glutamate Decarboxylase / genetics
Glutamate Decarboxylase / metabolism
Limbic System / drug effects*
Limbic System / pathology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Receptors, Dopamine D1 / genetics
Receptors, Dopamine D1 / metabolism
Self Administration
Sucrose / administration & dosage
Synaptic Transmission / drug effects
Synaptic Transmission / physiology*
Time Factors

Substances

Channelrhodopsins
Dopamine Plasma Membrane Transport Proteins
Dopamine Uptake Inhibitors
Drd1 protein, mouse
GABA Antagonists
Receptors, Dopamine D1
Sucrose
Glutamate Decarboxylase
Cocaine
Clozapine
clozapine N-oxide