title: Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction.
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.
authors.affiliation: Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Pascoli
authors.affiliation: Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Terrier
authors.affiliation: Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Agnès
authors.initials: A
authors.lastname: Hiver
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D000075402:Channelrhodopsins; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000473:pathology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D005508:Food Deprivation; D018756:GABA Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D008032:Limbic System / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D000075402:Channelrhodopsins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C583261:Drd1 protein, mouse; D018756:GABA Antagonists; D017447:Receptors, Dopamine D1; D013395:Sucrose; D005968:Glutamate Decarboxylase; D003042:Cocaine; D003024:Clozapine; C079149:clozapine N-oxide