Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction

• Published in: Neuron (Cambridge, Mass.) Mass.), 2015-12, Vol.88 (5), p.1054-1066
• Main Authors: Pascoli, Vincent, Terrier, Jean, Hiver, Agnès, Lüscher, Christian
• Format: Article
• Language: English
• Subjects: Acquisitions & mergers; Addictions; Addictive behaviors; Animals; Behavior; Channelrhodopsins; Clozapine - analogs & derivatives; Clozapine - pharmacology; Cocaine; Cocaine - administration & dosage; Cocaine - pharmacology; Cocaine-Related Disorders - pathology; Conditioning, Operant - drug effects; Conditioning, Operant - physiology; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine Uptake Inhibitors - administration & dosage; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - physiology; Drug dosages; Food Deprivation; GABA Antagonists - pharmacology; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - metabolism; Hypotheses; Lasers; Limbic System - drug effects; Limbic System - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D1 - metabolism; Rodents; Self Administration; Studies; Sucrose; Sucrose - administration & dosage; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Time Factors
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.10.017

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. [Display omitted] •Dopamine neuron self-stimulation evokes synaptic plasticity in the NAc, driving relapse•Dopamine is sufficient to trigger compulsive taking•Neurons in the orbitofrontal cortex are hyperexcitable in mice resistant to punishment•Chemogenetic inhibition of the OFC reduces compulsive self-stimulation Pascoli, Terrier et al. demonstrate that DA neuron self-stimulation in mice is sufficient to induce key features of addiction, such as synaptic plasticity in the NAc, cue-associated relapse, and perseverance of consumption despite negative consequences. The orbitofrontal cortex drives the transition to compulsivity.