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Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse
Journal article   Open access   Peer reviewed

Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Stephen V Mahler, Zachary D Brodnik, Brittney M Cox, William C Buchta, Brandon S Bentzley, Julian Quintanilla, Zackary A Cope, Edwin C Lin, Matthew D Riedy, Michael D Scofield, …
The Journal of neuroscience, v 39(3), pp 503-518
16 Jan 2019
DOI: https://doi.org/10.1523/JNEUROSCI.0537-18.2018
PMID: 30446532
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1523/jneurosci.0537-18.2018View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open
url
https://doi.org/10.1523/JNEUROSCI.0537-18.2018View
Published, Version of Record (VoR) Open

Abstract

Animals Behavior, Animal Cocaine-Related Disorders - genetics Cocaine-Related Disorders - physiopathology Cocaine-Related Disorders - psychology Dopaminergic Neurons - drug effects Drug-Seeking Behavior GTP-Binding Proteins - physiology Limbic System - drug effects Male Motor Activity - drug effects Prosencephalon - drug effects Rats Rats, Transgenic Recurrence Reward Self Administration Signal Transduction - drug effects Stress, Psychological - psychology Ventral Tegmental Area - drug effects Ventral Tegmental Area - physiopathology
Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors in male rats, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of G signaling, but not G signaling, in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory G signaling in DA neurons blunted the reinforcing and priming effects of cocaine, reduced stress-potentiated reinstatement, and altered behavioral strategies for cocaine seeking and taking. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein-signaling cascades, and DA neuron efferent targets, highlighting their multifaceted roles in addiction. G-protein-coupled receptors are crucial modulators of ventral tegmental area (VTA) dopamine neuron activity, but how this metabotropic signaling impacts the complex roles of dopamine in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs (designer receptors exclusively activated by designer drugs) during a variety of cocaine-seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. G and G stimulation activated dopamine neurons, but only G stimulation robustly enhanced cocaine seeking. G inhibitory signaling reduced some, but not all, types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and point to potential new approaches for intervening in these processes to treat addiction.

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66 citations in Web of Science
66 citations in Scopus

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#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
Web of Science research areas
Neurosciences
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