Journal article
Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse
The Journal of neuroscience, Vol.39(3), pp.503-518
16 Jan 2019
PMCID: PMC6335749
PMID: 30446532
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse
- Creators
- Stephen V Mahler - Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425-8610Zachary D Brodnik - Drexel UniversityBrittney M Cox - University of California, IrvineWilliam C Buchta - Medical University of South CarolinaBrandon S Bentzley - Medical University of South CarolinaJulian Quintanilla - University of California, IrvineZackary A Cope - Medical University of South CarolinaEdwin C Lin - Medical University of South CarolinaMatthew D Riedy - Medical University of South CarolinaMichael D Scofield - Medical University of South CarolinaJustin Messinger - Medical University of South CarolinaChristina M Ruiz - University of California, IrvineArthur C Riegel - Medical University of South CarolinaRodrigo A España - Drexel UniversityGary Aston-Jones - Rutgers, The State University of New Jersey
- Publication Details
- The Journal of neuroscience, Vol.39(3), pp.503-518
- Publisher
- Society for Neuroscience
- Grant note
- TL1 TR001415 / NCATS NIH HHS R01 DA033342 / NIDA NIH HHS R00 DA040004 / NIDA NIH HHS R01 DA046476 / NIDA NIH HHS P50 DA044118 / NIDA NIH HHS F31 DA042505 / NIDA NIH HHS R01 DA031900 / NIDA NIH HHS K99 DA035251 / NIDA NIH HHS R01 DA006214 / NIDA NIH HHS F31 DA036989 / NIDA NIH HHS T32 DA007288 / NIDA NIH HHS P50 DA015369 / NIDA NIH HHS R00 DA035251 / NIDA NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Identifiers
- 991019167902604721
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- Web of Science research areas
- Neurosciences