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Chemogenetic Manipulation of Dopamine Neurons Dictates Cocaine Potency at Distal Dopamine Transporters
Journal article   Open access   Peer reviewed

Chemogenetic Manipulation of Dopamine Neurons Dictates Cocaine Potency at Distal Dopamine Transporters

Zachary D Brodnik, Wei Xu, Aashita Batra, Stacia I Lewandowski, Christina M Ruiz, Ole V Mortensen, Sandhya Kortagere, Stephen V Mahler and Rodrigo A España
The Journal of neuroscience, v 40(45), pp 8767-8779
04 Nov 2020
DOI: https://doi.org/10.1523/JNEUROSCI.0894-20.2020
PMID: 33046544
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1523/jneurosci.0894-20.2020View
Published, Version of Record (VoR)CC BY-NC-SA V4.0,  Open
url
https://doi.org/10.1523/JNEUROSCI.0894-20.2020View
Published, Version of Record (VoR) Open

Abstract

Animals Axons - drug effects Clozapine - pharmacology Cocaine - pharmacology Cocaine-Related Disorders - genetics Dopamine Agonists - pharmacology Dopamine Plasma Membrane Transport Proteins - drug effects Dopamine Uptake Inhibitors - pharmacology Dopaminergic Neurons - drug effects Male Microinjections Phosphorylation Rats Rats, Long-Evans Self Administration Ventral Tegmental Area
The reinforcing efficacy of cocaine is largely determined by its capacity to inhibit the dopamine transporter (DAT), and emerging evidence suggests that differences in cocaine potency are linked to several symptoms of cocaine use disorder. Despite this evidence, the neural processes that govern cocaine potency remain unclear. In male rats, we used chemogenetics with intra-VTA microinfusions of the agonist clozapine-n-oxide to bidirectionally modulate dopamine neurons. Using fast scan cyclic voltammetry, pharmacological probes of the DAT, biochemical assessments of DAT membrane availability and phosphorylation, and cocaine self-administration, we tested the effects of chemogenetic manipulations on cocaine potency at distal DATs in the nucleus accumbens as well as the behavioral economics of cocaine self-administration. We discovered that chemogenetic manipulation of dopamine neurons produced rapid, bidirectional modulation of cocaine potency at DATs in the nucleus accumbens. We then provided evidence that changes in cocaine potency are associated with alterations in DAT affinity for cocaine and demonstrated that this change in affinity coincides with DAT conformation biases and changes in DAT phosphorylation state. Finally, we showed that chemogenetic manipulation of dopamine neurons alters cocaine consumption in a manner consistent with changes in cocaine potency at distal DATs. Based on the spatial and temporal constraints inherent to our experimental design, we posit that changes in cocaine potency are driven by alterations in dopamine neuron activity. When considered together, these observations provide a novel mechanism through which GPCRs regulate cocaine's pharmacological and behavioral effects. Differences in the pharmacological effects of cocaine are believed to influence the development and progression of cocaine use disorder. However, the biological and physiological processes that determine sensitivity to cocaine remain unclear. In this work, we use a combination of chemogenetics, fast scan cyclic voltammetry, pharmacology, biochemistry, and cocaine self-administration with economic demand analysis to demonstrate a novel mechanism by which cocaine potency is determined These studies identify a novel process by which the pharmacodynamics of cocaine are derived , and thus this work has widespread implications for understanding the mechanisms that regulate cocaine consumption across stages of addiction.

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15 citations in Web of Science
17 citations in Scopus

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UN Sustainable Development Goals (SDGs)

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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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