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- Title
Chemogenetic Manipulation of Dopamine Neurons Dictates Cocaine Potency at Distal Dopamine Transporters.
- Authors
Brodnik, Zachary D.; Wei Xu; Batra, Aashita; Lewandowski, Stacia I.; Ruiz, Christina M.; Mortensen, Ole V.; Kortagere, Sandhya; Mahler, Stephen V.; España, Rodrigo A.
- Abstract
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 in vivo remain unclear. In male rats, we used chemogenetics with intra-VTA microinfusions of the agonist clozapine-n-oxide to bidirectionally modulate dopamine neurons. Using ex vivo 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.
- Subjects
DOPAMINERGIC neurons; COCAINE-induced disorders; COCAINE; DOPAMINE analysis; MONOAMINE transporters; DOPAMINE; NUCLEUS accumbens
- Publication
Journal of Neuroscience, 2020, Vol 40, Issue 45, p8767
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0894-20.2020