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Pan-striatal reduction in the expression of the astrocytic dopamine transporter precedes the development of dorsolateral striatum dopamine-dependent incentive heroin seeking habits.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Hynes, Tristan 
Fouyssac, Maxime 
Puaud, Mickaël 
Joshi, Dhaval 
Chernoff, Chloe 

Abstract

The emergence of compulsive drug-seeking habits, a hallmark feature of substance use disorder, has been shown to be predicated on the engagement of dorsolateral striatal control over behaviour. This process involves the dopamine-dependent functional coupling of the anterior dorsolateral striatum (aDLS) with the nucleus accumbens core, but the mechanisms by which this coupling occurs have not been fully elucidated. The striatum is tiled by a syncytium of astrocytes that express the dopamine transporter (DAT), the level of which is altered in individuals with heroin use disorder. Astrocytes are therefore uniquely placed functionally to bridge dopamine-dependent mechanisms across the striatum. Here we tested the hypothesis that exposure to heroin influences the expression of DAT in striatal astrocytes across the striatum before the development of DLS-dependent incentive heroin seeking habits. Using Western-blot, qPCR, and RNAscope™, we measured DAT protein and mRNA levels in whole tissue, culture and in situ astrocytes from striatal territories of rats with a well-established cue-controlled heroin seeking habit and rats trained to respond for heroin or food under continuous reinforcement. Incentive heroin seeking habits were associated with a reduction in DAT protein levels in the anterior aDLS that was preceded by a heroin-induced reduction in DAT mRNA and protein in astrocytes across the striatum. Striatal astrocytes were also shown to be susceptible to direct dopamine- and opioid-induced downregulation of DAT expression. These results suggest that astrocytes may critically regulate the striatal dopaminergic adaptations that lead to the development of incentive heroin seeking habits.

Description

Keywords

addiction, astrocytes, dopamine, dopamine transporter, heroin, incentive habits, Animals, Dopamine Plasma Membrane Transport Proteins, Astrocytes, Corpus Striatum, Male, Rats, Drug-Seeking Behavior, Heroin, Dopamine, Motivation, Heroin Dependence, Rats, Sprague-Dawley

Journal Title

Eur J Neurosci

Conference Name

Journal ISSN

0953-816X
1460-9568

Volume Title

Publisher

Wiley
Sponsorship
MRC (2426794)
Biotechnology and Biological Sciences Research Council (2274747)
MRC (MR/W019647/1)