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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
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  • Tristan Hynes,
  • Maxime Fouyssac,
  • Mickaël Puaud,
  • David Belin
Tristan Hynes
University of Cambridge
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Maxime Fouyssac
university of Cambridge
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Mickaël Puaud
University of Cambridge
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David Belin
University of Cambridge

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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 striatum (DLS) control over behaviour, which is underpinned by a dopamine-dependent functional coupling of the nucleus accumbens and the DLS. However, 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), whose expression is altered in individuals with a heroin use disorder. Thus, astrocytes are uniquely placed functionally to bridge dopamine-dependent mechanisms across the striatum. Thus, here we tested the hypothesis that exposure to heroin, which does not interact with DAT, influences its expression in 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, cultured or 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 DLS (aDLS) that was preceded by a heroin-induced reduction in DAT mRNA and protein content in astrocytes across the striatum. aDLS astrocytes were also shown to be uniquely 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 habits for heroin.
18 Sep 2023Submitted to European Journal of Neuroscience
19 Sep 2023Assigned to Editor
19 Sep 2023Submission Checks Completed
19 Sep 2023Review(s) Completed, Editorial Evaluation Pending
22 Sep 2023Reviewer(s) Assigned
24 Oct 2023Editorial Decision: Revise Major