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