The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats.

ABSTRACT: The dopamine transporter (DAT) regulates dopamine (DA) neurotransmission by recapturing DA into the presynaptic terminals and is a principal target of the psychostimulant cocaine. The sigma-1 receptor (?1R) is a molecular chaperone, and its ligands have been shown to modulate DA neuronal signaling, although their effects on DAT activity are unclear. Here, we report that the prototypical ?1R agonist (+)-pentazocine potentiated the dose response of cocaine self-administration in rats, consistent with the effects of the ?R agonists PRE-084 and DTG (1,3-di-o-tolylguanidine) reported previously. These behavioral effects appeared to be correlated with functional changes of DAT. Preincubation with (+)-pentazocine or PRE-084 increased the Bmax values of [3H]WIN35428 binding to DAT in rat striatal synaptosomes and transfected cells. A specific interaction between ?1R and DAT was detected by co-immunoprecipitation and bioluminescence resonance energy transfer assays. Mutational analyses indicated that the transmembrane domain of ?1R likely mediated this interaction. Furthermore, cysteine accessibility assays showed that ?1R agonist preincubation potentiated cocaine-induced changes in DAT conformation, which were blocked by the specific ?1R antagonist CM304. Moreover, ?1R ligands had distinct effects on ?1R multimerization. CM304 increased the proportion of multimeric ?1Rs, whereas (+)-pentazocine increased monomeric ?1Rs. Together these results support the hypothesis that ?1R agonists promote dissociation of ?1R multimers into monomers, which then interact with DAT to stabilize an outward-facing DAT conformation and enhance cocaine binding. We propose that this novel molecular mechanism underlies the behavioral potentiation of cocaine self-administration by ?1R agonists in animal models.

SUBMITTER: Hong WC 

PROVIDER: S-EPMC5500793 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature