Substance P and dopamine interact to modulate the distribution of delta‐opioid receptors on cholinergic interneurons in the striatum

It has been recently demonstrated that predictive learning induces a persistent accumulation of delta‐opioid receptors ( DOP rs) at the somatic membrane of cholinergic interneurons ( CIN s) in the nucleus accumbens shell (Nac‐S). This accumulation is required for predictive learning to influence subsequent choice between goal‐directed actions. The current experiments investigated the local neurochemical events responsible for this translocation. We found that (1) local administration of substance P into multiple striatal sub‐territories induced DOP r translocation and (2) that this effect was mediated by the NK 1 receptor, likely through its expression on CIN s. Interestingly, whereas intrastriatal infusion of the D1 agonist chloro‐ APB reduced the DOP r translocation on CIN s and infusion of the D2 agonist quinpirole had no effect, co‐administration of both agonists again generated DOP r translocation, suggesting the effect of the D1 agonist alone was due to receptor internalisation. In support of this, local administration of cocaine was found to increase DOP r translocation as was chloro‐ APB when co‐administered with the DOP r antagonist naltrindole. These studies provide the first evidence of delta‐opioid receptor translocation in striatal cholinergic interneurons outside of the accumbens shell and suggest that, despite differences in local striatal neurochemical microenvironments, a similar molecular mechanism – involving an interaction between dopamine and SP signalling via NK 1R – regulates DOP r translocation in multiple striatal regions. To our knowledge, this represents a novel mechanism by which DOP r distribution is regulated that may be particularly relevant to learning‐induced DOP r trafficking.