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

Abstract

It has been recently demonstrated that predictive learning induces a persistent accumulation of delta-opioid receptors (DOPrs) at the somatic membrane of cholinergic interneurons (CINs) 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 DOPr translocation and (2) that this effect was mediated by the NK1 receptor, likely through its expression on CINs. Interestingly, whereas intrastriatal infusion of the D1 agonist chloro-APB reduced the DOPr translocation on CINs and infusion of the D2 agonist quinpirole had no effect, co-administration of both agonists again generated DOPr 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 DOPr translocation as was chloro-APB when co-administered with the DOPr 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 NK1R - regulates DOPr translocation in multiple striatal regions. To our knowledge, this represents a novel mechanism by which DOPr distribution is regulated that may be particularly relevant to learning-induced DOPr trafficking.

How predictive learning influences choice: Evidence for a GPCR‐based memory process necessary for Pavlovian‐instrumental transfer

“…D2-SPNs release enkephalin which is the endogenous ligand of DOPR (Le Merrer et al, 2009;Steiner & Gerfen, 1998) and enkephalin binding on DOPR causes these receptors to internalize, reducing membrane expression (Faget et al, 2012). Consistent with these findings, we have found that DOPR accumulation on NAc-S CINs requires concurrent D1-SPN stimulation (and SP release) and D2-SPN inhibition (Heath et al, 2018). As such, reducing D2-SPN activity should be predicted to: (1) prevent enkephalin release; (2) prevent DOPR internalization; (3) increase the accumulation of DOPR on NAc-S CINs, and (4) ensure the formation of a stable S-O memory necessary for predictive learning to guide choice between actions.…”

“…To determine whether SP and NK1R are also involved in DOPR accumulation, DOPR-eGFP mice received an infusion of SP into the NAc-S in one hemisphere and SP combined with an NK1R antagonist into the contralateral hemisphere. We found that SP alone produced a robust increase in DOPR expression on CINs in the NAc-S that was abolished contralaterally in the presence of the NK1R antagonist (Heath et al, 2018). In a separate experiment, we stimulated BLA terminals in the NAc-S of DOPR-eGFP mice in the presence or absence of the NK1R antagonist (Morse et al, 2020).…”

Basolateral Amygdala Drives a GPCR-Mediated Striatal Memory Necessary for Predictive Learning to Influence Choice

“…We confirmed the finding that SP produces robust activation in NAc-S CINs (Figures S2I-S2K). Interestingly, we have recently reported that NAc-S infusion of SP induces DOPR accumulation in striatal CINs and that this effect is abolished by NK1R blockade (Heath et al, 2018). Accordingly, we evaluated whether NK1R antagonism could prevent BLA-mediated DOPR accumulation on NAc-S CINs.…”

The Meaning of Behavior: Discriminating Reflex and Volition in the Brain

“…In contrast, the formation of outcome-specific Pavlovian predictions and their influence on choice depends on the BLA (Ostlund and Balleine, 2008) and its inputs to the NACsh (Shiflett and Balleine, 2010). In this latter case, there is now good evidence that these predictions involve BLA modulation of cholinergic processes in the shell, again mediated by CINs (Heath et al, 2018), although, importantly, both the input and output processes and the intrinsic circuitry of the NACsh differs markedly from the dorsal striatum (see Gonzales and Smith, 2015 for a thoroughgoing review of these distinctions). These stimulus-outcome relationships appear to be physically encoded in a G-protein-coupled-receptor-mediated cellular ''memory'' in the NACsh; delta opioid receptors on CINs in the shell accumulate on the membrane in a manner reflecting specific Pavlovian relationships and regulate the excitatory output from D1-expressing SPNs to medial ventral pallidum (VPm) and thence to the mdT when retrieved (Bertran-Gonzalez et al, 2013;Laurent et al, 2014;Leung and Balleine, 2015;Zahm, 1999;Figures 3B and 3d).…”