δ-opioid receptor trafficking in the striatum

Abstract

While primarily studied for its role in analgesia and reward processing, the δ-opioid receptor (DOPr) has also been shown to play an important role in choice. DOPr – which is trafficked to the somatic membrane of cholinergic interneurons (CINs) in the nucleus accumbens shell (NAc-S) during Pavlovian conditioning – is necessary for animals to use environmental cues to guide choice. In this thesis, I aimed to characterise the cellular and circuit level processes that regulate DOPr translocation to the somatic membrane of CINs in the striatum. Pharmacological manipulations of striatal signalling revealed that both substance P signalling, and concurrent activation of both the dopamine D1 receptor and dopamine D2 receptor induced DOPr export to the plasma membrane of CINs in a neurokinin-1 receptor-dependent manner. Chemogenetic stimulation of BLA afferents in the NAc-S also induced DOPr translocation to the somatic membrane of CINs in an NK1R-dependent manner. Together these data suggest that glutamatergic and dopaminergic signals in the striatum regulate DOPr distribution on CINs via SP signalling. Optogenetic stimulation of BLA afferents in the NAc-S revealed that following Pavlovian conditioning the strength of BLA synapses to D1-MSNs positively correlated with conditioned responding, providing preliminary evidence that this striatal microcircuit is activated by learning processes that induce DOPr translocation. However inhibition of NK1R does not prevent DOPr translocation induced either by Pavlovian conditioning, or by contingency reversal learning (a manipulation that I showed also induces DOPr accumulation at the membrane of CINs). Together these results suggest that a complex striatal microcircuit integrating glutamate, dopamine and SP signalling regulates DOPr distribution in striatal CINs, though it remains to be demonstrated whether this microcircuit plays a direct role in learning-induced DOPr translocation