Cell-type specific excitability and molecular mechanisms of opioid seeking - Project Summary / Abstract Substance use disorders (SUDs) afflict 1 in 10 individuals, and opioid overdose deaths have quintupled over the last 20 years. There is a critical need to develop interventions that can reverse or block opioid-induced changes that can reduce relapse in patients with SUD. Our long-term goal is to better understand how drug seeking is increased by drug-induced neural adaptations. Drug reward and craving are encoded in part by the nucleus accumbens (NAc) and one NAc cellular adaptation that may influence opioid seeking is a change in the intrinsic excitability of NAc medium spiny neurons (MSNs). However, there is disagreement in the literature about the specific effects of opioid use on NAc excitability. We hypothesize that these disparate findings are due to separate adaptations in separable neuronal populations. These populations may include NAc MSNs that differentially express dopamine 1 (D1) or dopamine 2 (D2) receptors, as they both contribute to drug-related behaviors. However, the NAc also contains parvalbumin (PV) and choline acetyltransferase (ChAT) interneurons, but their roles in opioid seeking and opioid-induced excitability changes have not been thoroughly studied. Indeed, neither a systematic study on cell-type specific changes in opioid-induced intrinsic excitability nor a study examining opioid-induced changes in self-administering animals has ever been performed, thus limiting the field. In addition, our group recently showed that heroin self-administration reduces the expression of a sodium channel subunit called SCN1b in the NAc. Mimicking this NAc SCN1b reduction increases NAc excitability and increases heroin seeking, suggesting a novel molecular mechanism of heroin seeking that could explain opioid-induced cellular changes in excitability. However, there is a critical gap in knowledge of the cellular and cell-type specific mechanisms of action of both SCN1b and opioids. Here, we will investigate opioid-induced NAc mechanisms in two related, but separate areas both focusing on cell-type specific NAc neuronal adaptations. In Aim 1 we will systematically investigate the cell-specific effects of heroin self-administration on NAc intrinsic excitability in D1-, D2-, PV-, or ChAT-containing NAc neurons. Then, in Aim 2, we will determine in which accumbal cell types SCN1b acts to reduce heroin seeking by using a novel, validated, cre-dependent viral vector that can reduce SCN1b in combination with D1-, D2-, PV-, or ChAT-cre transgenic rats. Our central hypothesis is that opioids change NAc excitability in a cell-type specific manner through reductions in SCN1b that may cause increased opioid seeking. These studies are innovative due to our inclusion of 4 major NAc cell types, especially since PV and ChAT interneurons remain understudied. We are also the first group to examine a potential novel therapeutic target, NAc SCN1b channels, and their effect on intrinsic excitability as a potential mechanism underlying heroin seeking. In addition, our team including the Anderson, Ogundele, and Lee Labs at LSU have all the expertise and materials needed to complete these studies. We are well positioned to conduct these experiments to discover new effects of SCN1b and opioids on both excitability and drug seeking.
