Novel modulators of the dopamine transporter for alcohol and nicotine use disorders

Abstract: The parent award is to develop novel medications for alcohol and nicotine use disorders. Thesedisorders have increased during COVID19 [e.g. Clay and Parker 2020] and are associated withincreased susceptibility to, and severity of, infection. This supplemental proposal is focused onhow mechanisms of COVID-19 infection and neurotoxicity are influenced by alcohol and nicotine,and how these novel medications interact with these mechanisms. The applicants have previouslyused organotypic hippocampal neuronal cultures to study interactions between nicotine, alcoholwithdrawal and viral protein neurotoxicity, and these cultures will be used here. First, nicotine hasbeen reported to up-regulate the viral "receptor" angiotensin converting enzyme 2 (ACE2) onneurons, providing a mechanism for increased SARS CoV2 infectivity and neurotoxicity insmokers and "vapers" [see Kabbani & Olds 2020]. The nicotinic receptor partial agonists(lobinaline N-oxides) from the parent award should inhibit this effect of nicotine, and this will betested in the first specific aim using immunohistochemistry to evaluate ACE2 expression inorganotypic cultures. Once CNS infection has occurred, coronaviruses cause "excitotoxicity" thatis inhibited by inhibitors of neuronal glutamate /NMDA receptors (NMDARs) [Hasanagic &Serdeveric, 2020]. This is similar to alcohol withdrawal (AWD) [Stepanyan et al, 2008] and soshould be ameliorated by drugs that prevent neurotoxicity in AWD. Once again, the nicotinicactivity of lobinaline N-oxides may be valuable, but another medication under development by thecompany for alcohol use disorder, the aryliminoguanidine, JR220, is even more directly relevantbecause it is an inhibitory modulator of the NMDAR [Barron et al, 2012], The neuroprotectivepossibilities for these drugs will be evaluated against viral protein neurotoxicity in organotypiccultures in specific aim 2. The hypothesis is therefore that coronavirus infectivity and neurotoxicityare enhanced in patients with nicotine and alcohol use disorders, and that both the disorders andthe COVID19 consequences should be inhibited by the medications under development. Thesenovel therapeutic targets for lobinaline N-oxides and JR220 in COVID-19 infection will stronglysupport the therapeutic and commercial value of products from the parent award.