Jibran Younis Khokhar, Ph.D. - US grants

Although alcohol use disorder (AUD) occurs commonly in patients with schizophrenia (SCZ) and dramatically worsens their overall clinical course, most medications used to treat SCZ do not decrease their alcohol use. The one antipsychotic medication that appears to decrease alcohol use in these patients, clozapine, is infrequently used because of its toxicity. Green (my mentor) and colleagues have proposed that a dysregulated brain reward circuit underlies alcohol use in patients with SCZ. However, the exact neural mechanisms contributing to AUD in SCZ, as well as the basis of clozapine?s actions, remain unknown. I have been looking to establish a novel animal model of AUD in SCZ that has mechanistic relevance and can be used to test potential therapeutic agents to reduce alcohol drinking in this difficult-to-treat population. Toward this end, I have recently begun studies with the NVHL (neonatal ventral hippocampal lesion) rat, a neurodevelopmental animal model of SCZ. We (and others) have demonstrated that if exposed to alcohol as an adolescent, the adult NVHL rat displays increased alcohol drinking. Moreover, our initial pharmacologic studies suggest that, like in patients with SCZ, clozapine decreases alcohol drinking in this animal. Thus, the adolescent-alcohol- primed adult NVHL rat can serve as a model of AUD in SCZ. In my K99-R00 program, I will study this animal to elucidate the neural mechanisms underlying AUD in SCZ, mechanisms that could provide targets for development of new treatment approaches for AUD in SCZ. During the K99 phase, I will use multi-modal magnetic resonance (MR) imaging techniques to study (a) levels of glutamate, glutamine and GABA via MR spectroscopy, and (b) brain reward circuit connectivity via resting state functional connectivity, before and during alcohol drinking in adolescent-alcohol-primed adult NVHL rats. My preliminary studies have suggested that these techniques can detect brain reward circuit abnormalities in glutamine and GABA levels, and in functional connectivity, in such adult NVHL rats. During the R00 phase, I will assess the effects of clozapine on these measures to establish a mechanistic blueprint for its ability to decrease alcohol drinking. Then, I will use a glutamine synthetase inhibitor targeting the identified glutamine dysfunction to assess whether it can also reverse the neurometabolic and connectivity dysfunctions, and whether it also decreases alcohol drinking. Data gained from these studies will be impactful, since they provide important clues about the mechanisms underlying alcohol drinking in this model, as potential targets for new therapeutic agents. During the K99 phase, under continued mentorship by Dr. Green, and co-mentorship by Drs. Elliot Stein, Hanbing Lu and Hermes Yeh, I will receive didactic and hands-on training in rodent MR spectroscopy and resting state functional connectivity, in neurodevelopmental effects of alcohol exposure, and in translational research, grant writing and research program development. This mentorship, combined with advanced coursework, will prepare me for a career as a translational scientist studying co-occurring psychiatric and alcohol use disorders.