Impacts of morphine and HIV-Tat exposures and dimethylfumarate treatment on brain BDNF and mitochondrial and behavioral dysfunction.

点击翻译按钮获取中文摘要

Summary/Abstract More than 75,000 drug overdose deaths this past year were associated with opioids. To address this epidemic, NIH has prioritized the development of more effective opioid use disorder (OUD) treatments, as current interventions are helpful but inadequate. OUD is common among people living with Human Immunodeficiency Virus (HIV) and comorbid OUD/HIV increases risk for mental and physical health impairments of greater severities. Thus, comorbid OUD/HIV patients constitute a vulnerable group and basic research must study factors relevant to this group. We and others have data indicating that when combined, opioids and HIV proteins induce convergent deleterious effects that likely engender problematic opioid use behaviors and impair general health. This basic science R01 program aims to fill knowledge gaps in the individual and combined effects of the prototypical opioid, morphine, and HIV transactivator of transcription (Tat) protein, on mitochondrial function, brain derived neurotrophic factor (BDNF) expression, and on animal behavior, including those analogous to human behaviors that moderate health outcomes in patients with OUD and comorbid OUD/HIV. Improving our understanding of Tat protein’s effects is critical to better understanding effects of HIV because despite nearly complete viral suppression during antiretroviral therapy for HIV (ART), Tat is detectible with repeat testing in 40% of ART-treated patients at least once over the course of a year. This is important because Tat expression in animals induces phenotypes analogous to those observed in people living with HIV, including impairments in anxiety, inhibitory control, and brain structural and functional deficits. Tat’s relevance to comorbid OUD/HIV is illustrated in our pilot behavioral data indicating that Tat amplifies morphine taking, seeking, and post-extinction reinstatement. We also test effects of dimethylfumarate (DMF), which we have shown moderates morphine withdrawal symptoms. Studies in SIV-infected macaques report that DMF protects mitochondria and other studies show that DMF stimulates BDNF signaling. We focus on mitochondria because they supply most of the energy needed for neuronal and higher order brain function and they are impaired by morphine, Tat, and in human brain in vivo in people with OUD or HIV. Our working hypothesis is that morphine, Tat, and their combination will increase morphine self-administration, impair learning, memory, and cognitive flexibility, impair in vivo brain mitochondrial function assessed with phosphorus (31P) magnetic resonance spectroscopy, and will lower levels of mitochondrial biogenesis factors including Nuclear Respiratory Factor 1 and 2 expression, as determined postmortem. DMF, by protecting mitochondria and by increasing BDNF levels, will limit morphine’s and Tat’s deleterious effects. This basic science program aims to fill important knowledge gaps on the individual and combined effects of opioids, Tat, and DMF, and could yield data that support applied studies of novel treatments for OUD and HIV studied by us and by others, including DMF.