Acute Dolutegravir Impact on Cocaine Induced Response in Mice

1.2 million people in the United States are living with HIV. Dolutegravir (DTG) is a first line integrase inhibitor used for HIV treatment. Unfortunately there are well-documented neuropsychiatric adverse effects such as depression, anxiety, and substance abuse associated with chronic DTG administration that leads to treatment discontinuation. Understanding the mechanism behind these adverse effects is essential to combat drug non-compliance with DTG. Our primary goal is to assess the role of chronic DTG administration in the development of neuropsychiatric adverse effects, but we must first establish whether there is an impact from acute DTG administration. This strategy allows us to characterize immediate pharmacological responses before progressing to chronic treatment, which may involve more complex neuroadaptive effects. To study the interaction between chronic DTG administration and substance use disorder as a form of neuropsychiatric adverse effects, we measured cocaine-induced behavior in mice via locomotion activity. In addition, we measured physiological responses to cocaine and DTG through the expression of Immediate Early Genes (IEGs). We hypothesize that acute injections of DTG will not enhance the behavioral response to cocaine nor will strengthen the physiological response to cocaine in the hippocampus and striatum in mice. Twelve 8-12 week old C57Bl/6J male mice were divided into 4 groups of n= 3: Vehicle + Saline, DTG (50 mg/kg) + Saline, Vehicle + Cocaine (15 mg/kg), and DTG + Cocaine. Intraperitoneal injections of the first treatment were given 2 hours prior to transcardial perfusion. 15 minutes after the first injection of DTG or vehicle, the mice were given their second injection of saline or cocaine and subsequently placed in an open field to measure their locomotive movement for 15 minutes. The mice were anesthetized using isoflurane and perfused using 4% PFA to fix their brain tissue. After perfusion, each brain was stored in 30% sucrose at 4℃ before freezing and slicing the tissue at 40 microns using the cryostat to obtain samples highlighting the striatum and hippocampus. Then immunohistochemistry (IHC) protocol was applied with antibodies for IEGs, c-fos and Egr1, to estimate expression of neuronal activity. Acute administration of DTG does not show a significant difference in cocaine-induced locomotive activity. As expected, the c-fos positive cell counts in the striatum increased due to the cocaine injection. Furthermore, acute DTG did not demonstrate any changes on cocaine-induced c-fos positive cell counts in the striatum or the Egr1 positive cell counts in the dorsal hippocampus. The data supports our hypothesis that acute DTG injections will not enhance behavioral and physiological response to cocaine. Subsequent studies will focus on chronic DTG administration to further assess adverse effects in mice. The route of administration of DTG using intraperitoneal injections will also be evaluated because chronic, daily injections introduce additional stress to the mice. A reduced-stress oral route of delivery, such as gummies, may offer a better alternative for chronic DTG administration and thus a more accurate assessment of physiological and behavioral outcomes. In addition, we will use patch clamp electrophysiology to provide precise measures of neuronal activity.