The role of monoaminergic, gabaergic and nitrergic neurotransmission systems in anxiogenic and depression-like effects of efavirenz

Aim: Efavirenz (EFV) is an antiretroviral drug and frequently used in HIV-1 treatment. Several neuropsychiatric side effects occur during the first weeks of EFV administration and these side effects restrict the using EFV in the HIV-1 treatment. In this study, it was aimed to investigate the acute effects of EFV administration including anxiogenic and depression-like effects in mice and to understand potential neurotransmission mechanisms of these effects during the acute EFV administration. In addition, the effects of EFV administration on neuronal and mitochondrial functions, oxidative stress and inflammation mechanisms were also examined. Material and Method: For those purposes, BALB/c type male mice were divided into 10 equal groups (n=7) as following; Control, EFV, EFV+ATR, EFV+BCL, EFV+M10907, EFV+SHTN, EFV+HPDL, EFV+FBZM, EFV+PRPL and EFV+AMGN. In treatment groups, one of monoaminergic, GABAergic or nitrergic receptor antagonists (i.p.) was administered to mice 30 min before EFV administration (20 mg/kg, i.p.). Sixty min after the last drug administration, psychopharmacological experiments (open field test, elevated plus maze, light/dark box test, tail suspension test, and forced swimming test) were performed. The expression profiles of BDNF, VEGF-A, PGC-1, TFAM, UCP-2, IL-1β, IL-6 and TNF- genes in mice brain prefrontal cortex (pFK) were detected by using Real-time PCR. Level of Malondialdehyde in pFK tissues were measured and biochemical parameters in brain samples were detected. Results: Acute EFV administration caused anxiety and depression-like behavioral changes in mice. Developing depression and anxiety statement was reversed with atropine and aminoguanidine. While EFV administration significantly decreased expression levels of BDNF and TFAM genes in pFK tissues, level of IL-1β gene was increased. However, in EFV+SHTN and EFV+AMGN groups, IL-1β mRNA levels were decreased. In EFV+M10907 group, BDNF mRNA level was increased, compared to EFV group. EFV also caused an increase in malondialdehyde level in pFK tissues. Conclusion: This study clearly indicates that nitrergic and cholinergic neurotransmission systems play important roles in response to the anxiogenic and depression-like effects of EFV. It was also found that EFV administration disrupts neuronal functions and mitochondrial energy homeostasis and may trigger mechanisms related to inflammatory and oxidative stress.