Efavirenz induces anergia in animal models for the study of the activational deficits observed in depression : therapeutic effect of the chatecolamine uptake inhibitor bupropion

Abstract

A high degree of behavioral activation and work output are observed in motivated behaviors. Mesolimbic DA plays an important role in the regulation of this activational component of motivation. Anergia and fatigue are common symptoms observed in some psychiatric disorders such as depression. Efavirenz (EFV) is an antiretroviral drug prescribed for HIV-infected patients. This drug has adverse effects on the CNS, and it produces depressive-like behavior. EFV has demonstrated to bind to the vesicular monoamine transporter type 2 (VMAT-2) that can lead to DA depletion. Bupropion is an antidepressant that acts as a DA uptake blocker effective for the treatment of motivational impairments observed in depressed patients as well as reverting motivational impairments induced by DA interferences in animals. In animal models, behavioral activation can be studied using voluntary running wheels (RW) and tasks offering choices between high effort options leading to highly valued reinforces vs. low effort/low reward options are used to study effort-based decision making. In the present study we assess the effect of EFV on behavioral activation as well as the effect of bupropion to revert EFVinduced motivational impairments.Adult CD1 male mice received EFV (1.25, 2.5, 5 and 10 mg/kg, IP), or EFV (5 mg/kg)-Bupropion (2.5, 5 and 10 mg/kg, IP), and were tested in a RW and in a T-maze with barrier in the high-density of food arm. Control mice chose to jump the barrier and consume more sucrose pellets. However, EFV biased animals towards the loweffort/low-reward option in the T-maze, and dose-dependently reduced voluntary RW activity. The suppressing effect of EFV on voluntary RW was reversed by the antidepressant bupropion. EFV induces motivational symptoms in rodents such as anergia and this effect can be reversed by bupropion. This action may be of interest for the better understanding of the depressive symptoms observed in HIV patients exposed to EFV.