HIV-1 proteins dysregulate motivational processes and dopamine circuitry

Sarah J Bertrand,Rosemarie M Booze,Landhing M Moran,Steven B Harrod,Charles F Mactutus

doi:10.1038/s41598-018-25109-0

Abstract

Motivational alterations, such as apathy, in HIV-1+ individuals are associated with decreased performance on tasks involving frontal-subcortical circuitry. We used the HIV-1 transgenic (Tg) rat to assess effect of long-term HIV-1 protein exposure on motivated behavior using sucrose (1–30%, w/v) and cocaine (0.01–1.0 mg/kg/infusion) maintained responding with fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. For sucrose-reinforced responding, HIV-1 Tg rats displayed no change in EC50 relative to controls, suggesting no change in sucrose reinforcement but had a downward shifted concentration-response curves, suggesting a decrease in response vigor. Cocaine-maintained responding was attenuated in HIV-1 Tg rats (FR1 0.33 mg/kg/infusion and PR 1.0 mg/kg/infusion). Dose-response tests (PR) revealed that HIV-1 Tg animals responded significantly less than F344 control rats and failed to earn significantly more infusions of cocaine as the unit dose increased. When choosing between cocaine and sucrose, control rats initially chose sucrose but with time shifted to a cocaine preference. In contrast, HIV-1 disrupted choice behaviors. DAT function was altered in the striatum of HIV-1 Tg rats; however, prior cocaine self-administration produced a unique effect on dopamine homeostasis in the HIV-1 Tg striatum. These findings of altered goal directed behaviors may determine neurobiological mechanisms of apathy in HIV-1+ patients.

Highlights

Apathy is a common motivational alteration in HIV-1+ individuals, affecting between 30–60% of the population, despite antiretroviral therapy[1,2]
Motivational alterations in HIV-1+ individuals are associated with decreased performance on tasks known to involve frontal-subcortical circuitry[21], and are associated with decreased volume of the NAc22
Motivational alterations in HIV-1+ individuals are associated with decreased performance on tasks known to involve frontal-subcortical circuitry[21], and with decreased volume of the NAc22

Summary

Introduction

Apathy is a common motivational alteration in HIV-1+ individuals, affecting between 30–60% of the population, despite antiretroviral therapy[1,2]. Goal-directed behavior is maintained by motivational and cognitive processes, such as the animals’ homeostatic state, an expectation about the reinforcer, the current value of the reinforcer, environmental cues, and other learning phenomena, such as generalization and discrimination[14,15]. Motivational processes have received little attention in experimental models of HIV-1, despite apathy/ motivational disturbances being common in the HIV-1 population[3]. Brains from HIV-1+ patients without HIV-1 viral RNA/p24 (without active viremia, i.e., latent infections) show a reduction of synaptodendritic markers[16] and the presence of HIV-1 Tat protein in the cerebral spinal fluid[17]. Operant schedules of reinforcement were used to assess potential differences in sensitivity to the reinforcer[23] and changes in reinforcement efficacy[24] to assess motivational alterations in transgenic rats that constitutively express multiple proteins associated with the HIV-1 virus

Methods

Results

Conclusion