Behavioral manipulations for the improvement of anergia: impact on the mesolimbic dopaminergic system

Abstract

Studies with animals have shown that exercise can have neuroprotective effects which has led to suggestions that physical exercise could have positive effects in the prevention/treatment of various neurologic or psychiatric pathologies. It has been shown that physical exercise positively correlated with expression levels of certain neurochemical parameters related to the dopamine (DA) system. Thus, it has been shown that physical exercise has a protective effect in Parkinson's disease, and most work studying the relationship between physical exercise and the DA system have focused on the nigrostriatal pathway. In the present work we studied whether physical training will have also an impact on the DA mesolimbic pathway, and more specifically in nucleus Accumbens (Nacb). It is well known that Nacb DA has an important role in modulating the activational component of motivated behaviors, and is a key player in effort-based decision making. Thus, the first objective of this study is to explore the effect of pre-exposure to physical exercise in decision-making tasks that allow to choose between some natural reinforcers with different activational requirements. The second objective is to assess whether reduction of DA levels via tetrabenazine (TBZ) administration has any effect on that decision and whether this effect can be prevented by prior exposure to physical training. Finally, we want to assess the impact of physical training and administration of TBZ in the expression of a cellular marker related to the activity of DA receptors in the Nacb; pDARPP- 34. A total of 20 CD1 male mice 4 weeks old at the begining of the study, were used for the present experiments. The study was divided into three phases. In the first phase, the sample was divided into two groups: sedentary group (control) and exercise group. Training lasted for 9 weeks. In the second phase, animals were exposed to a T-maze with 3 different reinforcers: running wheel (RW), 50% sucrose pellets, and a non-social othor. After 1 week of exposure to these reinforcers the test phase started. In the test phase either vehicle or TBZ (2 mg/kg) were administered once a week, following a within-subject design. The third and final part of the study involved removal of the brains and immunohistochemical analysis of pDARPP32-Thr34. Results demonstrate no-significant differences in the amount of food eaten and on body weight of mice during the training phase. All animals spent more time in the more active reinforcer (RW) and spent also some time eating sweet pellets. During the test phase, control animals treated with TBZ demonstrated to shift preferences: reducing RW time and increasing sedentary consumption of sucrose. This change is not observed in trained animals, which suggests some protection against the effects of TBZ-induced anergia. Finally, significantly more pDARPP32-Thr34 was observed in the control animals after TBZ administration, an effect that mimiqued the behavioral results.