Efeitos de um inibidor da calcineurina em um modelo animal de adicção induzido por cocaína

Abstract

Despite the growing number of studies in the literature on the brain mechanisms that contribute to cocaine dependence, therapeutic treatments are still limited. Furthermore, we know that cocaine use is associated with significant social and medical issues and represents a serious public health problem. Studies indicate a relationship between calcineurin in hippocampus-based learning and synaptic plasticity. FK506, an immunosuppressant that inhibits calcineurin, has been associated with important neural effects, including neurotransmitter release, production of neurotrophic factors, and protection against neurotoxicity, as well as the ability to modify locomotor activity and sensitization induced by other psychostimulants. However, its role in neuroinflammation and synaptic plasticity involved in the addiction process is not fully established. Therefore, the objective of the work was to evaluate the effects of a calcineurin inhibitor on behavior and the neuroinflammatory process in an animal model of cocaine-induced addiction. C57Bl/6 mice, male and female, aged between 9 and 12 weeks (CEUA: 261/2021) were used. The calcineurin inhibitor, FK506 (5 mg/kg), was given by subcutaneous injection 90 minutes before cocaine (15 mg/kg). The latter was, in turn, administered by intraperitoneal injection immediately before each behavioral test. The behavioral sensitization test was used to assess locomotor activity and the conditioned preference for place test. After each test, the animals were euthanized by perfusion and the brains were dissected, removing the hippocampus and striatum for BDNF, GDNF, NGF, TNF-α, IL-6, IL-10 and CX3CL1 dosage through ELISA. Results were analyzed by two-way ANOVA followed by Tukey's post-test. The difference between groups was considered statistically significant when P <0.05. FK506 significantly attenuated locomotor sensitization induced by cocaine in males from the fourth day onwards (p<0.05). Despite this, no statistical differences were found in the behavior of females. No differences were found in the conditioned place preference test for either sex. In groups treated with cocaine, FK506 reduced the concentrations of GDNF (p=0.0130), TNF-α (p=0.0397) and IL-10 (p=0.0259) in the hippocampus of males when compared to groups treated only with cocaine. There was also an increase in IL-10 in the striatum of the cocaine-treated group compared to the control group (p=0.0180). No differences were found in the concentrations of BDNF, NGF, IL-6 and CXCL1 in the hippocampus and BDNF, GDNF, NGF, TNF-α, IL-6 and CXCL1 in the striatum of males. Our results suggest the involvement of the calcineurin pathway in the locomotor effects caused by cocaine in males. This effect could be related to changes in the concentration of neurotrophic factors and inflammatory mediators. Despite this, further studies are needed to establish the relationship between calcineurin and substance use disorder.