| dc.description.abstract | Addiction, which is characterized by the desire and the search for the drug, despite negative
consequences, is a serious health problem, causing impairments to the individual, your family, and
society. Thus, the developing of strategies to better understand neurobiological mechanisms related to
this disorder are extremely relevant. Studies revealed that adverse experiences during the
adolescence period could lead to neural circuit impairments facilitating neuropsychiatric disorders
development, which could be manifested throughout life and even into adulthood. In this perspective,
the inadequate use of licit prescribed psychostimulant drugs during adolescence has become a social
concern nowadays. The objective of the current study was to evaluate the influence of modafinil
(MOD) administration, a prescription drug, during adolescence on the conditioned place preference
(CPP) for amphetamine (AMPH) in rats. The study is based on the hypothesis that prolonged MOD
exposure during adolescence could modify the expression of molecular biomarkers related to memory
(pro-BDNF, BDNF, Trk-B e GDNF) and targets of the mesolimbic dopaminergic pathway (D1R, D2R,
DAT, TH e VMAT-2), affecting the cerebral oxidative status leading to behavioral alterations. From the
pilot study (experimental protocol I), when we evaluate the MOD (64mg/kg p.o.) exposure influence on
adolescent rats for 14 days, MOD improves short-term memory without causes changes in locomotor
or anxiety parameters in the animals. Concerning the oxidative status, the MOD increased the
catalase (CAT) activity decreasing oxidative damage markers in the prefrontal cortex, striatum and
ventral tegmental área (VTA), as one exception the hippocampus, which MOD did not exert
significative influence on the parameters evaluated. From the experimental protocol II, adolescent
animals were exposed to MOD and consecutively conditioned with AMPH in the CPP paradigm in
adulthood, when we observed that MOD reduced the preference for the drug, preventing locomotor
alterations, anxiety-like symptoms, and memory impairments during withdrawal. MOD also showed
antioxidant activity and beneficial influences on biomarkers related to memory (pro-BDNF, BDNF, and
Trk-B), acting as a modulator of the hippocampal dopaminergic system (DAT, D1R, and D2R). The
experimental protocol III was aimed to evaluate whether the same MOD beneficial influences would be
repeated when these animals were AMPH-exposed still during adolescence. Again, MOD exposure
reduced AMPH-CPP reducing the anxiety-like symptoms during withdrawal. Oxidative and molecular
alterations in the dopaminergic system were observed in the VTA and striatum of this animals when
MOD exerted an upregulation of striatal dopaminergic targets (TH, DAT, D1R, and D2R) after AMPH
exposure, possibly preventing the decrease of dopamine levels during withdrawal and this could be
reflected in the behaviors presented. From the experimental protocol IV, the MOD exposure occurred
after AMPH-CPP was established, it was proposed as a treatment in the relapse. Such approach
showed that MOD treatment prevented the AMPH relapse acting beneficially on memory. At the
molecular level, the MOD caused beneficial changes in the dopaminergic system as well in
neurotrophins related to the maintenance of this pathway upon AMPH exposure in the ventral
striatum. In conclusion of these studies, it is possible to infer that MOD exerted beneficial behavioral
effects on the preference and relapse for AMPH when administered during adolescence. Those
behaviors occurred together with positive responses on oxidative status and molecular in brain areas
related to addiction. So far, until this moment it is possible to propose that MOD could be acting as a
modulator of the dopaminergic system against the damage caused by AMPH in rats. | |
