The role of neurotrophic factors in manic-, anxious- and depressive-like behaviors induced by amphetamine sensitization: implications to the animal model of bipolar disorder

Background: Bipolar disorder (BD) and substance use disorders share common symptoms, such as behavioral sensitization. Amphetamine-induced behavioral sensitization can serve as an animal model of BD. Neurotrophic factors have an important role in BD pathophysiology. This study evaluated the effects of amphetamine sensitization on behavior and neurotrophic factor levels in the brains of rats.Methods: Wistar rats received daily intraperitoneal (i.p) injections of dextroamphetamine (D-AMPH) 2 mg/kg or saline for 14 days. After seven days of withdrawal, the animals were challenged with D-AMPH (0.5 mg/kg, i.p) and locomotor behavior was assessed. In a second protocol, rats were similarly treated with D-AMPH (2 mg/kg, i.p) for 14 days. After withdrawal, without D-AMPH challenge, depressive-and anxiety-like behaviors were evaluated through forced swimming test and elevated plus maze. Levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum.Results: D-AMPH for 14 days augmented locomotor sensitization to a lower dose of D-AMPH (0.5 mg/kg) after the withdrawal. D-AMPH withdrawal induced depressive-and anxious-like behaviors. BDNF, NGF, and GDNF levels were decreased, while NT-3 and NT-4 levels were increased in brains after D-AMPH sensitization.Limitations: Although D-AMPH induces manic-like behavior, the mechanisms underlying these effects can also be related to phenotypes of drug abuse.Conclusions: Together, vulnerability to mania-like behavior following D-AMPH challenge and extensive neurotrophic alterations, suggest amphetamine-induced behavioral sensitization is a good model of BD pathophysiology

Differences between dextroamphetamine and methamphetamine: behavioral changes and oxidative damage in brain of Wistar rats

In this study methamphetamine (m-AMPH) and dextroamphetamine (d-AMPH) were compared to determine the potency of the two drugs on behavior and oxidative damage in brain of rats. Male adult Wistar rats were given single (acute administration) or repeated (chronic administration, 14 days) intraperitoneal injections of saline (0.9% NaCl), d-AMPH (2 mg/kg) or m-AMPH (0.25, 0.5, 1 or 2 mg/kg). Locomotor activity was evaluated in open-field apparatus 2 h after the last drug injection. Additionally, thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation were measured in the prefrontal cortex, amygdala, hippocampus and striatum. in both experiments, d-AMPH and m-AMPH (all doses administered) increased the locomotor activity of animals, meantime, no significant difference between d-AMPH and m-AMPH was observed. d-AMPH and m-AMPH increased lipid and protein damage, but m-AMPH was more potent than d-AMPH, however, this effect varies depending on the brain region and the experimental protocol. the results of this study show that d-AMPH and m-AMPH have similar behavioral effects, which previous studies had already reported. On the other hand, this study demonstrated that the m-AMPH induces oxidative damage greater than d-AMPH, showing neurochemical differences previously unknown.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESCUniv Extremo Catarinense, UNASAU, PPGCS, Lab Neurociencias, BR-88806000 Criciuma, SC, BrazilUniv So Santa Catarina, Lab Neurosci, BR-88806000 Criciuma, SC, BrazilUniv So Santa Catarina, Hlth Sci Unit, Postgrad Program Hlth Sci, Natl Inst Translat Med INCT TM, BR-88806000 Criciuma, SC, BrazilUniv So Santa Catarina, Lab Expt Pathophysiol, BR-88806000 Criciuma, SC, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04024002 São Paulo, BrazilWeb of Scienc