Efeitos do N, N-dimetiltriptamina (DMT) em modelo de depressão resistente induzida por corticosterona: investigação da influência do sexo

Abstract

Depression is a multifaceted psychiatric disorder that profoundly influences the quality of life of individuals, requiring the exploration of innovative therapeutic modalities. The corticosterone-induced depression (CORT) paradigm modifies the hypothalamic-pituitary adrenal axis, thus affecting neurochemical processes and behavioral outcomes. This investigation aimed to evaluate the AdMetox profile of compounds derived from N, N Dimetiltriptamina (DMT) crystal isolated from Mimosa tenuiflora, in conjunction with fluoxetine (FLX), and to explore the pharmacological impacts of DMT within a CORT-induced resistant depression model. Male and female BALB/c mice were subjected to CORT treatment (20 mg/kg, administered subcutaneously; s.c) for a period of 21 days. Subsequently, mice received FLX (10 mg/kg, administered orally; p.o.) from day 22 to day 28, and those that exhibited resistance to fluoxetine treatment were subsequently administered DMT (10 mg/kg, intranasal; i.n.) on day 29. After a four-hour interval, mice were subjected to a series of behavioral assessments (forced swim test, sucrose spray, elevated cross-maze, and open field). CORT administration resulted in an increase in the duration of immobility, with a more pronounced effect observed in males (~200 s) relative to females (~150 s). In male animals, FLX significantly attenuated the time spent in immobility, whereas females exhibited resistance to treatment, indicating a sex-specific differential response, although a percentage of animals showed resistance. DMT, when administered to males and females, led to a reduction in immobility duration, an increase in grooming behavior during the sucrose spray test, and exhibited anxiolytic effects in females within the elevated cross-maze apparatus. Regarding the AdMetox profile, FLX demonstrated favorable absorption and distribution characteristics, although accompanied by metabolic interactions and hepatotoxic potential. On the other hand, DMT did not exhibit hepatotoxicity, along with greater intestinal absorption, superior bioavailability, and a lower risk of drug interactions. In Vivo, results indicated that CORT induced resistant depression in mice is equivalent to human depressive disorders. The efficacy of FLX was not fully realized, particularly in females, highlighting the need for more personalized therapeutic approaches. DMT treatment exhibited significant efficacy in mitigating depressive and anxiolytic-like behaviors, suggesting its viability as a therapeutic strategy, particularly in cases of resistant depression.