Investigation of reproductive parameters in male rats exposed to the psychostimulant Lysdexamphetamine from the juvenile period to peripuberty

Author(s)

Julia Stein

• Document type: Master's Dissertation
• Press: Botucatu. 2023-03-14.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências. Botucatu
• Defense date: 2023-02-28
• Advisor: Arielle Cristina Arena

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents, with a higher incidence of diagnoses in male sex. Inattention, hyperactivity and impulsivity in levels above expected are the main symptoms in ADHD, negatively affecting patients’ daily life. Proper treatment is essential and it is based on a multimodal strategy, with cognitive-behavioral interventions and pharmacological treatment, usually with stimulants medications. One of the main drugs is Lisdexamfetamine Dimesylate (LDX), an extended-release formulation since it is a prodrug of dextroamphetamine, hydrolyzed inside erythrocytes. Its action is mediated by increased levels of catecholamines, mainly dopamine and noradrenaline, in synaptic clefts. Neurotransmitters influence hormonal control and act directly in gonads, so LDX could interfere in reproductive performance. Juvenile and peripubertal period are critical windows of development, more susceptible to the effect of exogenous substances. The aim was to evaluate the effects of exposure to Lisdexamfetamine during the juvenile to peripubertal period on parameters of systemic and reproductive toxicity of male rats. Male Wistar rats (23 days old) were divided into a control group (deionized water) and three groups exposed to LDX in therapeutic doses (converted to animal doses): 5.2; 8.6 and 12.1 mg/kg/day. The treatment occurred from post-natal day 23 (PND) to 53, by gavage. During the treatment, clinical signs of toxicity, body weight, water, and food intake, play behavior and puberty onset were evaluated. On postnatal day (PND) 54, half of the animals were killed for organ weight, hematological and biochemical analysis, testis histology and oxidative stress of the testis. In adult life (PND 90), the animals were evaluated in relation to male sexual behavior and fertility parameters. On PND 120, the animals were killed to record organ weight, hematological parameters, sperm parameters, contractile of vas deferens, testis histology and oxidative stress. There was a reduction in the daily food and water consumption during the treatment period. On play behavior evaluation, the animals presented a reduction in total social behaviors. No experimental group had the day of preputial separation altered compared to control, but the weight of the animals in the highest dose group were reduced on this day. At PND 54, several parameters were altered, mainly related to systemic toxicity: reduction in body weight gain, increase in the relative weight of the liver, the spleen and the seminal gland, reduction in the erythrocyte and leukocyte count, reduced total protein levels and a disturbance in oxidative parameters. At adulthood, the male sexual behavior and fertility were not altered. But at PND 120, there was an increase in type C sperm (immobile), reduced sperm count in testis and epididymis, histological alterations in Leydig cells and seminiferous tubules, and oxidative parameters altered. Based on the data presented, LDX was able to induce disturbances in systemic toxicological parameters (mainly during treatment) and in reproductive function (mainly in adult life), indicating that the use of this medication should consider these aspects. (AU)

• FAPESP's process: 21/02225-6 - Investigation of reproductive parameters in male rats exposed to the psychostimulant Lysdexamphetamine from the juvenile period to peripuberty
• Grantee: Julia Stein
• Support Opportunities: Scholarships in Brazil - Master