Neonatal programming with estradiol valerate increases behavioral and neurochemical effects of morphine in the adulthood

Abstract

Neonatal programming with sex hormones produces long-term functional changes in various tissues, including the brain. For example, neonatal exposure to estrogens and androgens increases the catecholamine content and dopamine release in brain circuits related to reward and locomotion. On the other hand, sex hormones can increase the expression of muopioid receptor and beta-endorphins. Therefore, neonatal programming with sex hormones could alter the morphine response during adulthood in rats and predispose them to addiction-like behaviors. The aim of this work was to evaluate the behavior (locomotor activity and conditioned place preference) and neurochemical (content and release of dopamine in Nucleus Accumbens) induced by morphine in Sprague-Dawley adult rats exposed during the first postnatal day to sesame oil, estradiol valerate or testosterone propionate. The locomotor activity and conditioned place preference protocol were performed using morphine (3 mg/Kg s.c.) or saline (1 mL/Kg s. c.). On the other hand, dopamine release was measured in vivo in Nucleus Accumbens using morphine (5 mg/Kg i.v.). The results show that locomotor activity and conditioned place preference induced by morphine was significantly higher in animals treated with estradiol than control animals. At neurochemical level, the dopamine release in Nucleus Accumbens of rats treated with estradiol was greater than the observed in control rats. However, animals treated with testosterone had a place preference behavior and morphine-induced neurochemistry similar to control rats, although they showed an increase in locomotor activity. Our results demonstrated an enhancement of pharmacological effects produced by morphine in rats programmed with estradiol valerate. Despite that, the expression of the morphine pharmacological target has not been measured, it can hypothesized that this potentiation could be explained by a greater expression of mu-opioid receptors in GABAergic interneurons of Ventral Tegmental Area or Nucleus Accumbens. Our results could show that early exposure to sex hormones is a factor of vulnerability for addiction to opioidergic drugs such as morphine and heroin in adulthood.