Programming of Dopaminergic Neurons by Early Exposure to Sex Hormones: Effects on Morphine-Induced Accumbens Dopamine Release, Reward, and Locomotor Behavior in Male and Female Rats.

Victoria B Velásquez,Ramón Sotomayor-Zárate,Gonzalo E Torres,Christian Bonansco,Gabriel A Zamorano,Pablo Jara,Jonathan Martínez-Pinto,Georgina M Renard

doi:10.3389/fphar.2019.00295

Abstract

Neonatal programming with sex hormones produces long-term functional changes in various tissues, including the brain. Previously, we demonstrated a higher content of dopamine and an increase in potassium-induced dopamine release in the nucleus accumbens of adult rats exposed to estradiol valerate. On the other hand, sex hormones also affect the opioid system increasing the expression of the μ opioid receptor and β-endorphins. Here, we investigated if neonatal programming with sex hormones alters the response to morphine during adulthood in rats and predispose them to neurochemical, rewarding and behavioral activating effects. We examined the effects of neonatal exposure to a single dose of estradiol valerate or testosterone propionate on morphine-induced (5 mg/kg, i.v.) dopamine release in the nucleus accumbens and morphine-induced (3 mg/kg, s.c.) locomotor activity and conditioned place preference when these rats were adults. Our results showed a significant increase in morphine-induced dopamine release in the nucleus accumbens of rats that were exposed neonatally to estradiol compared with control rats. This effect was correlated with higher place preference and locomotor activity induced by morphine in adult rats neonatally exposed to estradiol valerate. However, the effect of morphine on dopamine release and behaviors was similar in rats treated with testosterone compared to control rats. Additionally, the expression of mu (μ) opioid receptor, dopamine receptor type 1 (D1) and dopamine receptor type 2 (D2) in the nucleus accumbens of adult rats was not different after treatment with sex hormones. Taken together, our results demonstrated an enhancement of pharmacological effects produced by morphine in rats neonatally programmed with estradiol valerate, suggesting that early exposure to sex hormones could represent a vulnerability factor in the development of addiction to opioid drugs such as morphine and heroin in adulthood.

Highlights

Drug addiction is defined as a chronic brain disease characterized by compulsive use of the drug, loss of control in drug intake and the emergence of a negative emotional state that is exacerbated by abstinence
Our data show that neonatal exposure to estradiol valerate (EV) increases the rewarding effects of morphine and it represents a vulnerability factor that may enhance the development of opioid dependence
We have shown that neonatal EV administration produces a higher increase in morphine-induced nucleus accumbens (NAcc) DA release in both female and male adult rats compared to control rats

Summary

Introduction

Drug addiction is defined as a chronic brain disease characterized by compulsive use of the drug, loss of control in drug intake and the emergence of a negative emotional state that is exacerbated by abstinence. Clinical studies have been shown prevalence that the abuse for opioid analgesics and tranquilizers is higher in women than men (UNODC, 2012), women increase drug intake and develop dependence more quickly than men (Becker and Hu, 2008) and when levels of estrogens are high and progesterone is low (follicular phase) the rewarding effects of cocaine are greater than the effects observed during luteal phase (progesterone is high) (Sofuoglu et al, 1999) These sex differences are associated with a modulation of the reward system (mesolimbic pathway) by sex hormones (Cummings et al, 2014; Becker and Koob, 2016; Becker et al, 2016). We postulate that neonatal EV and TP administration will increase morphine activating effects such as NAcc DA release, CPP and locomotor activity in adult male and female rats

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