Velásquez Victoria B, Zamorano Gabriel A, Martínez-Pinto Jonathan, Bonansco Christian, Jara Pablo, Torres Gonzalo E, Renard Georgina M, Sotomayor-Zárate Ramón
Laboratorio de Neuroquímica y Neurofarmacología, Valparaíso, Chile.
Laboratorio de Neurofisiología, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
Front Pharmacol. 2019 Mar 26;10:295. doi: 10.3389/fphar.2019.00295. eCollection 2019.
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 (D) and dopamine receptor type 2 (D) 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.
性激素诱导的新生儿编程会在包括大脑在内的各种组织中产生长期的功能变化。此前，我们证明了成年大鼠伏隔核中多巴胺含量较高，且在暴露于戊酸雌二醇后，钾诱导的多巴胺释放增加。另一方面，性激素也会影响阿片系统，增加μ阿片受体和β-内啡肽的表达。在此，我们研究了性激素诱导的新生儿编程是否会改变成年大鼠对吗啡的反应，并使其易受神经化学、奖赏和行为激活效应的影响。我们检测了新生期单次暴露于戊酸雌二醇或丙酸睾酮对成年大鼠伏隔核中吗啡诱导（静脉注射5mg/kg）的多巴胺释放、吗啡诱导（皮下注射3mg/kg）的运动活动及条件性位置偏爱。我们的结果显示，与对照大鼠相比，新生期暴露于雌二醇的大鼠伏隔核中，吗啡诱导的多巴胺释放显著增加。这种效应与新生期暴露于戊酸雌二醇的成年大鼠中吗啡诱导的更高位置偏爱和运动活动相关。然而，与对照大鼠相比，用睾酮处理的大鼠中，吗啡对多巴胺释放和行为的影响相似。此外，成年大鼠伏隔核中μ阿片受体、1型多巴胺受体（D）和2型多巴胺受体（D）在性激素处理后的表达并无差异。综上所述，我们的结果表明，在新生期经戊酸雌二醇编程的大鼠中，吗啡产生的药理效应增强，这表明早期暴露于性激素可能是成年期对吗啡和海洛因等阿片类药物成瘾发展中的一个易损因素。
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