Wang Dongmei, Zhang Jianjun, Bai Yunjing, Zheng Xigeng, Alizamini Mirmohammadali M, Shang Wen, Yang Qingxiong, Li Ming, Li Yonghui, Sui Nan
CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China.
Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
J Psychopharmacol. 2020 Apr;34(4):478-489. doi: 10.1177/0269881119895521. Epub 2020 Jan 7.
Identifying neural substrates that are differentially affected by drugs of abuse and natural rewards is key to finding a target for an efficacious treatment for substance abuse. Melanin-concentrating hormone is a polypeptide with an inhibitory effect on the mesolimbic dopamine system. Here we test the hypothesis that melanin-concentrating hormone in the lateral hypothalamus and nucleus accumbens shell is differentially involved in the regulation of morphine and food-rewarded behaviors.
Male Sprague-Dawley rats were trained with morphine (5.0 mg/kg, subcutaneously) or food pellets (standard chow, 10-14 g) to induce a conditioned place preference, immediately followed by extinction training. Melanin-concentrating hormone (1.0 µg/side) or saline was infused into the nucleus accumbens shell or lateral hypothalamus before the reinstatement primed by morphine or food, and locomotor activity was simultaneously monitored. As the comparison, melanin-concentrating hormone was also microinjected into the nucleus accumbens shell or lateral hypothalamus before the expression of food or morphine-induced conditioned place preference.
Microinfusion of melanin-concentrating hormone into the nucleus accumbens shell (but not into the lateral hypothalamus) prevented the reinstatement of morphine conditioned place preference but had no effect on the reinstatement of food conditioned place preference. In contrast, microinfusion of melanin-concentrating hormone into the lateral hypothalamus (but not in the nucleus accumbens shell) inhibited the reinstatement of food conditioned place preference but had no effect on the reinstatement of morphine conditioned place preference.
These results suggest a clear double dissociation of melanin-concentrating hormone in morphine/food rewarding behaviors and melanin-concentrating hormone in the nucleus accumbens shell. Melanin-concentrating hormone could be a potential target for therapeutic intervention for morphine abuse without affecting natural rewards.
确定受滥用药物和自然奖赏差异影响的神经基质是找到有效治疗药物滥用靶点的关键。促黑素是一种对中脑边缘多巴胺系统有抑制作用的多肽。在此，我们检验如下假设：下丘脑外侧和伏隔核壳中的促黑素在吗啡和食物奖赏行为的调节中发挥不同作用。
对雄性斯普拉格-道利大鼠进行训练，使其对吗啡（5.0毫克/千克，皮下注射）或食物颗粒（标准饲料，10 - 14克）产生条件性位置偏爱，随后立即进行消退训练。在由吗啡或食物引发复吸前，将促黑素（1.0微克/侧）或生理盐水注入伏隔核壳或下丘脑外侧，同时监测运动活动。作为对照，在食物或吗啡诱导的条件性位置偏爱表达前，也将促黑素微量注射到伏隔核壳或下丘脑外侧。
向伏隔核壳（而非下丘脑外侧）微量注射促黑素可阻止吗啡条件性位置偏爱的复吸，但对食物条件性位置偏爱的复吸没有影响。相反，向下丘脑外侧（而非伏隔核壳）微量注射促黑素可抑制食物条件性位置偏爱的复吸，但对吗啡条件性位置偏爱的复吸没有影响。
这些结果表明，促黑素在吗啡/食物奖赏行为中的作用以及在伏隔核壳中的作用存在明显的双重解离。促黑素可能是治疗吗啡滥用而不影响自然奖赏的潜在干预靶点。
