Nicotine is a significant public health concern because it is the primary pharmacological agent in tobacco use disorder. One neural system that has been implicated in the symptoms of several substance use disorders is the melanin-concentrating hormone (MCH) system. MCH regulates various motivated behaviors depending on sex, yet little is known of how this interaction affects experience with drugs of abuse, particularly nicotine. The goal of this study was to determine the effect of MCH receptor antagonism on experience-dependent nicotine-induced locomotion after chronic exposure, particularly on the expression of locomotor sensitization. Adult female and male Wistar rats were given saline then cumulative doses of nicotine (0.1, 0.32, 0.56, and 1.0 mg/kg) intraperitoneally to determine the acute effects of nicotine (day 1). Next, rats were treated with 1.0 mg/kg nicotine for 6 days, given an identical series of cumulative doses (day 8), and then kept in a drug-free state for 6 days. On day 15, rats were pretreated with vehicle or the MCH receptor antagonist GW803430 (10 or 30 mg/kg) before another series of cumulative doses to assess response to chronic nicotine. After vehicle, male rats increased nicotine locomotor activation from day 1 to day 15, and both sexes showed a sensitized response when normalized to saline. The lower dose of GW803430 decreased locomotion compared to vehicle in females, while the higher dose decreased locomotion in males. Both sexes showed nicotine dose-dependent effects of GW803430, strongest at lower doses of nicotine. Controlling for sex-based locomotor differences revealed that females are more sensitive to GW803430. The high dose of GW803430 also decreased saline locomotion in males. Together, the results of our study suggest that MCH is involved in the expression of nicotine locomotor sensitization, and that MCH regulates these nicotine behavioral symptoms differently across sex.

尼古丁是一个重要的公共卫生问题，因为它是烟草使用障碍的主要药物。黑色素浓缩激素（MCH）系统是与多种物质使用障碍的症状有关的一种神经系统。MCH 根据性别调节各种动机行为，但人们对这种相互作用如何影响滥用药物（尤其是尼古丁）的体验知之甚少。本研究的目的是确定长期接触尼古丁后，MCH 受体拮抗作用对经验依赖性尼古丁诱导的运动的影响，特别是对运动敏化表达的影响。成年雌性和雄性Wistar 大鼠腹腔注射生理盐水，然后腹腔注射累积剂量的尼古丁（0.1、0.32、0.56 和 1.0 mg/kg），以确定尼古丁的急性作用（第 1 天）。接下来，用1.0 mg/kg尼古丁治疗大鼠6天，给予相同系列的累积剂量（第8天），然后保持无药物状态6天。第15天，在进行另一系列累积剂量以评估对慢性尼古丁的反应之前，用载体或MCH受体拮抗剂GW803430（10或30mg/kg）对大鼠进行预处理。使用媒介物后，雄性大鼠从第 1 天到第 15 天增加了尼古丁运动激活，并且当对盐水进行标准化时，两性均表现出敏化反应。与赋形剂相比，较低剂量的 GW803430 减少了雌性的运动，而较高剂量则减少了雄性的运动。GW803430 对两性均表现出尼古丁剂量依赖性效应，在较低剂量的尼古丁下最强。控制基于性别的运动差异后发现，女性对 GW803430 更敏感。高剂量的 GW803430 也降低了雄性的盐水运动。总之，我们的研究结果表明，MCH 参与尼古丁运动敏化的表达，并且 MCH 对这些尼古丁行为症状的调节因性别而异。