Neurocircuitry of Motivated Behavior Laboratory, Department of Psychology, University of Nebraska-Lincoln, 1220 T St., Lincoln, NE 68588, United States of America.
Neurocircuitry of Motivated Behavior Laboratory, Department of Psychology, University of Nebraska-Lincoln, 1220 T St., Lincoln, NE 68588, United States of America; Rural Drug Addiction Research Center, University of Nebraska-Lincoln, 660 N 12th St., Lincoln, NE 68588, United States of America.
Pharmacol Biochem Behav. 2023 Nov;232:173649. doi: 10.1016/j.pbb.2023.173649. Epub 2023 Oct 2.
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.
尼古丁是一个重大的公共卫生关注点，因为它是烟草使用障碍的主要药理学药物。一个与多种物质使用障碍的症状有关的神经递质系统是黑色素浓缩激素（MCH）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的体验知之甚少，尤其是尼古丁。这项研究的目的是确定 MCH 受体拮抗剂对慢性暴露后尼古丁诱导的运动的经验依赖性的影响，特别是对运动敏感化的表达的影响。成年雌性和雄性 Wistar 大鼠分别接受生理盐水和累积剂量的尼古丁（0.1、0.32、0.56 和 1.0mg/kg）腹膜内注射，以确定尼古丁的急性作用（第 1 天）。接下来，大鼠接受 1.0mg/kg 尼古丁治疗 6 天，给予相同的累积剂量系列（第 8 天），然后在无药物状态下保持 6 天。在第 15 天，大鼠用载体或 MCH 受体拮抗剂 GW803430（10 或 30mg/kg）预处理，然后再进行另一系列累积剂量，以评估对慢性尼古丁的反应。在载体之后，雄性大鼠从第 1 天到第 15 天增加了尼古丁的运动激活，并且当与生理盐水相比时，两种性别都显示出敏感化反应。较低剂量的 GW803430 降低了雌性动物的运动，而较高剂量的 GW803430 降低了雄性动物的运动。两种性别都显示出 GW803430 的尼古丁剂量依赖性效应，在较低剂量的尼古丁作用更强。控制基于性别的运动差异表明，雌性对 GW803430 更敏感。高剂量的 GW803430 也降低了雄性的生理盐水运动。总之，我们的研究结果表明，MCH 参与了尼古丁运动敏感化的表达，并且 MCH 以不同的方式调节这些尼古丁行为症状在性别之间。
