Kharas Natasha, Yang Pamela, Castro-Alvarado Daniel, Rose Kevelyn, Dafny Nachum
Department of Neurobiology & Anatomy, University of Texas McGovern Medical School, Houston, TX, 77030, United States.
Department of Biology, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, CA 92866.
Behav Brain Res. 2019 Apr 19;362:36-45. doi: 10.1016/j.bbr.2018.12.018. Epub 2018 Dec 14.
Attention Deficit Hyperactivity Disorder (ADHD) is a developmental, behavioral disorder that is characterized by patterns of impulsivity and limited attention. Stimulants, such as methylphenidate (MPD) and amphetamine (Amph), are utilized as first-line agents in the treatment of ADHD. While Amph is known to elicit dependence, MPD is not. Interdependence between MPD and Amph is a growing concern. Therefore, it is important to explore this interaction in animal models to gain insight on its mechanisms. In experimental studies, drugs that elicit behavioral sensitization and cross-sensitization in animals are considered to have the potential to elicit dependence. This study evaluated whether chronic repetitive MPD exposure in adolescence and/or adulthood in various genetic strains of female rats elicits behavioral sensitization as well as cross-sensitization with Amph. We used three strains: SHR (ADHD model), WKY, and SD rats. The three rat strains were exposed to chronic MPD in their adolescence and adulthood or exposed to chronic MPD only in adulthood. When the female rats were treated with MPD only in adulthood, the SHR strain exhibited cross-sensitization to Amph but the WKY and SD strains did not. Whereas, when the female rats were pretreated with MPD in adolescence and adulthood, the SHR and WKY strains exhibited cross-sensitization response to Amph, but the SD strain did not. This study showed that the genetic strain and age of exposure to MPD plays a crucial role in cross-sensitization to Amph in female rodents. Furthermore, we showed that genetics associated with ADHD pre-dispose animals to dependence between drugs even if the exposure starts in adulthood compared to control strains that did not show dependence with adult only MPD exposures. Genetic variability, age of initial drug exposure, and sex of the subject are key variables that should be accounted in studies that explore effects of psychostimulants.
注意缺陷多动障碍（ADHD）是一种发育性的行为障碍，其特征为冲动行为模式和注意力受限。兴奋剂，如哌甲酯（MPD）和苯丙胺（Amph），被用作治疗ADHD的一线药物。虽然已知Amph会引发依赖性，但MPD不会。MPD和Amph之间的交叉依赖性日益受到关注。因此，在动物模型中探索这种相互作用以深入了解其机制很重要。在实验研究中，在动物身上引发行为敏化和交叉敏化的药物被认为具有引发依赖性的潜力。本研究评估了在不同遗传品系的雌性大鼠的青春期和/或成年期长期重复暴露于MPD是否会引发行为敏化以及与Amph的交叉敏化。我们使用了三个品系：SHR（ADHD模型）、WKY和SD大鼠。这三个大鼠品系在青春期和成年期暴露于慢性MPD中，或仅在成年期暴露于慢性MPD中。当雌性大鼠仅在成年期接受MPD治疗时，SHR品系对Amph表现出交叉敏化，而WKY和SD品系则没有。然而，当雌性大鼠在青春期和成年期用MPD进行预处理时，SHR和WKY品系对Amph表现出交叉敏化反应，但SD品系没有。这项研究表明，MPD暴露的遗传品系和年龄在雌性啮齿动物对Amph的交叉敏化中起着关键作用。此外，我们表明，与ADHD相关的基因使动物更容易产生药物之间的依赖性，即使暴露始于成年期，而对照品系仅在成年期暴露于MPD时未表现出依赖性。遗传变异性、初始药物暴露的年龄和受试者的性别是探索精神兴奋剂作用的研究中应考虑的关键变量。
