Carmack Stephanie A, Howell Kristin K, Rasaei Kleou, Reas Emilie T, Anagnostaras Stephan G
Molecular Cognition Laboratory, Department of Psychology, University of California, San Diego, California 92093-0109, USA.
Learn Mem. 2014 Jan 16;21(2):82-9. doi: 10.1101/lm.033613.113.
Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01-10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1-10 mg/kg, i.p.), bupropion (0.5-20 mg/kg, i.p.), and citalopram (0.01-10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.
哌甲酯（MPH）于60多年前被引入，目前注意力缺陷多动障碍（ADHD）处方中有三分之二是该药。尽管许多研究已对MPH对执行功能的影响进行了建模，但几乎没有研究直接对其对长期记忆（LTM）的影响进行建模，尽管改善LTM是ADHD治疗干预的关键目标。我们研究了一系列剂量的MPH（0.01 - 10毫克/千克，腹腔注射）对巴甫洛夫恐惧学习（一种主要的记忆模型）的影响。然后将MPH的效果与托莫西汀（0.1 - 10毫克/千克，腹腔注射）、安非他酮（0.5 - 20毫克/千克，腹腔注射）和西酞普兰（0.01 - 10毫克/千克，腹腔注射）的效果进行比较。在低剂量、临床相关剂量下，MPH增强恐惧记忆；在高剂量下则损害记忆。MPH的记忆增强作用不受其对运动或焦虑影响的干扰。此外，MPH诱导的记忆增强似乎需要多巴胺和去甲肾上腺素转运体抑制。最后，使用条件性位置偏爱和行为敏化范式，将MPH（1毫克/千克和10毫克/千克）的成瘾潜力与另外两种精神兴奋剂苯丙胺（0.005毫克/千克和1.5毫克/千克）和可卡因（0.15毫克/千克和15毫克/千克）的成瘾潜力进行比较。我们发现，在低剂量下观察到的精神兴奋剂的记忆增强作用很容易与其在高剂量下的强化和运动激活作用区分开来。总之，我们的数据表明，恐惧条件反射将是药物开发中模拟精神兴奋剂对LTM影响的一个特别有成效的平台。
