Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Psychopharmacology (Berl). 2012 Feb;219(4):1055-63. doi: 10.1007/s00213-011-2433-y. Epub 2011 Aug 11.
Enhanced sensitivity to the euphoric and locomotor-activating effects of psychostimulants may influence an individual's predisposition to drug abuse and addiction. While drug-induced behaviors are mediated by the actions of several neurotransmitter systems, past research revealed that the corticotropin-releasing factor (CRF) system is important in driving the acute locomotor response to psychostimulants.
We previously reported that genetic deletion of the CRF type-2 receptor (CRF-R2), but not the CRF type-1 receptor (CRF-R1) dampened the acute locomotor stimulant response to methamphetamine (1 mg/kg). These results contrasted with previous studies implicating CRF-R1 in the locomotor effects of psychostimulants. Since the majority of previous studies focused on cocaine, rather than methamphetamine, we set out to test the hypothesis that these drugs differentially engage CRF-R1 and CRF-R2.
We expanded our earlier findings by first replicating our previous experiments at a higher dose of methamphetamine (2 mg/kg), and by assessing the effects of the CRF-R1-selective antagonist CP-376,395 (10 mg/kg) on methamphetamine-induced locomotor activity. Next, we used both genetic and pharmacological tools to examine the specific components of the CRF system underlying the acute locomotor response to cocaine (5-10 mg/kg).
While genetic deletion of CRF-R2 dampened the locomotor response to methamphetamine (but not cocaine), genetic deletion and pharmacological blockade of CRF-R1 dampened the locomotor response to cocaine (but not methamphetamine).
These findings highlight the differential involvement of CRF receptors in acute sensitivity to two different stimulant drugs of abuse, providing an intriguing basis for the development of more targeted therapeutics for psychostimulant addiction.
对精神兴奋剂的欣快和运动激活作用的敏感性增强，可能会影响个体对药物滥用和成瘾的易感性。虽然药物诱导的行为是由几种神经递质系统的作用介导的，但过去的研究表明，促肾上腺皮质激素释放因子（CRF）系统在驱动对精神兴奋剂的急性运动反应中很重要。
我们之前报道过，CRF 型 2 受体（CRF-R2）的基因缺失，但不是 CRF 型 1 受体（CRF-R1），减弱了对甲基苯丙胺（1mg/kg）的急性运动刺激反应。这些结果与以前将 CRF-R1 牵连到精神兴奋剂的运动效应的研究结果形成对比。由于大多数以前的研究集中在可卡因上，而不是甲基苯丙胺上，我们着手检验这样一种假设，即这些药物对 CRF-R1 和 CRF-R2 的作用不同。
我们首先在更高剂量的甲基苯丙胺（2mg/kg）上重复了我们之前的实验，验证了我们之前的实验结果，并用 CRF-R1 选择性拮抗剂 CP-376,395（10mg/kg）评估了其对甲基苯丙胺诱导的运动活动的影响，从而扩展了我们早期的发现。接下来，我们使用基因和药理学工具来研究急性可卡因（5-10mg/kg）反应背后的 CRF 系统的特定成分。
虽然 CRF-R2 的基因缺失减弱了对甲基苯丙胺的运动反应（但不减弱对可卡因的运动反应），但 CRF-R1 的基因缺失和药理学阻断减弱了对可卡因的运动反应（但不减弱对甲基苯丙胺的运动反应）。
这些发现强调了 CRF 受体在两种不同的滥用兴奋剂的急性敏感性中的不同作用，为开发针对精神兴奋剂成瘾的更有针对性的治疗方法提供了一个有趣的基础。
