Manwell Laurie A, Satvat Elham, Lang Stefan T, Allen Craig P, Leri Francesco, Parker Linda A
Department of Psychology, University of Guelph, Guelph, ON N1G2W1, Canada.
Pharmacol Biochem Behav. 2009 Nov;94(1):154-62. doi: 10.1016/j.pbb.2009.08.002. Epub 2009 Aug 19.
Converging evidence suggests that the endogenous cannabinoid (eCB) system is involved in extinction of learned behaviours. Using operant and classical conditioning procedures, the potential of the fatty acid amide (FAAH) inhibitor, URB-597, and the CB(1) antagonist/inverse agonist, SR141716, to promote and inhibit (respectively) extinction of learned responses previously motivated by either rewarding or aversive stimuli was investigated. In the operant conditioning procedure (Expt. 1), rats previously trained to lever press for sucrose reward were administered URB-597 (0.3 mg/kg) or the CB(1) antagonist/inverse agonist SR141716 (2.5 mg/kg) prior to each of three extinction trials. In the conditioned floor preference procedure (Expts 2a-d), rats trained to associate morphine with one of two distinctive floors were administered one of several doses of the CB(1) antagonist/inverse agonist, AM-251 (Expt 2a) or URB-597 (Expt 2b and 2d) prior to each extinction/test trial wherein a choice of both floors was presented and prior to forced exposure to each floor (Expt 2c). In the conditioned floor aversion procedure (Expt. 3), rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered URB-597 or SR141716 prior to each of 24 extinction/testing trials. URB-597 did not promote and SR141716 did not reduce extinction rates for sucrose reward-induced operant responding (Expt. 1) or morphine-induced conditioned floor preference (Expts. 2a-d). In contrast, URB-597 facilitated, whereas SR141716 impaired, extinction of the conditioned floor aversion (Expt. 3). These data support previous reports that the eCB system selectively facilitates extinction of aversive memories. URB-597 may prove useful in targeting extinction of aversively motivated behaviours.
越来越多的证据表明，内源性大麻素（eCB）系统参与了习得行为的消退。采用操作性条件反射和经典条件反射程序，研究了脂肪酸酰胺水解酶（FAAH）抑制剂URB - 597和CB(1)拮抗剂/反向激动剂SR141716分别促进和抑制先前由奖励或厌恶刺激激发的习得反应消退的潜力。在操作性条件反射程序（实验1）中，先前训练为按压杠杆以获取蔗糖奖励的大鼠，在三次消退试验的每一次之前，给予URB - 597（0.3 mg/kg）或CB(1)拮抗剂/反向激动剂SR141716（2.5 mg/kg）。在条件性地板偏好程序（实验2a - d）中，训练大鼠将吗啡与两个不同地板中的一个联系起来，在每次呈现两个地板供选择的消退/测试试验之前以及在强制暴露于每个地板之前（实验2c），给予几种剂量的CB(1)拮抗剂/反向激动剂AM - 251（实验2a）或URB - 597（实验2b和2d）。在条件性地板厌恶程序（实验3）中，训练大鼠将纳洛酮诱发的吗啡戒断与地板线索联系起来，在24次消退/测试试验的每一次之前，给予URB - 597或SR141716。URB - 597没有促进，SR141716也没有降低蔗糖奖励诱导的操作性反应（实验1）或吗啡诱导的条件性地板偏好（实验2a - d）的消退率。相反，URB - 597促进了，而SR141716损害了条件性地板厌恶的消退（实验3）。这些数据支持了先前的报道，即eCB系统选择性地促进厌恶记忆的消退。URB - 597可能被证明对针对厌恶动机行为的消退有用。
