Department of Psychology, Boston University, 64 Cummington Street, Boston, MA 02215, USA.
Drug Alcohol Depend. 2012 Apr 1;122(1-2):119-26. doi: 10.1016/j.drugalcdep.2011.09.017. Epub 2011 Oct 10.
Combining extinction training with cognitive-enhancing pharmacotherapy represents a novel strategy for improving the efficacy of exposure therapy for drug relapse prevention. We investigated if the selective glycine transporter-1 (GlyT-1) inhibitor RO4543338 could facilitate extinction of cocaine-conditioned responses and attenuate reacquisition of cocaine-seeking behavior.
Rats were trained to self-administer cocaine (0.3mg/kg), which was associated with a 2-s light cue under a second-order schedule of i.v. drug injection. Rats received vehicle, 30 or 45mg/kg of RO4543338 prior to three 1-h extinction-training sessions spaced at weekly intervals. Responses were extinguished by substituting saline for cocaine while maintaining response-contingent cue presentations. Reacquisition of cocaine-seeking behavior during self-administration sessions began 1 week after the last extinction session. Control experiments were conducted under conditions that precluded explicit extinction of cocaine-conditioned responses.
Compared to vehicle, 30 and 45mg/kg RO4543338 significantly decreased responding early in extinction training and during subsequent reacquisition sessions. The latter effect persisted for at least five sessions. In control studies, reacquisition of cocaine-seeking behavior was not altered when RO4543338 was administered either prior to weekly self-administration control sessions or prior to weekly control sessions in which cocaine and cues were omitted and the levers retracted.
As the GlyT-1 inhibitor facilitated cocaine-cue extinction learning and attenuated subsequent reacquisition of cocaine-seeking behavior, this class of compounds may have utility as a pharmacological adjunct to cocaine-cue exposure therapy in addicts.
将灭绝训练与认知增强的药物治疗相结合，代表了一种提高暴露疗法预防药物复吸疗效的新策略。我们研究了选择性甘氨酸转运体-1（GlyT-1）抑制剂 RO4543338 是否可以促进可卡因条件反应的灭绝，并减轻可卡因寻求行为的再获得。
大鼠接受可卡因（0.3mg/kg）的自我给药训练，该可卡因与静脉内药物注射的二级时间表下的 2 秒光提示相关联。大鼠在每周间隔的三个 1 小时灭绝训练课程之前接受载体、30 或 45mg/kg 的 RO4543338。通过用盐水替代可卡因来灭绝反应，同时保持与反应相关的提示呈现。在最后一次灭绝课程后 1 周开始进行可卡因寻求行为的再获得。在排除可卡因条件反应明确灭绝的条件下进行了对照实验。
与载体相比，30 和 45mg/kg 的 RO4543338 显著减少了灭绝训练早期和随后的再获得期间的反应。后一种效应至少持续了五节课。在对照研究中，当 RO4543338 要么在每周自我给药对照课程之前给予，要么在每周对照课程中给予，其中可卡因和提示被省略并且杠杆缩回时，可卡因寻求行为的再获得没有改变。
由于 GlyT-1 抑制剂促进了可卡因-提示灭绝学习，并减轻了随后可卡因寻求行为的再获得，因此这类化合物可能作为药物辅助物在吸毒者中用于可卡因-提示暴露疗法。
