Berro Laís F, Andersen Monica L, Tufik Sergio, Howell Leonard L
Yerkes National Primate Research Center, Emory University, 954 Gatewood Road N.E., Atlanta, GA 30329, USA; Department of Psychobiology, Universidade Federal de São Paulo, R. Napoleão de Barros, 925, 04021002 São Paulo, SP, Brazil.
Department of Psychobiology, Universidade Federal de São Paulo, R. Napoleão de Barros, 925, 04021002 São Paulo, SP, Brazil.
Neuropharmacology. 2017 Sep 1;123:299-309. doi: 10.1016/j.neuropharm.2017.05.010. Epub 2017 May 8.
GABA receptor positive allosteric modulators (GABA receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABA receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABA receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABA receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABA receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABA receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine.
γ-氨基丁酸（GABA）受体正性变构调节剂（GABA受体调节剂）常用于治疗失眠。然而，这些化合物对精神兴奋剂所致睡眠障碍的影响却知之甚少。由于已表明GABA受体调节剂可降低精神兴奋剂的滥用相关效应，因此本研究的目的是评估两种GABA受体调节剂替马西泮（0.3、1.0或3.0毫克/千克）和艾司佐匹克隆（0.3、1.0或3.0毫克/千克）对成年恒河猴（n = 5）甲基苯丙胺行为神经药理学的影响。使用活动监测仪评估类似睡眠的指标和白天的总体活动。在上午时段评估甲基苯丙胺的自我给药（0.03毫克/千克/次）。通过针对伏隔核的体内微透析评估甲基苯丙胺诱导的多巴胺溢出。替马西泮或艾司佐匹克隆夜间治疗对改善因甲基苯丙胺自我给药而扰乱的类似睡眠的指标无效。在自我给药前急性给予低剂量替马西泮预处理可增加甲基苯丙胺的自我给药量，且不影响正常白天笼内活动。高剂量时，急性替马西泮预处理可减少甲基苯丙胺的自我给药量，并减弱甲基苯丙胺诱导的伏隔核多巴胺增加，同时不降低白天的总体活动。急性艾司佐匹克隆治疗对甲基苯丙胺摄入量或药物诱导的多巴胺增加无影响。我们的研究表明，基于GABA受体调节剂的治疗方法对治疗精神兴奋剂使用情况下的睡眠障碍无效。此外，不同的GABA受体调节剂对甲基苯丙胺的滥用相关效应有不同的调节作用，高效GABA受体调节剂替马西泮的急性治疗可降低甲基苯丙胺的行为和神经化学效应。
