Department of Environmental Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA; Department of Psychology, West Virginia University, Morgantown, WV, USA.
Department of Psychology, West Virginia University, Morgantown, WV, USA; School of Nursing, University of Connecticut, Storrs, CT, USA.
Neuropharmacology. 2021 Jun 1;190:108554. doi: 10.1016/j.neuropharm.2021.108554. Epub 2021 Apr 15.
Cannabis is the most frequently used federally illicit substance in the United States. However, there are currently no FDA-approved pharmacotherapies to mitigate the withdrawal symptoms associated with cessation in heavy users. A promising, readily available, non-cannabinoid therapy are the gabapentinoids. Although currently approved for epilepsy and neuropathic pain, gabapentinoids are increasingly used for their "off-label" efficacy in treating various psychiatric conditions and substance abuse. Gabapentin (GBP) synergizes with cannabinoid agonism in neuropathic pain models, substitutes for Δ-tetrahydrocannabinol (THC) in drug discrimination procedures, and reduced withdrawal symptoms in an outpatient clinical trial. However, there are limited data on the biological plausibility of the therapeutic action of gabapentinoids in cannabinoid withdrawal in preclinical models. The purpose of the current study was to determine the efficacy of GBP on attenuating THC withdrawal in mice, using an array of tests targeting withdrawal-induced and withdrawal-suppressed behaviors. Separate cohorts of male and female mice were administered THC (10 mg/kg, s.c.) or vehicle for 5.5 days, and withdrawal was precipitated by the CB antagonist rimonabant (2 or 3 mg/kg, i.p.) on the sixth day. GBP (≥10 mg/kg) reduced somatic signs of withdrawal (i.e., paw tremors and head twitches), but had no effect in locomotor activity or conditioned place preference. GBP (50 mg/kg) also restored withdrawal-suppressed responding on a progressive ratio reinforcement schedule. However, GBP (50 mg/kg) had no effect in withdrawal-suppressed marble burying or tail suspension struggling and did not normalize the stress response induced by THC withdrawal, as indicated by plasma corticosterone. These data suggest gabapentin may be effective at treating cannabinoid withdrawal symptoms including somatic and affective symptoms but may act independently of endocrine stress activation.
大麻是美国最常被滥用的联邦非法药物。然而，目前尚无 FDA 批准的药物疗法来缓解重度使用者戒断时出现的症状。一种有前途的、易于获得的非大麻类治疗方法是加巴喷丁类药物。尽管目前已被批准用于治疗癫痫和神经病理性疼痛，但加巴喷丁类药物因其在治疗各种精神疾病和药物滥用方面的“非标签”疗效而越来越被广泛使用。加巴喷丁 (GBP) 在神经病理性疼痛模型中与大麻素激动剂协同作用，在药物辨别程序中替代 Δ-四氢大麻酚 (THC)，并在门诊临床试验中减少戒断症状。然而，在临床前模型中，关于加巴喷丁类药物在大麻素戒断中的治疗作用的生物学合理性的数据有限。本研究的目的是确定 GBP 对减轻小鼠 THC 戒断的疗效，使用一系列针对戒断诱导和戒断抑制行为的测试。雄性和雌性小鼠的单独队列接受 THC（10mg/kg，sc）或载体 5.5 天，第六天用 CB 拮抗剂利莫那班（2 或 3mg/kg，ip）引发戒断。GBP（≥10mg/kg）减少了戒断引起的躯体症状（即，爪子震颤和头部抽搐），但对运动活动或条件性位置偏好没有影响。GBP（50mg/kg）还恢复了在递增比率强化时间表上抑制的反应。然而，GBP（50mg/kg）在抑制的大理石埋藏或尾巴悬挂挣扎中没有效果，也没有使 THC 戒断引起的应激反应正常化，如血浆皮质酮所示。这些数据表明，加巴喷丁可能有效治疗大麻素戒断症状，包括躯体和情感症状，但可能与内分泌应激激活无关。
