Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, 03550 San Juan de Alicante, Spain.
J Psychopharmacol. 2010 May;24(5):757-65. doi: 10.1177/0269881109106910. Epub 2009 Oct 13.
Previous studies in our laboratory showed that cannabinoid CB1 receptor knockout mice (CB1-/-) presented increased anxiety-like behaviours that did not respond to the anxiolytic actions of benzodiazepines. These results suggest that the pharmacological effects of benzodiazepines may involve the participation of cannabinoid CB1 receptors. Therefore, the purpose of this study was to examine the effects of alprazolam and the cannabinoid CB1 receptor antagonist AM251 on behavioural assays (light-dark box test, neurological severity score and step-down inhibitory avoidance test) and on the functional activity of the CB1 receptor (WIN-55,212-stimulated [(35)S] guanosine triphosphate (GTP) gamma binding autoradiography).The administration of alprazolam (40 microg/kg, intraperitoneal (i.p.)) decreased anxiety-like behaviours in the light-dark box test and significantly reduced WIN-55,212-stimulated [(35)S]GTPgamma binding autoradiography in the amygdala and in the CA1 field of the hippocampus, but was without effects on CA2, CA3 and the dentate gyrus (DG) of the hippocampus. The administration of AM251 (3 mg/kg, i.p.) blocked the anxiolytic action of alprazolam (40 microg/kg, i.p.), significantly reduced the sedative (ataxia, neurological severity score in the 0.5 cm bar) and the amnesic actions (short time term memory (1 h after electric shock)) of alprazolam (0.5 mg/kg, i.p.).Taken together, these findings revealed that cannabinoid CB1 receptor plays a pivotal role in the pharmacological actions of benzodiazepines. Furthermore, these results suggest that blockade of cannabinoid CB1 receptors may be useful in the treatment of patients with problems related to the consumption of benzodiazepines. Further clinical trials are needed to test this hypothesis.
先前我们实验室的研究表明，大麻素 CB1 受体基因敲除（CB1-/-）小鼠表现出焦虑样行为增加，而苯二氮䓬类药物的抗焦虑作用对其无效。这些结果表明，苯二氮䓬类药物的药理学作用可能涉及大麻素 CB1 受体的参与。因此，本研究旨在探讨阿普唑仑和大麻素 CB1 受体拮抗剂 AM251 对行为检测（明暗箱试验、神经损伤严重程度评分和避错性抑制试验）和 CB1 受体功能活动（WIN-55,212-刺激 [35S] 鸟苷三磷酸（GTP）γ结合放射自显影）的影响。阿普唑仑（40μg/kg，腹腔注射）的给药降低了明暗箱试验中的焦虑样行为，并显著减少了杏仁核和海马 CA1 区 WIN-55,212 刺激 [35S]GTPγ 结合放射自显影，但对 CA2、CA3 和海马齿状回（DG）无影响。AM251（3mg/kg，腹腔注射）给药阻断了阿普唑仑（40μg/kg，腹腔注射）的抗焦虑作用，显著降低了阿普唑仑（0.5mg/kg，腹腔注射）的镇静（共济失调，0.5cm 棒神经损伤严重程度评分）和健忘（短时间记忆（电击后 1 小时））作用。综上所述，这些发现表明大麻素 CB1 受体在苯二氮䓬类药物的药理学作用中发挥着关键作用。此外，这些结果表明，阻断大麻素 CB1 受体可能有助于治疗与苯二氮䓬类药物使用相关的问题。需要进一步的临床试验来验证这一假设。
