Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat
Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat
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DOI：
10.1007/s00213-002-1240-x
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发表时间：
2003-01-01
影响因子：
3.4
通讯作者：
Lowe, DA
中科院分区：
文献类型：
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作者：
Martin, RS;Secchi, RL;Lowe, DA
理由：众所周知，马兜铃酸对人类有精神影响。在这项研究中，我们使用感觉运动门控，多动和刻板的大鼠模型，以探讨是否CB，受体刺激或阻断诱导行为的变化与拟精神病或抗精神病药物，分别一致。目的：我们确定了（a）大麻素激动剂CP 55940是否如拟精神病药物所预期的那样降低前脉冲抑制（PPI），以及（B）选择性CB受体拮抗剂SR 141716 A是否对PPI本身或在拟精神病药物破坏后有任何影响。此外，我们研究了SR 141716 A对d-苯丙胺引起的活动过度和刻板反应水平升高的影响。研究方法：这些研究是在大鼠中进行的，使用标准方法测定PPI后的声音刺激，和d-苯丙胺诱导的多动症和刻板。结果如下：在不存在和存在73 dB前脉冲的情况下，在CP 55940（0.1 mg/kg IP）处理的大鼠中观察到对120 dB刺激的惊吓反应降低。SR 141716 A（分别为5和10 mg/kg）可逆转这些效应。SR 141716 A（0.1、5、10 mg/kg）单独或在阿扑吗啡、d-苯丙胺或MK-801破坏后对PPI无影响。相反，在单独的实验中，不同的抗精神病药物逆转了d-苯丙胺（氟哌啶醇），阿朴吗啡（氟哌啶醇或氯氮平）或MK-801（氯氮平或奥氮平）诱导的PPI中断。此外，与氟哌啶醇不同，SR 141716 A（5 mg/kg）未逆转d-苯丙胺介导的多动或刻板反应增加。结论：CP 55940介导的惊吓幅度降低混淆了CB 1受体激活对PPI影响的评估。SR 141716 A未能逆转非大麻素类拟精神病药物诱导的PPI、多动或刻板障碍，表明CB 1受体本身的阻断不足以用于抗精神病治疗。
Rationale: Marijuana is known to have psychotropic effects in humans. In this study, we used rat models of sensorimotor gating, hyperactivity and stereotypy to explore whether CB, receptor stimulation or blockade induces behavioral changes consistent with psychotomimetic or antipsychotic agents, respectively. Objectives: We determined whether (a) the cannabinoid agonist CP 55940 decreased pre-pulse inhibition (PPI) as might be expected from a psychotomimetic agent, and (b) the selective CB, receptor antagonist, SR 141716A, had any effect on PPI on its own or following disruptions by psychotomimetic agents. In addition, we investigated the effects of SR 141716A on elevated levels of hyperactivity and stereotypy elicited by d-amphetamine. Methods: These studies were conducted in rats using standard methodologies for determination of PPI following acoustic stimuli, and d-amphetamine-induced hyperactivity and stereotypies. Results: Decreased startle responses to 120 dB stimuli were observed in rats treated with CP 55940 (0.1 mg/kg IP) in the absence and presence of a 73 dB pre-pulse. These effects were reversed by SR 141716A (5 and 10 mg/kg, respectively). SR 141716A (0.1, 5, 10 mg/kg) had no effect on PPI on its own or following disruptions by apomorphine, d-amphetamine or MK-801. Conversely, in separate experiments different antipsychotic agents reversed disruptions in PPI induced by d-amphetamine (haloperidol), apomorphine (haloperidol or clozapine) or MK-801 (clozapine or olanzapine). In addition, unlike haloperidol, SR 141716A (5 mg/kg) did not reverse d-amphetamine-mediated increases in hyperactivity or stereotypy. Conclusions: The CP 55940-mediated decreases in startle amplitude confound assessment of the effects of CB1 receptor activation on PPI. The failure of SR 141716A to reverse disruptions in PPI, hyperactivity or stereotypy induced by noncannabinoid psychotomimetic agents suggests that blockade of the CB1 receptor on its own is not sufficient for antipsychotic therapy.