Rationale

Psychedelic drugs, which share in common 5-HT_2A receptor agonist activity, have shown promise in treating alcohol-use disorders (AUDs). Repeated exposure to ethanol (EtOH) induces molecular and behavioural changes reflective of neuroadaptations that may contribute to addiction. Psychedelic drugs can induce neuroplasticity also, raising the possibility that their potential clinical effects in AUD may involve an action to reverse or offset effects of long-term changes induced by EtOH. This possibility was examined by investigating whether psilocybin, or the 5-HT_2A receptor agonist TCB-2, counteracted established sensitization of EtOH-induced locomotor activity. Methods.

Male DBA/2J mice received repeated injections of 2.2 g/kg EtOH to induce a sensitized locomotor activity response. In two experiments separate groups of mice were then injected with psilocybin (0, 0.3 and 1 kg/kg) or TCB-2 (0, 1 and 3 mg/kg) on 5 consecutive days. Next, mice were challenged with 1.8 g/kg EtOH and locomotor activity measured for 15 min.

Results

Relative to naïve controls, previously sensitized mice showed enhanced locomotor activity to the challenge dose. Despite reducing locomotor activity in their own right psilocybin and TCB-2 did not alter the strength of this sensitized response.

Conclusion

Psilocybin and TCB-2 at behaviorally effective doses did not reverse sensitization of EtOH-induced activity. This suggests that mechanisms involved in mediating short-term reductions in EtOH intake by psilocybin or TCB-2 may not involve a capacity of these drugs to offset enduring changes in behaviour and any underlying neural adaptations induced by repeated intermittent exposure to EtOH.

中文翻译：

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在雄性 DBA/2J 小鼠中，裸盖菇素或 5-HT2A 受体激动剂 TCB-2 不会逆转乙醇诱导的运动活性的既定致敏作用

基本原理

迷幻药具有共同的 5-HT _2A受体激动剂活性，在治疗酒精使用障碍 (AUD) 方面显示出良好的前景。反复接触乙醇 (EtOH) 会引起分子和行为变化，这些变化反映了可能导致成瘾的神经适应。迷幻药物还可以诱导神经可塑性，这增加了它们在 AUD 中的潜在临床效应可能涉及逆转或抵消 EtOH 引起的长期变化影响的可能性。通过研究裸盖菇素或 5-HT _2A受体激动剂 TCB-2 是否抵消了乙醇诱导的运动活动的既定致敏作用，检验了这种可能性。方法。

雄性 DBA/2J 小鼠重复注射 2.2 g/kg EtOH 以诱导敏化的运动活动反应。在两个实验中，连续 5 天向不同组的小鼠注射裸盖菇素（0、0.3 和 1 kg/kg）或 TCB-2（0、1 和 3 mg/kg）。接下来，用 1.8 g/kg EtOH 攻击小鼠并测量运动活性 15 分钟。

结果

相对于初始对照组，先前致敏的小鼠对攻击剂量表现出增强的运动活性。尽管裸盖菇素和 TCB-2 降低了其自身右侧的运动活性，但并没有改变这种敏化反应的强度。

结论

行为有效剂量的裸盖菇素和 TCB-2 不会逆转 EtOH 诱导的活性致敏作用。这表明裸盖菇素或 TCB-2 介导短期 EtOH 摄入量减少的机制可能不涉及这些药物抵消行为持久变化以及重复间歇性接触 EtOH 引起的任何潜在神经适应的能力。