Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Pharmacol Biochem Behav. 2024 Feb;235:173703. doi: 10.1016/j.pbb.2023.173703. Epub 2023 Dec 27.
Psychedelic drugs, which share in common 5-HT 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 receptor agonist TCB-2, counteracted established sensitization of EtOH-induced locomotor activity.
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.
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.
Psilocybin and TCB-2 at behaviourally 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.
具有 5-HT 受体激动剂活性的致幻剂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，反映出可能导致成瘾的神经适应。致幻剂也可以诱导神经可塑性，这增加了它们在 AUD 中潜在的临床效果可能涉及逆转或抵消 EtOH 长期变化影响的可能性。通过研究是否可以用赛洛西宾或 5-HT 受体激动剂 TCB-2 来抵消 EtOH 诱导的运动活动的已建立的敏化作用，来检验这种可能性。
雄性 DBA/2J 小鼠接受重复注射 2.2 g/kg EtOH 以诱导敏化的运动活动反应。在两个实验中，分别将一组小鼠连续 5 天注射赛洛西宾（0、0.3 和 1 kg/kg）或 TCB-2（0、1 和 3 mg/kg）。然后，用 1.8 g/kg EtOH 对小鼠进行挑战，并测量 15 分钟的运动活动。
与未处理的对照相比，先前敏化的小鼠对挑战剂量的运动活动增强。尽管赛洛西宾和 TCB-2 本身会降低运动活动，但它们并没有改变这种敏化反应的强度。
在行为上有效的剂量下，赛洛西宾和 TCB-2 并未逆转 EtOH 诱导的活动敏化。这表明，赛洛西宾或 TCB-2 介导短期减少 EtOH 摄入量的机制可能不涉及这些药物抵消由重复间歇接触 EtOH 引起的行为和任何潜在的神经适应的能力。
