Established sensitization of ethanol-induced locomotor activity is not reversed by psilocybin or the 5-HT2A receptor agonist TCB-2 in male DBA/2J mice.

Psychedelic drugs that activate the 5-HT2A receptor, such as psilocybin, show promise for treating alcohol-use disorders. This study tested whether psilocybin or the 5-HT2A agonist TCB-2 could reverse the sensitized locomotor activity caused by repeated ethanol exposure in male DBA/2J mice. Mice received repeated ethanol injections to induce sensitization, then five daily doses of psilocybin (0, 0.3, or 1 mg/kg) or TCB-2 (0, 1, or 3 mg/kg). A subsequent ethanol challenge showed that sensitized mice still had enhanced activity, and neither psilocybin nor TCB-2 reduced this sensitized response. The results suggest that these drugs' short-term effects on ethanol intake may not involve reversing long-term behavioral or neural adaptations from repeated ethanol exposure.

Study at a glance

Abstract

Psychedelic drugs, which share in common 5-HT2A 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-HT2A 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.