Rearing behaviour in the mouse behavioural pattern monitor distinguishes the effects of psychedelics from those of lisuride and TBG

Psychedelics like DOM, mescaline, and psilocin reduce mouse locomotor activity at high doses and alter rearing behavior in an inverted U-shaped pattern. Blocking the 5-HT2A receptor with M100907 reversed changes in activity, rearings, and jumps from low-dose DOM, but not holepoking. The hallucinogenic 5-HT2A agonist 25CN-NBOH produced similar effects that were diminished by M100907, while nonhallucinogenic agonists TBG and lisuride did not increase rearing. Discriminant analysis distinguished all four psychedelics from nonhallucinogenic agonists based on behavior alone, suggesting increased rearing in mice may differentiate hallucinogenic from nonhallucinogenic 5-HT2A agonists.

Study at a glance

Abstract

Psychedelics alter consciousness and may have potential for drug development. As psychedelics are likely therapeutically active, it is important to study their effects and mechanisms using preclinical models. Here, we examined the effects of phenylalkylamine and indoleamine psychedelics on locomotor activity and exploratory behaviour using the mouse Behavioural Pattern Monitor (BPM). DOM, mescaline, and psilocin reduced locomotor activity at high doses and influenced rearings, an exploratory behaviour, in a characteristic inverted U-shaped dose-response function. Pretreatment with the selective 5-HT 2A antagonist M100907 reversed the drug-induced alterations in locomotor activity, rearings, and jumps after systemic administration of DOM at low doses. However, holepoking at the full range of doses tested was not blocked by M100907. Administration of the hallucinogenic 5-HT 2A agonist 25CN-NBOH induced striking similarities in response to that to psychedelics; these alterations were significantly diminished by M100907, whereas the putatively non-hallucinogenic 5-HT 2A agonist TBG did not affect locomotor activity, rearings, or jumps at the most effective doses. The nonhallucinogenic 5-HT 2A agonist lisuride failed to increase rearing. The results of these experiments provide strong evidence that DOM-elicited increases in rearing are due to mediation by the 5-HT 2A receptor. Finally, discriminant analysis was able to distinguish all four psychedelics from lisuride and TBG based on behavioural performance alone. Thus, increased rearing in mice could provide additional evidence of behavioural differences between hallucinogenic and nonhallucinogenic 5-HT 2A agonists.