Low (micro)doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increase effortful motivation in low-performing mice

Abstract

Treating amotivated states remains difficult. Classical psychedelic drugs (5-HT_2A receptor agonists) such as LSD and psilocybin have shown therapeutic potential in treating such symptoms, but their development has been hindered by their undesirable hallucinogenic effects. There is increasing evidence that administration of psychedelics at dose levels too low to evoke a hallucinogenic effect (“microdoses”) may have therapeutic value in contexts of mood and cognition. 2,5-Dimethoxy-4-propylamphetamine (DOPR) is a psychedelic phenethylamine compound acting as a 5-HT_2A receptor agonist. We used a combination of behavioral assays to determine the motivational and hallucinogenic-like effects of DOPR and identify the dose ranges at which each of these effects were observed. In mice, the motivational effects of psychedelic compounds were assessed using the progressive ratio breakpoint task (PRBT, n = 80), a translational assay sensitive to changes in motivation. Psychedelic-like effects were gauged using the mouse head-twitch response (HTR, n = 72) assay, a preclinical readout of psychedelic potential. Significant improvements in PRBT performance were seen at doses as low as 0.0106 mg/kg in animals with low baseline PRBT scores while high-performing PRBT mice were unaffected. DOPR only induced significant HTR at doses ≥0.1 mg/kg. Together, these results indicate that the psychedelic DOPR may increase motivation in those with a low motivated state. Importantly, these effects may be attainable at low doses below the threshold required to induce psychedelic subjective effects. Hence, the ability of low doses of DOPR and other psychedelic drugs to alleviate amotivated states in rodents manipulated to induce disease-relevant states should be investigated.