Effects of serotonergic hallucinogen R(−)‐2,5‐Dimethoxy‐4‐iodoamphetamine (DOI) on temporal discrimination in mice

Abstract

R(−)‐2,5‐Dimethoxy‐4‐iodoamphetamine (DOI) and other compounds with agonist affinity for serotonergic 5‐HT2A receptors are hallucinogenic drugs of abuse, but also have therapeutic potential in numerous neuropsychiatric conditions, including major depressive disorder, post‐traumatic stress disorder, and in the treatment of migraine and cluster headaches. Thus, commonly abused hallucinogens could serve as lead compounds in the development of new therapeutic drugs. While there are already behavioral assays useful in the study of these compounds, it remains difficult to measure the primary effects of hallucinogenic drugs, which are subjective and unobservable. The drug‐elicited head twitch response (HTR) is a technically‐simple observational assay which yields dose‐dependent data, is sensitive to 5‐HT2A antagonism, and has a strong predictive validity for hallucinogenic effects in humans. However, it is not clear which aspect of the cluster of hallucinogenic effects is modeled by the HTR. Because hallucinogens and other psychoactive drugs have been shown to disrupt temporal discrimination in rodents and in humans, a model incorporating time perception may have better face validity than the HTR. In these studies, we used a temporal discrimination assay to measure the effects of DOI in male Swiss‐Webster mice in order to validate the procedure by determining whether reliable drug effects would be achievable in mice, would be dose‐dependent, and would be reversible by 5‐HT2A antagonism. In this procedure, a light‐tone compound stimulus was presented for either a short (2.7 sec) or long (27 sec) duration. Responses in one nose‐poke aperture were reinforced after passage of a short stimulus presentation, while responses in the other nose‐poke aperture were reinforced after passage of long stimulus presentation. Mice required a relatively large number of sessions (>60) to reach criterion performance, but once trained, administration of DOI dose‐dependently disrupted temporal discrimination. The doses of DOI required to alter temporal discrimination were relatively high, and are on the descending limb of dose‐effect functions derived in HTR studies. Nevertheless, these effects were at least partially mediated by 5‐HT2A agonism, as the selective 5‐HT2A antagonist M100907 dose‐dependently reversed the effects of DOI on temporal discrimination. Despite the large time investment required to train murine subjects, temporal discrimination appears to be a useful behavioral pharmacology assay to specifically study the effects of novel hallucinogen‐like drugs on time perception, and may be a valuable in the preclinical development of new therapeutic drugs with serotonergic mechanisms.Support or Funding InformationThese studies were funded in part by an NIGMS IDeA Program award (GM110702) and by the UAMS Translational Research Institute (RR029884), and MPT received a Summer Undergraduate Research Fellowships from the American Society of Pharmacology and Experimental Therapeutics to work on these studies.