Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model

Abstract

Two primary animal models persist for assessing hallucinogenic potential of novel compounds and for examining the pharmacological and neurobiological substrates underlying the actions of classical hallucinogens, the two-lever drug discrimination procedure and the drug-induced head-twitch response (HTR) in rodents. The substituted amphetamine hallucinogen, serotonin 2 (5-HT(2) ) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) has emerged as the most popular pharmacological tool used in HTR studies of hallucinogens. Synthesizing classic, recent, and relatively overlooked findings, addressing ostensibly conflicting observations, and considering contemporary theories in receptor and behavioural pharmacology, this review provides an up-to-date and comprehensive synopsis of DOI and the HTR model, from neural mechanisms to utility for understanding psychiatric diseases. Also presented is support for the argument that, although both the two-lever drug discrimination and the HTR models in rodents are useful for uncovering receptors, interacting proteins, intracellular signalling pathways, and neurochemical processes affected by DOI and related classical hallucinogens, results from both models suggest they are not reporting hallucinogenic experiences in animals.

Figure 1

Commercial (a) and IUPAC (b) nomenclature for DOI.

Figure 2

Cumulative number of head-twitch responses (HTRs) following administration of various doses of (–)-DOI (mg/kg; IP) to male, C57Bl/6J mice. Each mouse (n = 4) was tested with all four doses (in random order) at approximately 1-week intervals. HTRs were counted in 2-min periods, every 10 min, beginning immediately following administration of drug. Note that (–)-DOI elicited HTRs began within the first 2-min period (Time 0), the frequency of HTRs were dose-dependent, and HTRs continued throughout the 2-h testing period.