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-HT2) 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.

When administered near the time of training, protein synthesis inhibitors such as anisomycin impair later memory. A common interpretation of these findings is that memory consolidation requires new protein synthesis initiated by training. However, recent findings support an alternative interpretation that abnormally large increases in neurotransmitter release after injections of anisomycin may be responsible for producing amnesia. In the present study, a local anesthetic was administered prior to anisomycin injections in an attempt to mitigate neurotransmitter actions and thereby attenuate the resulting amnesia. Rats received lidocaine and anisomycin injections into the amygdala 130 and 120 min, respectively, prior to inhibitory avoidance training. Memory tests 48 hr later revealed that lidocaine attenuated anisomycin-induced amnesia. In other rats, in vivo microdialysis was performed at the site of amygdala infusion of lidocaine and anisomycin. As seen previously, anisomycin injections produced large increases in release of norepinephrine in the amygdala. Lidocaine attenuated the anisomycin-induced increase in release of norepinephrine but did not reverse anisomycin inhibition of protein synthesis, as assessed by c-Fos immunohistochemistry. These findings are consistent with past evidence suggesting that anisomycin causes amnesia by initiating abnormal release of neurotransmitters in response to the inhibition of protein synthesis.

Development of serotonin 2C (5‐HT2C) receptor agonists for treatment of neuropsychiatric disorders including schizophrenia, substance abuse, and eating disorders is challenging due to ~75% sequence similarity and identical Gαq‐mediated signaling among the 5‐HT2 family. Essentially all reported selective 5‐HT2C receptor agonists (including FDA‐approved Belviq®) also activate 5‐HT2A and/or 5‐HT2B receptors at physiologically relevant doses, potentially causing hallucinations and/or cardiopulmonary toxicity in humans, respectively. Herein is described a novel, potent and efficacious 5‐HT2C receptor partial agonist, m80‐PAT (Ki = 7.2 (2.2) nM; EC50 = 16.6 (3.20) nM; Emax (relative to 5‐HT) = 84.4 (5.0) % for human 5‐HT2C receptor‐mediated PLC signaling), that does not activate 5‐HT2A or 5‐HT2B receptors. m80‐PAT is highly effective in preclinical C57Bl/6 mouse psychoses models, reducing the 2,5‐dimethoxy‐4‐iodoamphetamine (DOI)‐elicited head‐twitch response, and MK‐801 and amphetamine induced hyperlocomotion. Significantly, m80‐PAT does not alter locomotor activity on its own, nor in combination with DOI, and also decreases consumption of highly palatable food. m80‐PAT holds promise as an effective compound to treat drug‐induced psychoses without liability for weight gain, hallucinations, heart disease, or motoric abnormalities.