Effect of Hallucinogens on Unconditioned Behavior

Much of what is known about hallucinogen psychopharmacology comes from animal models due to ethical and regulatory constraints on human studies. This chapter reviews three rodent behavioral models: head twitch response (HTR), prepulse inhibition of startle (PPI), and exploratory behavior. HTR is useful for studying neurochemical actions, while PPI and exploratory behavior have clearer links to human experiences. Hallucinogen effects in rodents are primarily mediated by 5-HT2A receptor activation, matching the human mechanism, though other receptors may play secondary roles. Structure-activity relationships are reviewed for each model, focusing on HTR in rats and mice.

Study at a glance

Abstract

Because of the ethical and regulatory hurdles associated with human studies, much of what is known about the psychopharmacology of hallucinogens has been derived from animal models. However, developing reliable animal models has proven to be a challenging task due to the complexity and variability of hallucinogen effects in humans. This chapter focuses on three animal models that are frequently used to test the effects of hallucinogens on unconditioned behavior: head twitch response (HTR), prepulse inhibition of startle (PPI), and exploratory behavior. The HTR has demonstrated considerable utility in the neurochemical actions of hallucinogens. However, the latter two models have clearer conceptual bridges to human phenomenology. Consistent with the known mechanism of action of hallucinogens in humans, the behavioral effects of hallucinogens in rodents are mediated primarily by activation of 5-HT2A receptors. There is evidence, however, that other receptors may play secondary roles. The structure-activity relationships (SAR) of hallucinogens are reviewed in relation to each model, with a focus on the HTR in rats and mice