Animal Models of Serotonergic Psychedelics

Abstract

The serotonin 5-HT 2A receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.KEYWORDS: Psychedelic, hallucinogenic, schizophrenia, psychosis, serotonin 5-HT 2A receptor, G protein-coupled receptor (GPCR), lysergic acid diethylamide (LSD), mouse behavior models E lucidating the mechanisms by which psychedelics induce their unique neuropsychological effects has important implications for a better understanding of behavioral processes such as cognition, perception, emotion, and sense of self. 1−5 The term psychedelic was coined in 1957 by the British psychiatrist Humphry Osmond to describe the effects of psychoactive drugs such as psilocybin, mescaline, and lysergic acid diethylamide (LSD). 6 These drugs belong to a larger group of substances known as hallucinogens, which also includes dissociatives (e.g., ketamine and phencyclidine), and deliriants (e.g., scopolamine and atropine), as well as compounds such as salvinorin A. Psychedelics all behave as agonists or partial agonists at the serotonin 5-HT 2A receptor, whereas dissociatives and deliriants have been identified as noncompetitive NMDA receptor antagonists, and competitive muscarinic receptor antagonists, respectively. Salvinorin A is a potent κ-opioid receptor agonist. 7−12 Although all of these hallucinogenic drugs profoundly alter perception, according to the Hallucinogen Rating Scale (HRS) and the Five-Dimensional Altered States of Consciousness (5D-ASC) rating scale, there are also features that are unique to each of these groups. 13−15 Research using behavioral and cognitive tasks indicates that different groups of hallucinogens induce overlapping, yet distinct sets of changes in sensory processing. Recent findings regarding the molecular mechanism of action of psychedelic and other hallucinogenic drugs have been reviewed elsewhere. 7,8,11,16−24 In this review, we will discuss the effects of psychedelics in a range of animal behavioral assays, and their utility as preclinical models of the effects of these drugs in humans. ■ MODELING PSYCHOSIS IN ANIMALSModeling in rodents the neuropsychological effects induced by psychedelic drugs remains controversial. The above-mentioned psychometric rating scales HRS and 5D-ASC measure aspects of subjective experience such as "oceanic boundlessness", "dread of ego dissolution", and "spiritual expe...

Psychedelics

“…A review of the use of animal models of serotonergic psychedelics was recently published (Hanks and González-Maeso, 2013).…”

“…This advancement allows the HTR to be used as a fairly rapid high-throughput assay that has eliminated the need for tedious visual scoring by an observer, and it gives reliable, unbiased, and reproducible results. Use of the mouse HTR to study psychedelics has recently been reviewed (Fantegrossi et al, 2008a;Canal and Morgan, 2012;Halberstadt and Geyer, 2013a;Hanks and González-Maeso, 2013).…”

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

“…LSD, DOI, and psilocybin can induce schizophrenia-like psychosis in healthy human subjects (3,4,(44)(45)(46), and in the case of psilocybin, the effect can be blocked by ketanserin. Furthermore, these drugs induce schizophrenia-like traits in animals such as a PPI deficit (47,48) and stereotypic head twitches (16,17,49). Here, we combined these two factors, MIA and an acute injection of hallucinogenic drug DOI, and found that MIA offspring display stronger DOI-induced behavioral responses and greater brain activity as measured both by IEG induction and MEMRI.…”

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds

“…The validity of such assumptions are difficult to evaluate given the complex nature of the neuropsychiatric symptoms in humans. However, the administration of typical and atypical antipsychotics have been shown to attenuate the HTR, suggesting that the HTR, in conjunction with other rodent behavioral paradigms (including the PPI response, locomotor, exploratory and/or drug discrimination response, anxiolytic-like behaviors, time perception and/or cognitive processing), might be a valuable in vivo marker for identifying compounds with unique antipsychotic profiles (Hanks and Gonzalez-Maeso, 2012).…”

“…However, since neuropsychiatric disorders represent a heterogeneous array of symptoms, it has been difficult to identify an animal model systems that can mimic neuropsychiatric disorders for screening novel compounds for antipsychotic and/or antihallucinogenic activity (Swerdlow and Sutherland, 2005;Hanks and Gonzalez-Maeso, 2012). One of the models that has been explored is the head twitch response (HTR) that is elicited in rodents in response to the administration of known hallucinogens, including DOI (Schreiber et al, 1995;Fantegrossi et al, 2010;Canal et al, 2010Canal et al, , 2013Canal and Morgan, 2012;Rangel-Barajas et al, 2014).…”