Kate Lawson is a fifth year graduate student in Dr. Stephen Mahler's lab at the University of California, Irvine. She studies rodent models of psychiatric disorders and the persistent effects of stress, and is interested in exploring how these negative effects may be reversed. The recent resurgence of interest and study of psychedelic drugs has been a great opportunity to combine her long-standing interest in psychiatric disorders with these potentially therapeutic drugs. Kate works with rat models of psychiatric disorders to ask how psychedelics may rescue aberrations in both behavior and neuronal circuitry, and what factors may mediate the efficacy of the psychedelic “therapy”. Her projects utilize psychedelic 5-HT2A agonist drugs to ameliorate early life adversity induced alterations to natural reward seeking, and adulthood trauma induced alterations in fear learning in rats. Outside of the lab you can find her running, baking bread, or babying her dog.

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Developing animal models of psychedelic therapy: Methods and mechanisms for reversal of trauma-induced behavior in rats

Post-traumatic stress disorder (PTSD) is a common mental health disorder that affects millions of Americans each year but has few effective pharmacological treatments. Therefore, it’s necessary to develop treatments that are persistent and effective for broad patient populations. In the last few years, psychedelic drugs acting at serotonin 2A (5HT2A) receptors have re-emerged in psychiatry, with potential for treating psychiatric disorders including PTSD. Since mechanistic studies of these effects are difficult to conduct in humans, translationally relevant animal models of “psychedelic therapy” are required. Here, we validate such a model in rats using an acute dose of the 5HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI, 1mg/kg).

We used stress-induced enhanced fear learning, a well-validated rat model of adulthood trauma, to investigate the neural mechanisms by which DOI might reverse stress-induced excessive fear behaviors. We tested whether a single dose of DOI persistently decreased the impact of trauma upon subsequent responses to a modest stressor. We observed this decrease in fear expression in both sexes, and further interrogated the persistence of this effect and the necessity of prior fear extinction training. In addition, we examined whether the pleasantness of the environment in which DOI was administered impacted its ability to reduce trauma-like behavior. We used cFos as a marker of neuronal activation to query brain activity elicited by modest threat and asked whether DOI “therapy” altered neuronal responses in stress-related brain regions.

We found that acute DOI delivered in a comfortable environment suppressed trauma like responses in both sexes for at least 3 days, but that neuronal responses in stress-related brain regions were more complex and differed by sex. We found evidence for the importance of “set and setting”, with DOI effects vastly differing based on fear extinction training and on the pleasantness of the DOI administration environment.

Rodent models of “psychedelic therapy” can be designed to better capture key aspects of human trials, and these experimental details can markedly influence the behavioral and neural outcomes of preclinical studies of psychedelic mechanisms."