Are Behavioral Disorders of the Domestic Dog and Cat a Viable Model for the Study of Psychedelic Treatments?

The domestic dog (canis familiaris) and the domestic cat (felis catus) live in close contact with humans and experience external and internal stimuli comparable to those experienced by humans. Scientists working in cognitive and affective neuroscience are gathering an increasing amount of evidence on self-awareness, consciousness, and emotions experienced by animals. Primary emotional systems like fear, rage, and reward seeking have been recognized in animals (Panksepp 1998, 2005). Dogs and cats manifest abnormal behavior associated with affective and/or physical disorders treated by veterinary behavior specialists. Separation-related disorders (separation anxiety), affective aggression, fears and phobias, and abnormal repetitive behaviors are among the problems most commonly referred to the veterinary clinical behaviorist. This presentation will provide an overview of the affective disorders of dogs and cats, with or without an underlying physical component (pain, inflammation…), that are potentially useful models for the study of treatment with psychedelics.

Panksepp J (1998) Affective Neuroscience - The Foundations of Human and Animal Emotions. Oxford University Press , Oxford, England - Panksepp J (2005) Affective consciousness: Core emotional feelings in animals and humans. Consciousness and Cognition 14(1):30-80

Investigating the Mechanistic Relationship Between Glucocorticoid Release and Anxiolytic Effects of Psychedelics: Insights from Rodent Studies

While correlations between drug-induced cortisol elevation, self-reported anxiety, and treatment outcomes have been reported for human studies during psilocybin-assisted psychotherapy, the mechanistic relationship between psychedelic-associated alterations in plasma glucocorticoid responses and the time course of anxious responsiveness remains unclear. Using rodents, both time-bound manipulation of glucocorticoid concentrations and assessment of anxiety-like behaviors can be achieved. Here, 3 mg/kg IP psilocybin was found to have post-acute anxiolytic-like effects in C57BL/6 male mice, which were not altered by pretreatment with a 5-HT2AR antagonist but were blunted by pretreatment with a glucocorticoid receptor antagonist or suppression of psilocybin-induced corticosterone elevations. These post-acute anxiolytic-like effects were also observed following treatment with lisuride or ketamine at doses causing similar increases in plasma glucocorticoids, as well as following stress-induced (via repeated injection) glucocorticoid release alone. Psilocybin’s anxiolytic-like effects persisted at 7 days following administration. In contrast to the post-acute effects, this long-term outcome was not blocked by pre-treatment with a glucocorticoid receptor antagonist but was blocked by pretreatment with a 5-HT2AR antagonist. Long-term anxiolytic-like effects were also observed for lisuride. Furthermore, the long-term anxiolytic effects of psilocybin were reversed to yield an anxiogenic-like profile when psilocybin was administered to animals with ongoing chronic elevations in plasma corticosterone concentrations. Overall, these experiments indicate that acute psilocybin-induced glucocorticoid release drives the post-acute anxiolytic-like effects of psilocybin in mice, while its long-term anxiolytic-like effects are more dependent on 5HT2AR activity, and on the return of transient plasma glucocorticoid elevations back to baseline.

Long-lasting impacts of short-acting psychedelics on brain plasticity

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, improving patient access. The short-acting psychedelic is 5-MeO-DMT has been associated with improvement in depression and anxiety symptoms in early clinical studies. However relatively little is known about the behavioral effects and neural mechanisms of 5-MeO-DMT in mice. Methods: We characterized the effects of 5-MeO-DMT on innate behaviors using head-twitch response and social ultrasonic vocalization (USV). Head-twitch response, a behavioral measure that correlates with psychedelic potency in humans, was measured using an automated magnetic ear tag system. Social USVs were measured from male-female pairs of juvenile mice before and after 5-MeO-DMT, ketamine or psilocybin. We then measured the impact of 5-MeO-DMT on dendritic architecture using longitudinal in vivo two-photon microscopy. Results: We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT does not affect the size of dendritic spines. Conclusions: These data provide insights into the behavioral and neural consequences of 5-MeO-DMT and show that psychedelic drugs with short psychoactive effects can have long-lasting impacts on structural plasticity.

A gut feeling: How our intestinal cellular network could bidirectionally shape psychedelics and their therapeutic effects

The gastrointestinal (GI) tract is the most dense, dynamic, and heterogeneous organ in the human body; harboring a complex network comprised of trillions of microorganisms (the gut microbiota), >70% of the body’s immune cells, and ~500 million enteric neurons1. Apart from absorption and digestion, this network also coordinates gut motility, local sensory processing, epithelial and immune function, appropriate microbiota responses, and even central nervous system (CNS) function via the ‘gut-brain axis’2. Disorders of gut-brain interaction are a significant global health burden, affecting 40% of the population, and are characterized by any combination of motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered CNS processing3. In non-comorbid settings, antidepressants are emerging as possible therapies for inflammatory bowel disease and, conversely, individual members of the gut microbiota are strongly associated with depression and anxiety4. Recently, psychedelics with strong antidepressant effects, like psilocybin, ayahuasca, and ketamine, were shown to exhibit antimicrobial and immunomodulatory properties5,6. These findings, in combination with their established neuronal effects, suggest a profound remodeling of the GI network by psychedelics. In fact, many cellular receptor targets are also expressed on gut immune cells, enteric neurons, epithelial cells, and even some bacteria5. However, how these psychedelics broadly modulate gut function or indirectly modulate CNS functions is not well understood. Here, I review pharmacological aspects of select psychedelics that are most relevant to the GI network i.e., host metabolism, endocrine and neurotransmitter signaling, and antimicrobial activity. Moreover, I propose some research studies to interrogate these modes of action using a combination of in vivo and in vitro experimental approaches. Results from investigations like those proposed will determine whether psychedelic-induced remodeling of the GI network contribute to and/or impair therapeutic actions which could greatly inform their clinical use. Major implications for this work involve the characterization of non-responder populations, and evidence-based incorporation of gut-related modalities, such as dietary interventions, to mitigate side effects and maximize benefits. In sum, a holistic understanding of the systemic effects of psychedelics demands an integrated, interdisciplinary approach characterized by cross-pollination of ideas from neuroscience, gastroenterology, and likely many other fields.