OPEN Foundation

E. Kyzar

Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models

Abstract

Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Antimuscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations and form a separate group of hallucinogens known as “deliriants”. Although atropine and scopolamine are relatively well-studied drugs in cholinergic physiology, deliriants represent the least-studied class of hallucinogens in terms of their behavioral and neurological phenotypes. As such, novel approaches and new model organisms are needed to investigate the CNS effects of these compounds. Here, we comprehensively evaluate the preclinical effects of deliriant hallucinogens in various animal models, their mechanisms of action, and potential interplay with other signaling pathways. We also parallel experimental and clinical findings on deliriant agents and outline future directions of translational research in this field.

Volgin, A. D., Yakovlev, O. A., Demin, K. A., Alekseeva, P. A., Kyzar, E. J., Collins, C., … & Kalueff, A. V. (2018). Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models. ACS chemical neuroscience., 10.1021/acschemneuro.8b00433

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Psychedelic Drugs in Biomedicine

Abstract

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E., & Kalueff, A. V. (2017). Psychedelic Drugs in Biomedicine. Trends in Pharmacological Sciences. 10.1016/j.tips.2017.08.003
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Exploring Hallucinogen Pharmacology and Psychedelic Medicine with Zebrafish Models

Abstract

After decades of sociopolitical obstacles, the field of psychiatry is experiencing a revived interest in the use of hallucinogenic agents to treat brain disorders. Along with the use of ketamine for depression, recent pilot studies have highlighted the efficacy of classic serotonergic hallucinogens, such as lysergic acid diethylamide and psilocybin, in treating addiction, post-traumatic stress disorder, and anxiety. However, many basic pharmacological and toxicological questions remain unanswered with regard to these compounds. In this study, we discuss psychedelic medicine as well as the behavioral and toxicological effects of hallucinogenic drugs in zebrafish. We emphasize this aquatic organism as a model ideally suited to assess both the potential toxic and therapeutic effects of major known classes of hallucinogenic compounds. In addition, novel drugs with hallucinogenic properties can be efficiently screened using zebrafish models. Well-designed preclinical studies utilizing zebrafish can contribute to the reemerging treatment paradigm of psychedelic medicine, leading to new avenues of clinical exploration for psychiatric disorders.

Kyzar, E. J., & Kalueff, A. V. (2016). Exploring Hallucinogen Pharmacology and Psychedelic Medicine with Zebrafish Models. Zebrafish. http://dx.doi.org/10.1089/zeb.2016.1251

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Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert+/−) mice

Abstract

Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive–compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert+/− mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert+/− mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert+/+ and Sert+/− mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert+/− mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice.

Kyzar, E. J., Stewart, A. M., & Kalueff, A. V. (2016). Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert+/−) mice. Behavioural brain research, 296, 47-52. http://dx.doi.org/10.1016/j.bbr.2015.08.018
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