OPEN Foundation

A. Stewart

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

September 1, 2015 / LSD, Neuroscience, Other subjects, Papers, Psychology, Psychopharmacology, Publications / By / , ,

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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A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication

March 9, 2015 / Ayahuasca, Medicine, Other subjects, Papers, Publications / By / , , , , , ,

Abstract

Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (~2%) engaged in the cell cycle in the first year of life. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo–based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges.

Wang, P., Alvarez-Perez, J. C., Felsenfeld, D. P., Liu, H., Sivendran, S., Bender, A., … & Stewart, A. F. (2015). A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nature medicine. https://dx.doi.org/doi:10.1038/nm.3820
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30 April - Q&A with Rick Strassman

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