Psychedelics are being tested in over 200 clinical trials as potential treatments for psychiatric disorders, but how they work and their risks are not fully understood. The serotonin 2A receptor (5-HT2AR) is the main target of psychedelics. This study compared psychedelics with non-hallucinogenic analogues using cell and animal experiments, finding that 5-HT2AR signaling through a non-canonical Gi pathway is essential for hallucinogenic effects. Five cryo-electron microscopy structures of 5-HT2AR bound to these drugs were solved. A special contact between non-hallucinogenic analogues and the receptor biased signaling away from Gi. A derivative called DOI-NBOMe showed potent Gq-biased activity and therapeutic effects in mice without causing hallucinations. These findings reveal mechanisms of 5-HT2AR Gi signaling and guide the design of safer psychedelic-based drugs.
Chronic lithium exposure reduces mania-like behavior and c-Fos expression in the medial prefrontal cortex of adult male mice treated with ketamine. Transcriptome sequencing of the prefrontal cortex shows that lithium inactivates the PI3K-AKT signaling pathway. Inhibiting AKT signaling with MK2206 or knocking down AKT in the mPFC reverses ketamine-induced mania, while activating AKT with SC79 promotes mania in low-dose ketamine-treated mice. Inhibiting PI3K with LY294002 also reverses mania, but inhibiting mTOR with rapamycin has no effect. Lithium may therefore ameliorate ketamine-induced mania via the PI3K-AKT pathway, suggesting a novel target for bipolar disorder treatment.
Pretreatment with lithium moderates the effects of a single dose of ketamine on mania-like behavior and c-Fos expression in the mouse forebrain. Ketamine increased movement and induced higher c-Fos expression in several forebrain regions, including the lateral septal nucleus, hypothalamus, amygdala, and hippocampus. Chronic lithium treatment attenuated the ketamine-induced increase in movement and inhibited the rise in c-Fos-immunoreactive neurons in the dentate gyrus, CA1, dorsal and ventral subiculum, and amygdaloid nuclei. These findings may help understand mania episodes related to ketamine treatment for major depressive disorder and bipolar disorder.