Chronic treatment with the psychedelic N,N-dimethyltryptamine (DMT) alleviated cognitive impairment and reduced amyloid-beta accumulation in the hippocampus and prefrontal cortex of 3×TG-AD transgenic mice, a model of Alzheimer's disease. DMT restored decreased sigma-1 receptor levels, reinstated multiple mitochondria-associated membrane proteins, and prevented abnormal physical contact and calcium dynamics between the endoplasmic reticulum and mitochondria in both in vitro and in vivo pathological conditions. DMT also modulated oxidative phosphorylation and ATP synthase in an in vitro Alzheimer's model. The protective effects are linked to DMT's activation of the sigma-1 receptor and preservation of ER-mitochondria crosstalk, suggesting potential as a preventive and therapeutic agent against Alzheimer's disease.
The neuropeptide PACAP in the hippocampal dentate gyrus (DG) mediates rapid antidepressant responses. Chronic paroxetine increased hippocampal PACAP, and blocking PACAP in the DG slowed the antidepressant effect. PACAP levels were reduced in two depression models, and knocking down PACAP in the DG caused depression-like behaviors. A single infusion of PACAP into the DG produced a rapid and sustained antidepressant effect in normal and stressed mice. Optogenetic excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while inhibition induced depression-like behaviors. PACAP infusion inhibited CaMKII-eEF2 signaling and activated mTOR-BDNF signaling. Acute ketamine increased PACAP, and blocking PACAP attenuated ketamine's rapid antidepressant effect.