Alzheimer's disease (AD), the most common form of dementia, involves cognitive decline. Two sigma-1 receptor (S1R) agonists, dimethyltryptamine (DMT) and PRE084, were tested in a mouse model of AD induced by amyloid-beta (Aβ). DMT, which also binds strongly to serotonin receptors, reduced neurogenesis, likely due to its mixed receptor activity. In contrast, the highly selective S1R agonist PRE084 increased hippocampal cell proliferation and differentiation. Both DMT and PRE084 significantly reduced astrogliosis (a marker of neuroinflammation) caused by Aβ, but neither affected microglial activation. The findings suggest that selective S1R agonists like PRE084 may be promising therapeutic agents for AD, though further research is needed.
A new two-dimensional liquid chromatography method coupled to high-resolution tandem mass spectrometry was developed to measure the level of N,N-dimethyltriptamine (DMT) in rat plasma and brain tissue. The method achieved high recovery (90% in plasma, 88% in brain) and sensitivity (limit of detection 0.108 ng/mL in plasma, 0.212 ng/g in brain) within a 10-minute run. In an experimental model of cerebral ischemia/reperfusion, DMT concentration in rat plasma before hypoxia (49.3–114.3 ng/mL) was generally higher than after hypoxia (10.6–96.1 ng/mL). After treatment, brain DMT levels rose to 2–6.1 ng/g. The approach reliably detects and confirms DMT administered therapeutically.