Neurochemical and Neurophysiological Effects of Intravenous Administration of <i>N,N</i> -Dimethyltryptamine in Rats

Abstract

N , N -Dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans are well characterized, similar studies in animal models and data on the neurochemical effects of DMT are generally lacking, which are critical for a mechanistic understanding. Here, we combined behavioral analysis, high-density (32-channel) electroencephalography, and ultrahigh-performance liquid chromatography–tandem mass spectrometry to simultaneously quantify changes in behavior, cortical neural dynamics, and levels of 17 neurochemicals in medial prefrontal and somatosensory cortices before, during, and after intravenous administration of DMT (0.75, 3.75, 7.5 mg/kg) in male and female adult rats. All three doses of DMT produced head twitch response with most twitches observed after the low dose. DMT caused dose-dependent increases in serotonin and dopamine levels in both cortical sites, a reduction in EEG spectral power in theta (4–10 Hz) and low gamma (25–55 Hz), and an increase in spectral power in delta (1–4 Hz), medium gamma (65–115 Hz), and high gamma (125–155 Hz) bands. Functional connectivity decreased in the delta band and increased across the gamma bands. We detected cortical DMT in baseline wake condition in 70–80% of the animals tested at levels comparable to serotonin and dopamine, which, together with a previous study in the occipital cortex, motivates cross-species studies to confirm endogenous presence of DMT. This study represents one of the most comprehensive characterizations of psychedelic drug action in rats and the first to be conducted with intravenous DMT.