N,N‐Dimethyltryptamine ( DMT ) Acutely Exposed to Mouse Ventral Tegmental Area I h ‐Negative Neurons Alters the Firing Rate and Conductance in a Sex‐Dependent Manner

Depression and substance use disorder (SUD) affect millions globally and unfortunately, while established treatments exist, they are not always adequate. Psychedelics have emerged as a promising avenue for development of more effective pharmacological interventions. Dimethyltryptamine (DMT), a classic psychedelic, has shown anti‐depressive and anti‐addictive properties in preclinical studies, observational evaluations, and limited controlled trials; however, the exact mechanism(s) of action(s) are still unknown. In the present ex vivo study, we provide the first evaluation of the electrophysiological effects of acute DMT exposure at two concentrations in male and female I h ‐negative neurons of the mouse ventral tegmental area (VTA). The VTA plays a central role in regulating emotion and motivated behavior, and I h ‐negative neurons, which are putatively inhibitory, shape VTA output to downstream targets. At the lower concentration, DMT (500 nM) did not exert any effect on evaluated electrophysiological properties of female and male VTA I h ‐negative neurons. At the highest concentration (90 μM), DMT elicited a conductance change at subthreshold potentials and an increase in action potential firing; however, these actions were seen only in female VTA. At the higher concentration, DMT increased cytosolic calcium levels in both sexes. In conclusion, DMT has actions in both male and female I h ‐negative VTA neurons, but the alterations in firing and membrane conductance observed in females indicate activation of mechanisms beyond the calcium changes seen in males. Taken together, these findings highlight the importance of translational research to connect the cellular effects of DMT with its potential long‐term therapeutic outcomes in humans, while accounting for variables such as sex and dose‐dependent responses.