A single dose of the short-acting psychedelic 5-MeO-DMT alters expression of genes related to plasticity and neuronal activity in specific brain regions of mice, including the anterior cingulate cortex, basolateral amygdala, and ventral hippocampus. Immediate early genes Arc and Zif268 changed within hours, while TRIP8b, a modulator of neuronal activity, increased in the ventral hippocampus after five days. Behaviorally, 5-MeO-DMT produced mixed anxiety-reducing and anxiety-increasing effects in standard tests, but mice pre-treated with the compound and then exposed to acute stress showed lower corticosterone levels and strong anxiety-reducing effects. The findings suggest molecular pathways through which 5-MeO-DMT may produce anxiolytic effects.
A single high dose of the short-acting psychedelic 5-MeO-DMT alters gene expression in specific brain regions of mice, including the anterior cingulate cortex, basolateral amygdala, ventral hippocampus CA1 region, and dentate gyrus. The compound changed mRNA levels of immediate early genes Arc and Zif268 in several regions and increased TRIP8b expression in the ventral hippocampus after five days. Behaviorally, treated mice showed mixed anxiety-reducing and anxiety-increasing effects in standard tests. However, when pre-treated mice were subjected to acute stress, they had lower corticosterone levels and robust anxiety-reducing effects. These findings suggest molecular actions of 5-MeO-DMT related to its potential anxiolytic effects.
Heroin self-administration increases the density of perineuronal nets (PNNs) in the ventral pallidum (VP) of mice. Depleting these PNNs with an enzyme prevents cue-induced reinstatement of heroin seeking, reduces the intrinsic excitability of parvalbumin-expressing VP neurons, strengthens inhibitory synaptic inputs onto them, and lowers Fos expression in those neurons after reinstatement. Chemogenetic activation of VP parvalbumin neurons rescues the suppressive effect of PNN depletion on heroin seeking, while chemogenetic inhibition mimics it. VP parvalbumin neurons and their PNNs are critical drivers of opioid seeking, and targeting PNNs in the VP may offer a novel therapeutic approach for relapse in opioid use disorder.