A single high dose or four microdoses of LSD accelerated the extinction of morphine-induced conditioned place preference in both male and female mice. Whole-cell electrophysiology showed that excitatory synaptic plasticity in VTA GABA neurons, which was suppressed after morphine exposure, was restored 24 hours after a single high dose of LSD. Whole-brain DNA methylation analysis revealed significant differences in methylation profiles between morphine-treated mice that received LSD versus saline. These findings suggest that LSD may reverse or prevent morphine-induced changes in reward circuit plasticity and reduce measures of morphine preference.
In mice, three days of THC exposure eliminates a specific form of synaptic plasticity—CB1-dependent long-term depression (LTD)—in GABA neurons of the ventral tegmental area (VTA) in young but not adult animals. This age-dependent effect may help explain why adolescents are more sensitive to THC-induced changes in brain reward circuits. Quantitative PCR showed no THC-induced changes in mRNA levels for either age group, though several differences existed between young and adult control mice.