Three-day delta-9-tetrahydrocannabinol (THC) exposure eliminates long-term depression in ventral tegmental area of young, but not adult mice.

Ventral tegmental area (VTA) dopamine signaling plays a key role in reward learning and drug dependence. VTA dopamine cell activity is regulated in part by local GABA interneurons, which participate in regulating reward prediction. Previously, our lab identified a cannabinoid type 1 receptor (CB1)-dependent form of excitatory long-term depression (LTD) in VTA GABA cells. LTD was eliminated in both young and adult mice after 7-10-day delta-9-tetrahydrocannabinol (THC) exposure. To build off these previous findings, we used mouse ex vivo brain slices to examine whether young mice undergo THC-induced alterations to VTA GABA cell plasticity after fewer exposures than their adult counterparts, as human adolescents have increased sensitivity to THC. Whole-cell electrophysiological recordings were performed on young (P14-P54) and adult (P66-P240) mice treated with THC or vehicle control for 3 days, after which we attempted to induce CB1-dependent LTD ex vivo. Plasticity was eliminated in young but not adult mice after 3 days of THC treatment. Because our previous work illustrated age-dependent alterations to mRNA transcripts after chronic THC-treatment, we also performed quantitative real-time PCR to assess any age dependent differences of 3-day THC exposure on mRNA levels in the VTA. Quantitative PCR revealed no THC-induced changes for young or adult mice but did show several differences between young and adult control mice. This age-dependent impact of THC on synaptic activity could reveal a physiological mechanism underlying increased sensitivity of adolescents to THC-induced alterations to plasticity.