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Repeated cannabinoid administration induces ΔFosB and sensitizes mu opioid receptor activity in the nucleus accumbens

CB1 cannabinoid receptors (CB1Rs) mediate the central effects of Δ9‐tetrahydrocannabinol (THC), the main psychoactive constituent in marijuana. CB1Rs and endocannabinoids are expressed in striatum and regulate reward, motivation and motor activity. We reported that inducible transgenic expression of ΔFosB in D1/dynorphin medium spiny striatal neurons enhanced mu opioid receptor (MOR) signaling in the nucleus accumbens (NAc) and enhanced rewarding effects of morphine, without affecting MOR expression. Moreover, repeated THC administration induces the transcription factor ΔFosB in the NAc, but inducible transgenic expression of ΔFosB did not enhance CB1R signaling in this region. Here we show that repeated THC administration induced ΔFosB in both NAc and dorsal striatum. Interestingly, repeated THC administration also enhanced MOR‐mediated G‐protein activation in the NAc, whereas CB1R‐mediated G‐protein activity was not increased. Neither THC nor inducible transgenic expression of ΔFosB altered MOR‐mediated G‐protein activity in dorsal striatum. Finally, inducible transgenic expression of ΔcJun, a dominant negative inhibitor of ΔFosB‐mediated transcription, blocked THC‐induced enhancement of MOR‐mediated G‐protein activity in NAc. These results suggest that sensitization of MOR activity by repeated THC could be mediated by ΔFosB. Support: R01‐ DA014277 and R01‐DA030404 from NIDA