Abstract
The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ9-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Δ9-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ9-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.
Highlights
Cannabis is one of the most common drugs of abuse in the world (Alpar et al, 2016; Englund et al, 2017; Volkow et al, 2014)
After 4 hr, we evaluated the status of key autophagy protein markers
P62 overexpression per se decreased RotaRod performance in vehicle-treated animals, and this decrease was not additive to that induced by THC administration (10 mg/kg, i.p.) (F(7,28) = 5.641; THC-WT/post-treatment vs. vehicle-WT/post-treatment, p=0.0152; vehicle-D1 receptor (D1R)-Cre/pre-treatment vs. vehicle-WT/pre-treatment, p=0.0477; THC-D1R-Cre/pre-treatment vs. THC-WT/pre-treatment, p=0.0450) (Figure 6B). All these findings indicate that CB1 receptors located on D1R-medium spiny neurons (MSNs), but not on corticostriatal projections, are required for the autophagy-inhibiting and motor-dyscoordinating activity of THC
Summary
Cannabis is one of the most common drugs of abuse in the world (Alpar et al, 2016; Englund et al, 2017; Volkow et al, 2014). Several states in the USA, as well as a few countries in the world, have legalized the recreational use of cannabis. Cannabis preparations have been used in medicine for millennia, and nowadays there is a vigorous renaissance in the study and application of their therapeutic effects (Pertwee, 2012). In this context, THC and other cannabinoids are already approved by various regulatory agencies, including the Food and Drug Administration (FDA), the European Medicines Agency and Health Canada, as anti-emetic, anti-cachexic, analgesic
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