Abstract
The cannabis-derived molecules, ∆9 tetrahydrocannabinol (THC) and cannabidiol (CBD), are both of considerable therapeutic interest for a variety of purposes, including to reduce pain and anxiety and increase sleep. In addition to their other pharmacological targets, both THC and CBD are competitive inhibitors of the equilibrative nucleoside transporter-1 (ENT-1), a primary inactivation mechanism for adenosine, and thereby increase adenosine signaling. The goal of this study was to examine the role of adenosine A2A receptor activation in the effects of intraperitoneally administered THC alone and in combination with CBD or PECS-101, a 4′-fluorinated derivative of CBD, in the cannabinoid tetrad, elevated plus maze (EPM) and marble bury assays. Comparisons between wild-type (WT) and A2AR knock out (A2AR-KO) mice were made. The cataleptic effects of THC were diminished in A2AR-KO; no other THC behaviors were affected by A2AR deletion. CBD (5 mg/kg) potentiated the cataleptic response to THC (5 mg/kg) in WT but not A2AR-KO. Neither CBD nor THC alone affected EPM behavior; their combination produced a significant increase in open/closed arm time in WT but not A2AR-KO. Both THC and CBD reduced the number of marbles buried in A2AR-KO but not WT mice. Like CBD, PECS-101 potentiated the cataleptic response to THC in WT but not A2AR-KO mice. PECS-101 also reduced exploratory behavior in the EPM in both genotypes. These results support the hypothesis that CBD and PECS-101 can potentiate the cataleptic effects of THC in a manner consistent with increased endogenous adenosine signaling.
Highlights
PECS-101 reduced exploratory behavior in the elevated plus maze (EPM) in both genotypes. These results support the hypothesis that CBD and PECS-101 can potentiate the cataleptic effects of THC in a manner consistent with increased endogenous adenosine signaling
WT and A2AR knock out (A2AR-KO) mice were injected with vehicle or THC (1, 10 and 100 mg/kg) and were assayed in the cannabinoid tetrad in the order and with the timing described in the Methods and shown in Supplementary Materials Figure S4
The first goal of the study was to determine whether six behavioral effects commonly seen with CB1R agonist treatment were altered in mice with genetic deletion of the A2A subtype of adenosine receptor
Summary
The cannabis-derived molecules, ∆9 tetrahydrocannabinol (THC) and cannabidiol (CBD), are both of considerable therapeutic interest for a variety of purposes, including to reduce pain and anxiety and increase sleep. CBD nor THC alone affected EPM behavior; their combination produced a significant increase in open/closed arm time in WT but not A2AR-KO. Both THC and CBD reduced the number of marbles buried in A2AR-KO but not WT mice. PECS-101 reduced exploratory behavior in the EPM in both genotypes These results support the hypothesis that CBD and PECS-101 can potentiate the cataleptic effects of THC in a manner consistent with increased endogenous adenosine signaling.
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