Dissecting the role of CB1 and CB2 receptors in cannabinoid reward versus aversion using transgenic CB1- and CB2-knockout mice

Astroglial CB1 Cannabinoid Receptors Mediate CP 55,940-Induced Conditioned Place Aversion Through Cyclooxygenase-2 Signaling in Mice

“…This suggestion was substantiated by the experiments with CB1R knockout mice (Figures 2, 4) showing no CP 55,940-induced CPA. Therefore, our results are consistent with the previous findings that support a role CB1R (Scherma et al, 2008;Soria-Gomez et al, 2015;Han et al, 2017;Navabpour et al, 2021), but contradictory to other findings that support a role CB2R (Aracil-Fernandez et al, 2012;Ortega-Alvaro et al, 2015;Spiller et al, 2019;Li et al, 2021), in CB-associated modulation of aversive effects. Although CP 55,940 is an analog of 9 -THC, it differs from 9 -THC not only in the efficacy of activating CB receptors (McGregor et al, 1996;Singh et al, 2011), but also possibly in the receptor mechanisms of regulating brain functions which include temperature (Grim et al, 2016) as well as rewarding and aversion responses (Singh et al, 2011).…”

“…Although CP 55,940 is an analog of 9 -THC, it differs from 9 -THC not only in the efficacy of activating CB receptors (McGregor et al, 1996;Singh et al, 2011), but also possibly in the receptor mechanisms of regulating brain functions which include temperature (Grim et al, 2016) as well as rewarding and aversion responses (Singh et al, 2011). In our hands, 1 mg/kg CP 55,940 produces CPA, while Li et al (2021) reported the CPP of 1 mg/kg 9 -THC in mice. With regard to the direct effect of CBs on mice aversive behavior, our data convincingly reveal a role CB1R in mediating the CPA effect of CP 55,940 at a concentration of 1 mg/kg.…”

“…Some studies detected indirect effects of CBs on aversion, e.g., effects of CBs on the brain-stimulation reward of rats (Spiller et al, 2019), cocaine or ethanol reinforcing of mice (Aracil-Fernandez et al, 2012;Ortega-Alvaro et al, 2015), aversive memory of mice (Soria-Gomez et al, 2015), aversive responses in the rat model of panic attacks (Viana et al, 2019). Some other studies detected the direct effect of aversion against CBs in rat ( McGregor et al, 1996;Scherma et al, 2008) or mice (Han et al, 2017;Li et al, 2021). In our present study, we showed the potent CB receptor agonist CP 55,940, an synthetic analog of 9 -THC, is able to induce CPA directly at a high dose in mice, consistent with previous reports from rats (McGregor et al, 1996).…”

“…Systematic administration of high doses of non-specific agonist Δ 9 -THC or WIN55,212-2 produces suppressive effects on the brain-stimulation reward that can be blocked by CB2R antagonist ( Spiller et al, 2019 ). Using transgenic knockout mice, Li et al (2021) found that CB1R knockout attenuates Δ 9 -THC-induced CPP at a low dose and enables a high dose of Δ 9 -THC to induce CPA, and that CB2 receptor knockout display robust CPP, but no CPA ( Li et al, 2021 ).…”

Discordant Effects of Cannabinoid 2 Receptor Antagonism/Inverse Agonism During Adolescence on Pavlovian and Instrumental Reward Learning in Adult Male Rats

“…Acute CB2R activation has been shown to inhibit VTA DAergic neuronal firing and cocaine selfadministration (Zhang et al, 2014), possibly through decreased DA released into the NAc (Zhang et al, 2014;Chase et al, 2015;Galaj and Xi, 2019). Similarly, it has recently been shown that CB2R-null mice also show elevated DA levels in the NAc in response to THC, further implicated CB2R as important mediators of mesolimbic DA signaling (Li et al, 2021). The decreased sign-tracking behavior seen following CB2R antagonism/inverse agonism in our study may, therefore, be due to a compensatory increase in NAc-VTA receptor sensitivity and/or expression following prolonged inhibition during adolescence (Zhang et al, 2014).…”