Reversal of SR 141716A-induced head-twitch and ear-scratch responses in mice by delta 9-THC and other cannabinoids.

Recently, we have shown that cannabinoids of diverse structure block the ability of the selective 5-HT(2A/C) agonist DOI to produce the head-twitch response (HTR) and the ear-scratch response (ESR) in mice. The cannabinoid CB(1) antagonist/inverse agonist SR 141716A also induces these behaviors in mice. The purposes of the present study were: (1) to investigate whether Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and other cannabinoids HU-210 and WIN 55, 212-2 can prevent SR 141716A-induced HTR and ESR and (2) to evaluate any correlation between the ID(50) potency order of the cited cannabinoids in blocking SR 141716A-induced HTR and ESR and their ED(50) order of potency in reducing spontaneous locomotor activity and rearing behavior. For the SR 141716A reversal study, different groups of mice were injected intraperitoneally with either vehicle or varying doses of the following cannabinoids: Delta(9)-THC (2.5-20 mg/kg), Delta(8)-THC (5-20 mg/kg), HU-210 (0.05-0.5 mg/kg), CP 55, 940 (0.5-2.5 mg/kg) and WIN 55, 212-2 (2.5-10 mg/kg). Thirty minutes later, each mouse received SR 141716A (2.5 mg/kg ip) and the frequencies of the induced behaviors (mean +/- S.E.M.) were recorded for the next 30 min. The effects of the cited doses of cannabinoids were also examined on spontaneous locomotor activity and rearing frequency for a 20-min duration 10 min after cannabinoid injection. The tested cannabinoids reduced the frequencies of HTR and ESR in SR 141716A-injected mice. These agents also attenuated the cited naturally occurring repertoire of motor parameters in mice. Although large potency differences were observed among the cited cannabinoids, each tested cannabinoid was relatively equipotent in preventing locomotor parameters and SR 141716A-induced behaviors. The ID(50) potency order of cannabinoids in blocking SR 141716A-induced HTR and ESR were similar (HU-210>CP 55, 940>WIN 55, 212-2 > or = Delta 9)-THC=Delta(8)-THC), and are comparable with: (1) their ED(50) potency order in attenuating both spontaneous locomotor activity and rearing behavior (HU-210>CP 55, 940>WIN 55, 212-2>Delta(9)-THC=Delta(8)-THC) and (2) their published ED(50) potency order for producing the tetrad of behaviors in mice as well as their rank order of binding affinities for cannabinoid CB(1) receptors. The present data show that cannabinoids of diverse structure prevent SR 141716A-induced HTR and ESR, and inhibition of these behaviors by cannabinoids could be used as a new index of cannabimimetic activity.