Involvement of other neurotransmitters in behaviors induced by the cannabinoid CB1 receptor antagonist SR 141716A in naive mice

The receptor mechanisms by which the selective cannabinoid CB1 receptor antagonist/inverse agonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide] produces scratching and head-twitch response (HTR) in naive mice were examined. Acute intraperitoneal administration of varying doses of SR 141716A produced both scratchings (ED50 = 3.9mg/kg) and head-twitches (ED50 = 4.6mg/kg) in a dose-dependent manner. A dose of 10mg/kg SR 141716A was used to induce the cited behaviors for drug interaction studies. The selective 5-HT2A/C receptor antagonist, SR 46349B [trans-4-[(3Z)3-2-dimethylaminoethyl) oxyimino-3-(2-fluorophenyl) propen-1-yl] phenol] potently and completely blocked the head-twitches produced by SR 141716A (ID50 = 0.08mg/kg). The induced scratching behavior was partially (68%) and less potently (ID50 = 0.6 mg/kg) blocked by SR 46349B pretreatment. The AMPA/kainate receptor antagonist, CNQX [6-cyano-7-nitroquinoxaline-2,3-dione), partially attenuated (68-78%) the induced scratching and head-twitching behaviors. On the contrary, the selective NMDA antagonist, AP-3 [(+/-)-2-amino-3-phosphonopropionic acid), had no significant effect on these behaviors. The selective tachykinin NK1 antagonist, CP 94, 994 [(+/-)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], also partially attenuated both the scratching (64%) and the head-twitching (76%) symptoms produced by SR 141716A. Since SR 141716A lacks affinity for the discussed receptors, it appears that the induction of the cited behaviors probably involve indirect activation of their respective neurotransmitter systems.