CB1 receptor antagonists proved to be effective anti-obesity drugs, however, their depressive and anxiogenic effects became also evident. Finding solution to overcome these psychiatric side effects is still in focus of research. Based on the available clinical and preclinical results we hypothesized that the combination of CB1 and mGlu5 receptor antagonisms may result in a pharmacological intervention, where the anxiolytic mGlu5 receptor inhibition may counteract the anxiogenic psychiatric side effects of CB1 antagonism, while CB1 antagonism may ameliorate the memory impairing effect of mGlu5 receptor antagonism. Further, the two components will synergistically interact in blocking food-intake and reducing obesity.
For testing the interaction of mGlu5 and CB1 receptor antagonism MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pridine; SIB-1757, 6-methyl-2-(phenylazo)-3-pyridinol)] (mGlu5 antagonist) and rimonabant [(5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)hydrochloride] (CB1 antagonist) were used. All experiments were carried out in rats. Effects of the compounds on anxiety were tested in two foot shock induced ultrasonic vocalization paradigms, appetite suppression was assessed in the food intake test, while memory effects were tested in a context conditioned ultrasonic vocalization setup.
MTEP abolished the anxiogenic effect of rimonabant, while there was an additive cooperation in suppressing appetite. However, rimonabant did not ameliorate the memory impairing effect of MTEP.
By combination of CB1 and mGluR5 antagonism, anxiety related side effects might be attenuated, appetite suppression maintained, nevertheless, the possible emergence of unwanted memory impairments can overshadow its therapeutic success.Highlights
▸ CB1 antagonists are clinically effective antiobesity drugs, but induce severe anxiety. ▸ We tested if this profile can be improved by concurrent CB1 and mGluR5 antagonisms. ▸ Rimonabant and MTEP exerted synergistic effect in reducing food-intake in rats. ▸ Anxiogenic-like effect of rimonabant was abolished by MTEP in the adult rat USV test. ▸ Impaired fear-conditioning caused by MTEP was not ameliorated by rimonabant treatment.