Distinct effects of diazepam and NK1 receptor antagonists in two conflict procedures in rats

Convergent data suggest that SP, through the activation of neurokinin1 receptors (NK1-R), may be involved in anxiety. In particular, NK1-R antagonists have been reported to exert anxiolytic-like effects in a variety of animal procedures in which anxiety-related behaviour is induced by novelty. The present study investigated the effects of acute blockade of NK1-R in conflict paradigms, another category of anxiety-related procedures, in which positively reinforced responses are suppressed by contingent punishment. For this purpose, three selective antagonists with nanomolar affinity for rat NK1-R, GR205171, RP67580 and [2-cyclopropoxy-5-(5-(trifluoromethyl)tetrazol-1-yl)benzyl]-(2-phenylpiperidin-3-yl)amine (Compound L), were tested in the safety signal withdrawal operant paradigm. In this procedure, suppression of lever pressing for food was induced by the withdrawal of a conditioned signal for safety, with no presentation of a conditioned signal for punishment, and no punishment. Compound L was also tested in the punished drinking test, which consists of the contingent delivery of electric footshocks upon water drinking. As expected, the reference compound, diazepam (2 mg/kg s.c.), induced an anxiolytic-like effect, as indicated by significant increases of the number of responses emitted during conflict period in the operant procedure, and footshocks received in the drinking test. In contrast, GR205171 (10 mg/kg s.c.), RP67580 (0.25-8 mg/kg s.c.) and Compound L (10 and 30 mg/kg s.c.) failed to release lever pressing during the operant conflict period. In addition, punished drinking was not affected by Compound L (3-30 mg/kg s.c.). These data show that NK1-R blockade has no anxiolytic-like effects in conflict paradigms, thereby suggesting that the anxiolytic properties of NK1-R antagonists are less broad than those reported for benzodiazepines.