Discriminative stimulus properties of a new anxiolytic,DN-2327, in rats

In an operant learning lever-pressing procedure on an FR10 schedule of milk reinforcement, male Wistar rats were trained to discriminate between saline and 3 mg/kg IP DN-2327, a new anxiolytic which acts on benzodiazepine receptors, 3 mg/kg IP diazepam or 15 mg/kg IP pentylenetetrazol (PTZ). More than 80% appropriate lever responding was established after 27, 38 and 44 daily training sessions with DN-2327, diazepam and PTZ, respectively, as the training drug. Although rats trained with DN-2327 dose-dependently generalized to various doses of DN-2327 and diazepam, the cue of DN-2327 was more potent than that of diazepam: ED₅₀ values of DN-2327 and diazepam for stimulus generalization were 0.30 and 0.66 mg/kg, respectively. These animals partially generalized to pentobarbital (1–10 mg/kg) but did not generalize to buspirone (0.1–10 mg/kg). Rats trained with diazepam dose-dependently generalized to various doses of DN-2327, diazepam and pentobarbital with ED₅₀ values of 0.51, 0.47 and 4.5 mg/kg, respectively, but did not generalize to buspirone. In rats trained with PTZ, DN-2327 and diazepam antagonized the discriminative stimulus produced by 15 mg/kg PTZ in a dose-dependent manner with ED₅₀ values of 0.27 and 0.83 mg/kg, respectively, but buspirone neither antagonized nor was able to substitute for the PTZ-induced stimulus. The cue of DN-2327 was antagonized by flumazenil dose-dependently as was that of diazepam. Diazepam and pentobarbital reduced the total number of responses in all animals at 10 mg/kg, and buspirone did so at more than 3 mg/kg, while DN-2327 did not affect the total number of responses from 0.1 to 10 mg/kg. In conclusion, the cue of DN-2327 is similar to and more effective than that of diazepam; moreover, it is quite different from that of buspirone. In addition, the similarity of the interoceptive stimuli of DN-2327 and diazepam may suggest that they are not related to muscle relaxant and sedative properties, since the two drugs differ in this respect.