Effects of methoxyflurane and flurothyl in mice trained to discriminate pentylenetetrazol from saline

A procedure is described for training mice to discriminate 30mg/kg pentylenetetrazol (PTZ) from saline when lever pressing was maintained under a fixed-ratio 20 schedule of milk presentation. To define the pharmacological profile of the PTZ stimulus in mice, generalization testing was conducted with oxazepam and Ro 15-4513 (sarmazenil). Consistent with data obtained by others in rats, oxazepam (1mg/kg) blocked the PTZ stimulus whereas Ro 15-4513 substituted for PTZ, but only at a dose (2mg/kg) that also decreased rates of responding. The effects of both a depressant and excitatory vapor in this model were also determined. The volatile anesthetic methoxyflurane (1000-2000 ppm) blocked the discriminative stimulus effects of PTZ in a concentration-dependent manner, while the convulsant vapor flurothyl (900 ppm) produced greater than 90% PTZ-lever responding without disrupting rates of responding. The PTZ-like discriminative stimulus effects of flurothyl were dose-dependently blocked by oxazepam (0.03-1.0mg/kg). As has been shown in numerous previous studies in rats, PTZ could be established as a discriminative stimulus in mice. PTZ discrimination could be blocked by a benzodiazepine agonist and shares some properties with a benzodiazepine inverse agonist. Substitution and antagonism studies can also be performed with vapors, illustrating the utility of this model for comparing their behavioral effects to those of more widely studied drugs.