DISCRIMINATIVE STIMULUS EFFECTS OF DIAZEPAM IN RATS - EVIDENCE FOR A MAXIMAL EFFECT

  • 1 January 1983
    • journal article
    • research article
    • Vol. 227  (1) , 160-166
Abstract
Rats were trained to discriminate between saline and either 0.3, 1.0, 3.0 or 6.0 mg/kg of diazepam in a 2-choice, discrete-trial avoidance procedure. Diazepam, chlordiazepoxide, flurazepam and pentobarbital occasioned dose-related increases in diazepam-appropriate responding in all 4 training dose groups. Increasing the training dose of diazepam from 0.3 to 1.0 mg/kg resulted in approximately a 3-fold shift to the right in the dose-effect curves for each of these 4 drugs. Increasing the training dose to 3.0 or 6.0 mg/kg did not result in additional, concomitant shifts in these dose-effect curves. The dose-effect curves of 9 additional benzodiazepine analogs also did not differ markedly in rats trained with either 1.0 or 3.0 mg/kg of diazepam. The nonbenzodiazepines ethanol, phencyclidine, cyproheptadine and ketocyclazocine failed to produce diazepam-like discriminative stimuli in rats trained with either 0.3, 1.0 or 3.0 mg/kg of diazepam. In rats trained with 1.0 mg/kg of diazepam, Ro 11-6896 [(S)-S-(O-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one] but not its inactive stereoisomer Ro 11-6893 [(R)-5-(O-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benodiazepin-2-one] occasioned diazepam-appropriate responding. The selective benzodiazepine antagonist CGS8216 [2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one] blocked the effects of diazepam but not the diazepam-like effects of pentobarbital. Evidently, the discriminative effects of diazepam are qualitatively similar across this 20-fold range of training doses; quantitatively, the discriminative effects of diazepam appear to reach a maximum and plateau above a training dose of 1.0 mg/kg in rats. The discriminative effects of diazepam appear to be receptor mediated because the relative potencies of a series of analogs correlated significantly with their relative potencies for inhibiting [3H]diazepam binding, they exhibited stereospecificity and they were blocked by a selective benzodiazepine antagonist (CGS8216).