Novel discriminative stimulus effects of TPA023B, subtype-selective gamma-aminobutyric-acid(A)/benzodiazepine modulator: comparisons with zolpidem, lorazepam, and TPA023.

Anxiolytics with fewer unwanted effects may be created by varying GABAergic efficacy at the BZ binding site across GABA(A) receptor subtypes. TPA023 and TPA023B have in vitro antagonist efficacy at alpha(1) subtypes and partial-agonist efficacy at alpha(2/3) subtypes. TPA023B has partial-agonist efficacy at alpha(5); TPA023 has none. Drug discrimination procedures were used to determine whether the novel GABA(A) receptor efficacy profiles would be reflected in a model of subjective effects of BZ-site ligands. Rats were trained to discriminate TPA023, TPA023B, the nonselective BZ anxiolytic lorazepam, or the alpha(1)-selective hypnotic zolpidem. The lorazepam, zolpidem, and TPA023 discriminations were learned in < 50 sessions. The TPA023B training group showed no evidence of acquiring the TPA023B discrimination after 160 sessions despite various procedural manipulations. Neither zolpidem- nor lorazepam-trained rats generalized to TPA023B. Within the same dose range, however, TPA023-trained rats generalized fully and dose-dependently to TPA023B. Number of training sessions to regain criterion discrimination performance following TPA023B tests in the lorazepam, zolpidem, and TPA023 groups increased as a function of dose, likely due to effects of residual TPA023B. Together with previous data, the present results suggest that elimination of alpha(1) efficacy plus reductions in alpha(2/3) efficacy permits anxiolysis but decreases BZ-like interoceptive stimulus effects.