Novel discriminative stimulus effects of TPA023B, subtype-selective γ-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 α₁ subtypes and partial-agonist efficacy at α_2/3 subtypes. TPA023B has partial-agonist efficacy at α₅; 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 α₁-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 α₁ efficacy plus reductions in α_2/3 efficacy permits anxiolysis but decreases BZ-like interoceptive stimulus effects.