TPA-023B

Potential antianxiety medications are commonly assessed by measuring their ability to increase behavior that is suppressed by aversive events like shock. These procedures have good predictive validity, but they also have practical limitations, particularly in nonhuman primates. The goal of the current experiment was to determine the feasibility of a different procedure to evaluate potential antianxiety medications without using shock. In prior research, arranging transitions from favorable to unfavorable schedules of positive reinforcement (rich-lean transitions) reliably disrupts operant behavior, and these disruptions can be ameliorated via benzodiazepine administration. We evaluated the suitability of a rich-lean transition procedure for preclinical evaluation of putative antianxiety medications. Adult rhesus monkeys' lever presses were reinforced using a 2-component multiple schedule with equivalent fixed-ratio requirements. Components were differentially signaled by colored stimulus lights. Completing a lean component produced 1 food pellet, and completing a rich component produced 4 food pellets. Sessions consisted of 41 components arranged irregularly to produce 10 iterations of 4 transition types: lean-lean, lean-rich, rich-lean, and rich-rich. As in the prior research, extended pausing was observed in rich-lean transitions. Acute administration of benzodiazepines (midazolam, alprazolam) and an imidazotriazine (TPA-023B) selectively reduced pausing in rich-lean transitions, a behavioral effect consistent with clinically effective antianxiety drugs in other preclinical anxiolysis procedures. Morphine and (+)amphetamine selectively increased rich-lean pausing, an effect consistent with an anxiogenic response in other anxiolysis procedures. Altogether, our results indicate that the rich-lean procedure has utility in the assessment putative antianxiety medications. SIGNIFICANCE STATEMENT: Transitions from favorable to unfavorable (ie, rich-lean) schedules of reinforcement reliably disrupts operant behavior, and these disruptions can be ameliorated via benzodiazepine administration. Our results indicate that the rich-lean transition procedure has utility in the assessment of putative antianxiety medications.