Antalarmin, a putative CRH-RI antagonist, has transient reinforcing effects in rhesus monkeys

Rationale: During the course of our investigation of antalarmin, a corticotropin-releasing hormone (CRH) antagonist, in rhesus monkeys, we noticed that large, intravenous doses of antalarmin resulted in behavioral changes that resembled intoxication. Objectives: Antalarmin was evaluated in rhesus monkeys for its reinforcing effectiveness as well as for its effects on hypothalamic-pituitary-adrenal (HPA) axis activity. Methods: Twelve monkeys, each with a surgically implanted indwelling venous catheter, were trained to respond for and receive the short-acting barbiturate, methohexital. Monkeys responded on one of two schedules: a fixed ratio (FR) 10 (30 or 100), timeout (TO) 10 s schedule on which they received methohexital, antalarmin, vehicle or saline injections; or an FR30, TO 45 s during which saline, vehicle, or four different doses of methohexital or antalarmin were available. Each dose was available during a 25-min period separated by a 10-min TO. Blood samples were obtained from three monkeys before, during and after the self-administration sessions and assayed for ACTH and cortisol. Results: Antalarmin initially served as a reinforcer in 11 of 12 monkeys, although its reinforcing effects dissipated after three to four exposures under both operant schedules. Self-injection of antalarmin did not produce any change in cortisol levels, although methohexital did attenuate ACTH and cortisol release. Conclusions: This study provides the first evidence for transient reinforcing properties of a putative centrally acting CRH-R1 selective antagonist.