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

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.

Antalarmin was evaluated in rhesus monkeys for its reinforcing effectiveness as well as for its effects on hypothalamic-pituitary-adrenal (HPA) axis activity.

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.

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.

This study provides the first evidence for transient reinforcing properties of a putative centrally acting CRH-R1 selective antagonist.