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


OBJECTIVE
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.
Broadbear
Jillian H
JH
Department of Pharmacology, University of Michigan, Ann Arbor 48109-0632, USA.
Winger
Gail
G
Rice
Kenner C
KC
Woods
James H
JH
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000737:chemistry / Q000187:drug effects; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006854:Hydrocortisone / Q000097:blood / Q000737:chemistry; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D008723:Methohexital / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods; D013997:Time Factors
D018686:Anesthetics, Intravenous; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D000324:Adrenocorticotropic Hormone; D008723:Methohexital; D006854:Hydrocortisone