Effects of Ro 15-1788 and CGS 8216 in diazepam-dependent baboons

Baboons received continuous intragastric infusions of diazepam (20 mg/kg per day) for one or more months. While diazepam treatment continued, baboons received intragastric doses of Ro 15-1788 (0.032-32.0 mg/kg) or CGS 8216 (1.0-100.0 mg/kg) at intervals of two or more weeks. Baboons were observed following administration of these antagonists for the presence of precipitated withdrawal signs. The following results were obtained: (1) both Ro 15-1788 and CGS 8216 produced signs of precipitated withdrawal in the baboon; (2) a more severe overall withdrawal syndrome was precipitated with Ro 15-1788 than with CGS 8216 at testable doses; (3) Ro 15-1788 produced dose-related increases in the overall severity of withdrawal, while CGS 8216 did not produce a clear dose-related increase in the overall severity of withdrawal; (4) dose-effect curves for Ro 15-1788 for certain signs (e.g. limb-tremor) were monotonicly increasing, while for other signs dose-effect curves plateaued at lower doses of Ro 15-1788 (e.g. retching and vomiting) or were an inverted U-shape (e.g. scratching). CGS 8216 precipitated withdrawal signs were less clearly dose-dependent; (5) onset of Ro 15-1788 precipitated withdrawal signs were rapid (5-15 min) and reliable, while the onset of CGS 8216 precipitated withdrawal signs were generally slower (approximately 30 min) and more variable; (6) at doses of Ro 15-1788 and CGS 8216 that produced equal levels of vomiting and retching, Ro 15-1788 produced more limb-tremor than CGS 8216. These studies indicate that Ro 15-1788 and CGS 8216 may produce quantitatively and qualitatively different precipitated withdrawal syndromes.