Abstract
Preclinical research has sought to understand the role of the orexin system in cocaine addiction given the connection between orexin producing cells in the lateral hypothalamus and brain limbic areas. Exogenous administration of orexin peptides increased cocaine self-administration whereas selective orexin-1 receptor antagonists reduced cocaine self-administration in non-human animals. The first clinically available orexin antagonist, suvorexant (a dual orexin-1 and orexin-2 receptor antagonist), attenuated motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding, in rodents. This study aimed to translate those preclinical findings and determine whether suvorexant maintenance altered the pharmacodynamic effects of cocaine in humans. Seven non-treatment seeking subjects with cocaine use disorder completed this within-subject human laboratory study, and a partial data set was obtained from one additional subject. Subjects were maintained for at least three days on 0, 5, 10 and 20 mg oral suvorexant administered at 2230 h daily in random order. Subjects completed experimental sessions in which cocaine self-administration of 0, 10 and 30 mg/70 kg of intravenous cocaine was evaluated on a concurrent progressive ratio drug versus money choice task. Subjective and physiological effects of cocaine were also determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Suvorexant (10, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. Future research may seek to evaluate the effects of orexin-1 selective antagonists in combination with cocaine.