Adjusting alcohol-seeking behavior

“Given the increasingly recognized societal impact of substance abuse, and the lack of safe and effective therapies, we are very encouraged by the activity demonstrated by NYX-783 in these preclinical models of alcohol use disorder,” said Dr. Cassia Cearley, vice president of research at Aptinyx. “Together with the favorable safety and tolerability profile already demonstrated in a Phase 1 study, these data strongly support the development of NYX-783 in substance abuse conditions. With NYX-783 currently in Phase 2 development as a therapy for PTSD [post-traumatic stress disorder], the results from these preclinical studies support its potential to treat one of the more prevalent comorbidities associated with PTSD, and expand the potential indications in which the mechanism of NYX-783 may have relevance.”

In the recent preclinical studies, behavior was assessed in two different models of alcohol use disorder in which animals were trained to self-administer ethanol through lever pressing. In the first model, an alcohol dependence model, alcohol dependence was induced in rats by exposing animals to ethanol vapor, with exposure to air used as a comparative control. After alcohol dependence was established, rats were dosed with either 0.1 mg/kg NYX-783, 6 mg/kg NYX-783 or vehicle one hour prior to the first extinction session.

Three weeks after extinction, rats were evaluated for relapse-like behavior after re-exposure to alcohol associated cues. In the second model, a stress-induced alcohol-seeking model, rats were exposed to a stressor prior to being trained to self-administer ethanol. Stress exposure increased alcohol-seeking behavior and rendered rats resistant to extinction of alcohol-seeking behavior. This approach models the influence of PTSD on substance abuse. Animals were then evaluated during and after the same extinction paradigm as described in the alcohol dependence model.

In both the alcohol dependence model and the stress-induced alcohol seeking model, animals dosed with NYX-783 prior to extinction demonstrated a significantly more rapid elimination of alcohol-seeking behavior as compared to vehicle. Animals dosed with NYX-783 prior to extinction also demonstrated significantly less relapse-like behavior when exposed to alcohol-associated cues in the alcohol dependence model or stress-associated cues in the stress-induced alcohol-seeking model. In the stress-induced alcohol-seeking model, animals that were only dosed with NYX-783 prior to re-exposure to the stress-associated cue also demonstrated significantly less relapse-like behavior when compared to vehicle-treated rats.