Biased allosteric modulator of neurotensin receptor 1 reduces ethanol drinking and responses to ethanol administration in rodents by Graydon B. Gereau instant download

Biased allosteric modulator of neurotensin receptor 1 reduces ethanol drinking and responses to ethanol administration in rodents by Graydon B. Gereau instant download

ABSTRACTKeywords:Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse Neurotensinis the 7th leading cause of premature death [1]. Despite this, there are currently only 3 FDA approved pharAlcohol use disordermacological approaches for the treatment of AUDs in the United States. The neurotensin (Nts) system has long Beta-arrestinbeen implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, Mousethat biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psyRatchostimulant use. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, physiological sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.