Neurokinin‐1 receptor antagonist rolapitant suppresses anxiety and alcohol intake produced by repeated withdrawal episodes

• Published in: The FEBS journal 2022-08, Vol.289 (16), p.5021-5029
• Main Authors: Kokhan, Viktor S., Anokhin, Petr K., Abaimov, Denis A., Shamakina, Inna Yu, Soldatov, Vladislav O., Deykin, Alexey V.
• Format: Article
• Language: English
• Subjects: alcohol consumption; Alcohol use; Alcoholic beverages; Alcohols; Amygdala; Anxiety; Cerebral cortex; Hypothalamus; Motivation; Neocortex; Neurokinin; neurokinin‐1 receptor; Operant conditioning; Receptors; Reinforcement; Reinstatement; Rodents; rolapitant; withdrawal
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16400

Neurokinin‐1 receptor (NK1r) antagonists have been shown to suppress operant self‐administration of alcohol, voluntary alcohol consumption and stress‐induced reinstatement of alcohol‐seeking behaviour. Considering the long half‐life and anxiolytic‐like properties of NK1r antagonist rolapitant, we expected that it may be an effective option for reducing anxiety and alcohol motivation during early withdrawal. Voluntary alcohol intake (two‐bottles paradigm) was recorded in male Wistar rats during the three periods: 24 days (basal level), 6‐day period when rats received 5 mg·kg−1 rolapitant or vehicle and 12‐h period after repeated withdrawal episodes (alcohol cessation for 36 h). We found that upon intraperitoneal (i.p.) administration, rolapitant rapidly penetrated into specific rat brain regions – amygdala, hypothalamus and neocortex – implicated in the control of anxiety and reward. Rolapitant did not affect basal voluntary alcohol intake, but significantly suppressed anxiety‐like behaviour and alcohol consumption following withdrawal episodes. Our findings suggest that rolapitant should be further investigated as a novel treatment option for relapse prevention in alcohol‐dependent patients. Blockade of neurokinin‐1 receptor (NK1r) signalling may have beneficial effects on alcohol abuse and alcohol‐related behavioural problems. Herein, we investigated whether rolapitant, a NK1r antagonist, can attenuate voluntary alcohol consumption of alcohol‐preferring rats. Our study revealed that rolapitant significantly suppressed alcohol consumption and anxiety‐like behaviour following withdrawal episodes. Additionally, rolapitant was characterized by good penetration of brain regions implicated in the control of anxiety and reward.