Regulators Of G‐Protein Signaling 2 And 4 Differentially Regulate Nicotine‐Induced Affective Behavioral Responses

Abstract

High rates of tobacco smoking are observed in individuals suffering from anxiety or depression. Nicotine is a major psychoactive component of tobacco smoke and previous work has shown that nicotine can produce both anxiolytic‐ and antidepressant‐like effects. Regulators of G protein (RGS) signalling proteins negatively regulate intracellular signaling pathways of neurotransmitters (e.g. adrenaline, dopamine and serotonin), which mediate the antidepressant‐ and anxiolytic‐like effects of nicotine. The objective of the study was to determine the role of the RGS2 and RGS4 in the anxiolytic‐ and antidepressant‐like effects of nicotine. Antidepressant‐ and anxiolytic‐like effects were assessed using the tail suspension model and elevated plus maze, respectively. We used both male and female mice lacking either RGS2 (i.e. RGS2 KO) or RGS4 9i.e. RGS4 KO) and their wildtype counterparts. Both male and female RGS2 KO mice showed anxiolytic effects to nicotine (0.1 mg/kg; i.p., base) compared to respective saline controls. In contrast, no nicotine‐induced (1 mg/kg; i.p., base) antidepressant‐like effects were observed in male and female RGS2 KO mice compared to respective saline controls. Together, these data suggest that RGS2 plays a role in nicotine‐induced anxiolytic effects but not nicotine‐induced antidepressant‐like effects. In contrast, nicotine‐induced antidepressant‐like effects were observed in male RGS4 KO mice, but not female RGS4 KO mice compared to respective saline controls. Also, nicotine‐induced anxiolytic effects were not observed in either male or female RGS4 KO mice. Together, these data suggest that RGS2 and RGS4 differentially mediate nicotine‐induced affective responses. Clinically, these data support a role for targeting these proteins in treating nicotine addiction in patients suffering from comorbid anxiety and/or depression. Support or Funding Information This work was supported by a Bower, Bennett and Bennett grant awarded to Dr. Manoranjan S. D’Souza by the Raabe College of Pharmacy, Ohio Northern University (ONU), Ada, Ohio.