Lewis_2015_Biochem.Pharmacol_97(4)_488

Aggression is frequently comorbid with neuropsychiatric conditions and is a predictor of worse outcomes, yet current pharmacotherapies are insufficient and have debilitating side effects, precluding broad use. Multiple models of aggression across species suggest that the nicotinic acetylcholine receptor (nAChR) agonist nicotine has anti-aggressive (serenic) properties. Here we demonstrate dose-dependent serenic effects of acute nicotine administration in three distinct mouse strains: C57BL/6, BALB/c, and CD1. While acute nicotine administration (0.25mg/kg) modestly reduced solitary homecage locomotion, this could not account for nicotine's serenic effects since social encounters eliminated the hypolocomotor effect, and nicotine did not alter social interaction times. Pretreatment with the homomeric (alpha7 subunit) nAChR antagonist methyllycaconitine (5mg/kg), but not the heteromeric (beta2 or beta4 subunit-containing) nAChR antagonist dihydro-beta-erythroidine (DHbetaE, 3mg/kg), blocked the serenic effects of nicotine. By contrast, pretreatment with DHbetaE blocked the effect of acute nicotine administration on locomotion, uncoupling nicotine's serenic and hypolocomotor effects. Finally, the alpha7 nAChR partial agonist GTS-21 reduced aggression in C57BL/6 mice. These results support the idea that acute nicotine administration has serenic effects and provide evidence for specificity of this effect distinct from effects on locomotion. Furthermore, pharmacological studies suggest that activation of alpha7 nAChRs underlies the serenic effects of nicotine. Further studies of nAChRs could enhance understanding of the neurobiology of aggression and may lead to the development of novel, more specific treatments for pathological aggression.