Modulation of aggressive behavior in mice by nicotinic receptor subtypes

Abstract

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 (0.25 mg/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 (α7 subunit) nAChR antagonist methyllycaconitine (5 mg/kg), but not the heteromeric (β2 or β4 subunit-containing) nAChR antagonist dihydro-β-erythroidine (DHβE, 3 mg/kg), blocked the serenic effects of nicotine. By contrast, pretreatment with DHβE blocked the effect of acute nicotine administration on locomotion, uncoupling nicotine’s serenic and hypolocomotor effects. Finally, the α7 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 α7 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.

Hippocampal α7 nicotinic ACh receptors contribute to modulation of depression‐like behaviour in C57BL/6J mice

“…Physostigmine (Sigma Pharmaceuticals, North Liberty, IA, USA) was administered at a dose of 0.15 mg·kg −1 , 45 to 60 min before testing. Methyllycaconitine (MLA; Sigma) and GTS‐21‐OH (Tocris Bioscience, Bristol, UK) were injected 30 min before testing at doses of 5 and 17 mg·kg −1 , respectively, and as previously described (Lewis et al , ). This concentration of MLA was chosen because in vivo studies suggest that a higher dose (7.5 mg·kg −1 ) may have non‐specific effects (Franceschini et al , ) independent of α7 nAChRs (Klink et al , ; Mogg et al , ).…”

Cerebellar Purkinje cell activity modulates aggressive behavior

“…To assess the impact of cerebellar activity on social and aggressive behaviors we performed resident-intruder assays while optogenetically manipulating PC activity in the resident (aggressor) animal ( Figure 3a). Although resident mice reliably display aggressive behaviors in resident-intruder assays, attacks occur at a relatively infrequent rate of <1 attack per minute (Leypold et al, 2002;Yang et al, 2013;Lewis et al, 2015).…”

Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors

“…Resident-intruder tests were performed exactly as described previously (Lewis et al, 2015) and detailed in the Supplementary Materials and Methods.…”

“…α-bungarotoxin binding was performed as previously described (Mineur et al, 2016). Cardiac perfusion, tissue sectioning, and IF staining for c-Fos were performed as previously described (Lewis et al, 2015). Staining for Arc (guinea pig, 1 : 1000, Synaptic Systems 156005, Goettingen, Germany), CaMKII (mouse, 1 : 1000, Abcam ab22609 [6G9], Cambridge, MA, USA), GABA (rabbit, 1 : 500, Sigma-Aldrich A2052), or GFP (rabbit, 1 : 1000, Life Technologies 11122, Carlsbad, CA, USA) was performed as detailed in the Supplementary Materials and Methods.…”

“…In a mouse model of aggression, we recently found the α7 nAChR was necessary for the anti-aggressive, or 'serenic' effects of systemic administration of the pan-nAChR agonist nicotine, and that GTS-21, an α7 nAChR partial agonist, recapitulated the serenic effects of nicotine (Lewis et al, 2015). In humans, galantamine, a positive allosteric modulator at the α7 nAChR and an acetylcholinesterase inhibitor, was reported to successfully reduce persistent, severe rage outbursts in a man with 15q13.3DS (Cubells et al, 2011), while transdermal nicotine successfully reduced persistent aggressive behavior in an adolescent with idiopathic ASD (Van Schalkwyk et al, 2015).…”