The Role of Nicotinic Receptors in the Attenuation of Autism‐Related Behaviors in a Murine BTBR T + tf/J Autistic Model

Abstract

Nicotinic receptors are distributed throughout the central and peripheral nervous system. Postmortem studies have reported that some nicotinic receptor subtypes are altered in the brains of autistic people. Recent studies have demonstrated the importance of nicotinic acetylcholine receptors (nAChRs) in the autistic behavior of BTBR T + tf/J mouse model of autism. This study was undertaken to examine the behavioral effects of targeted nAChRs using pharmacological ligands, including nicotine and mecamylamine in BTBR T + tf/J and C57BL/6J mice in a panel of behavioral tests relating to autism. These behavioral tests included the three‐chamber social interaction, self‐grooming, marble burying, locomotor activity, and rotarod test. We examined the effect of various oral doses of nicotine (50, 100, and 400 mcg/mL; po) over a period of 2 weeks in BTBR T + tf/J mouse model. The results indicated that the chronic administration of nicotine modulated sociability and repetitive behavior in BTBR T + tf/J mice while no effects observed in C57BL/6J mice. Furthermore, the nonselective nAChR antagonist, mecamylamine, reversed nicotine effects on sociability and increased repetitive behaviors in BTBR T + tf/J mice. Overall, the findings indicate that the pharmacological modulation of nicotinic receptors is involved in modulating core behavioral phenotypes in the BTBR T + tf/J mouse model. Lay Summary The involvement of brain nicotinic neurotransmission system plays a crucial role in regulating autism‐related behavioral features. In addition, the brain of the autistic‐like mouse model has a low acetylcholine level. Here, we report that nicotine, at certain doses, improved sociability and reduced repetitive behaviors in a mouse model of autism, implicating the potential therapeutic values of a pharmacological intervention targeting nicotinic receptors for autism therapy. Autism Res 2020, 13: 1311–1334. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Curcumin Potentiates α7 Nicotinic Acetylcholine Receptors and Alleviates Autistic-Like Social Deficits and Brain Oxidative Stress Status in Mice

“…Also, the brain of the BTBR mouse, a well-studied idiopathic ASD model shown to display core ASD phenotypes (decreased sociability, altered vocalization, and repetitive behavior) [ 23 , 24 ], has decreased ACh levels and increased levels of kynurenic acid, a α7-nAChR antagonist, in medial prefrontal cortex [ 25 ]. Notably, decreased social interaction and repetitive behaviors, such as self-grooming, was significantly attenuated by the administration of α7-nAChR agonist, AVL-3288 [ 26 ], and nicotine [ 5 , 27 ] in BTBR mice. In clinical trials, the acetylcholinesterase inhibitor galantamine, an acetylcholinesterase inhibitor (AChEI), and positive allosteric modulator of α7-nAChR, showed beneficial effects in ASD individuals [ 28 , 29 ].…”

Menthol Flavor in E-Cigarette Vapor Modulates Social Behavior Correlated With Central and Peripheral Changes of Immunometabolic Signalings

“…In our current work, we have used a standard and precise vapor device to mimic the exposure of ENDS, which avoided the restraint stress that might have been caused by the nose-only aerosol exposure, and evaluated the social behaviors after long-term exposure with daily 30-min inhalation. As shown in the previous study, the effects of nicotine on social behaviors are complex regarding the dose, the schedule of administration, housing, and individual differences; nicotine may increase the social interaction at low doses but reduce it at high doses ( Blanco-Gandia et al, 2015 ); and it was also presented to improve the sociability and reduced repetitive behaviors in a mouse model of autism at certain doses while no effects were observed in the normal mice ( Mahmood et al, 2020 ). Consistent with some of these literature, we found in our experiment that, although the slight decrease in the social activity (no statistical difference) was observed in nicotine-vapored mice, the long exposure to menthol flavored ENDS was found to have compensatory enhancing effects on the sociability and preference for social novelty compared to the vapor exposure of nicotine alone, suggesting the antagonistic effect on the social functioning of menthol flavoring as a combinational ingredient with nicotine in ENDS.…”

Genetic Risk of Autism Spectrum Disorder in a Pakistani Population

“…GABA-mediated calcium signaling regulates a variety of developmental processes from cell proliferation, and therefore it is not unanticipated that some forms of neuro-developmental disorders including ASD showed alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits [ 75 ]. In the brain of ASD patients, insulin-signaling pathways and pathological involvement of cholinergic nuclei and altered expression of acetylcholine receptors, particularly nicotinic acetylcholine receptors, have also been reported [ 76 , 77 , 78 , 79 ].…”