Modulation of social deficits and repetitive behaviors in a mouse model of autism: the role of the nicotinic cholinergic system.
BACKGROUND
Accumulating evidence implicates the nicotinic cholinergic system in autism spectrum disorder (ASD) pathobiology. Neuropathologic studies suggest that nicotinic acetylcholine (ACh) receptor (nAChR) subtypes are altered in brain of autistic individuals. In addition, strategies that increase ACh, the neurotransmitter for nicotinic and muscarinic receptors, appear to improve cognitive deficits in neuropsychiatric disorders and ASD.


OBJECTIVE
The aim of this study is to examine the role of the nicotinic cholinergic system on social and repetitive behavior abnormalities and exploratory physical activity in a well-studied model of autism, the BTBR T(+) Itpr3 (tf) /J (BTBR) mouse.


METHODS
Using a protocol known to up-regulate expression of brain nAChR subtypes, we measured behavior outcomes before and after BTBR and C57BL/6J (B6) mice were treated (4 weeks) with vehicle or nicotine (50, 100, 200, or 400 μg/ml).


RESULTS
Increasing nicotine doses were associated with decreases in water intake, increases in plasma cotinine levels, and at the higher dose (400 μg/ml) with weight loss in BTBR mice. At lower (50, 100 μg/ml) but not higher (200, 400 μg/ml) doses, nicotine increased social interactions in BTBR and B6 mice and at higher, but not lower doses, it decreased repetitive behavior in BTBR. In the open-field test, nicotine at 200 and 400 μg/ml, but not 100 μg/ml compared with vehicle, decreased overall physical activity in BTBR mice.


CONCLUSIONS
These findings support the hypotheses that the nicotinic cholinergic system modulates social and repetitive behaviors and may be a therapeutic target to treat behavior deficits in ASD. Further, the BTBR mouse may be valuable for investigations of the role of nAChRs in social deficits and repetitive behavior.
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Divisions of Anesthesiology and Perioperative Medicine, Children's National Health System, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, Washington, DC, 20010, USA.
Li
L
Wang
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Divisions of Anesthesiology and Perioperative Medicine, Children's National Health System, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, Washington, DC, 20010, USA.
Luis E F
LE
Almeida
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Divisions of Anesthesiology and Perioperative Medicine, Children's National Health System, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, Washington, DC, 20010, USA.
Nicholas A
NA
Spornick
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Divisions of Anesthesiology and Perioperative Medicine, Children's National Health System, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, Washington, DC, 20010, USA.
Nicholas
N
Kenyon
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Divisions of Anesthesiology and Perioperative Medicine, Children's National Health System, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, Washington, DC, 20010, USA.
Sayuri
S
Kamimura
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Divisions of Anesthesiology and Perioperative Medicine, Children's National Health System, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, Washington, DC, 20010, USA.
Alfia
A
Khaibullina
Center for Sickle Cell Disease and Department of Internal Medicine, Howard University, Washington, DC, 20001, USA.
Mehdi
M
Nouraie
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Divisions of Anesthesiology and Perioperative Medicine, Children's National Health System, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue, Washington, DC, 20010, USA. zquezado@childrensnational.org.|Center for Neuroscience Research, Children's Research Institute, Children's National Health System, George Washington University School of Medicine and Health Sciences, Washington, DC, 20010, USA. zquezado@childrensnational.org.
Zenaide M N
ZM
Quezado
D000818:Animals; D001321:Autistic Disorder / Q000097:blood* / Q000523:psychology; D018678:Cholinergic Agents / Q000494:pharmacology*; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism*; D003367:Cotinine / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*
D018678:Cholinergic Agents; D009538:Nicotine; D003367:Cotinine
Autism; BTBR; Nicotine; Repetitive behavior; Social behavior; nAChR