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Modulation of social deficits and repetitive behaviors in a mouse model of autism: the role of the nicotinic cholinergic system

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Abstract

Rationale

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.

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Acknowledgments

The authors are grateful to LaShon Middleton for expert technical support during experiments. We thank the Children’s Research Institute neurobehavior core for the use of the facility. The work was supported by a grant from the Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s Research Institute, Children’s National Health System and by a grant from the National Institutes of Health Intellectual & Developmental Disabilities Research Center Grant P30HD040677

Conflict of interest

All authors have read the journal’s authorship agreement and policy on disclosure of potential conflicts of interest and have no conflict of interest to disclose

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    Authors and Affiliations

    1. 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 Wang, Luis E. F. Almeida, Nicholas A. Spornick, Nicholas Kenyon, Sayuri Kamimura, Alfia Khaibullina & Zenaide M. N. Quezado

    2. Center for Sickle Cell Disease and Department of Internal Medicine, Howard University, Washington, DC, 20001, USA

      Mehdi Nouraie

    3. 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

      Zenaide M. N. Quezado

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    1. Li Wang
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    4. Nicholas Kenyon
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    Correspondence to Zenaide M. N. Quezado.

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    In memoriam of Nicholas Kenyon

    Li Wang and Luis E. F. Almeida contributed equally to this work.

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    Wang, L., Almeida, L.E.F., Spornick, N.A. et al. Modulation of social deficits and repetitive behaviors in a mouse model of autism: the role of the nicotinic cholinergic system. Psychopharmacology 232, 4303–4316 (2015). https://doi.org/10.1007/s00213-015-4058-z

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