Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: A model of cholinergic capacity limits

NEUROPHARMACOLOGY

卷:75

Article

Paolone, Giovanna^1,2  Mallory, Caitlin S.^1,2  Cherian, Ajeesh Koshy^1,2  Miller, Thomas R.³  Blakely, Randy D.^4,5  Sarter, Martin^1,2 

[1] Univ Michigan, Dept Psychol, Ann Arbor, MI 48103 USA

[2] Univ Michigan, Neurosci Program, Ann Arbor, MI 48103 USA

[3] AbbVie Inc, Neurosci Discovery, N Chicago, IL 60064 USA

[4] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Dept Psychiat, Nashville, TN 37232 USA

关键词: Choline transporter;    Acetylcholine;    Attention;    Microdialysis;    Nicotinic acetylcholine receptor;    Mouse;   

DOI  :  10.1016/j.neuropharm.2013.07.032

来源: Elsevier

【 摘 要 】

Reductions in the capacity of the human choline transporter (SLC5A7, CHT) have been hypothesized to diminish cortical cholinergic neurotransmission, leading to risk for cognitive and mood disorders. To determine the acetylcholine (ACh) release capacity of cortical cholinergic projections in a mouse model of cholinergic hypofunction, the CHT+/- mouse, we assessed extracellular ACh levels while mice performed an operant sustained attention task (SAT). We found that whereas SAT-performance-associated increases in extracellular ACh levels of CHT+/- mice were significantly attenuated relative to wildtype littermates, performance on the SAT was normal. Tetrodotoxin-induced blockade of neuronal excitability reduced both dialysate ACh levels and SAT performance similarly in both genotypes. Likewise, lesions of cholinergic neurons abolished SAT performance in both genotypes. However, cholinergic activation remained more vulnerable to the reverse-dialyzed muscarinic antagonist atropine in CHT+/- mice. Additionally, CHT+/- mice displayed greater SAT-disrupting effects of reverse dialysis of the nAChR antagonist mecamylamine. Receptor binding assays revealed a higher density of alpha 4 beta 2* nAChRs in the cortex of CHT+/- mice compared to controls. These findings reveal compensatory mechanisms that, in the context of moderate cognitive challenges, can overcome the performance deficits expected from the significantly reduced ACh capacity of CHT+/- cholinergic terminals. Further analyses of molecular and functional compensations in the CHT+/- model may provide insights into both risk and resiliency factors involved in cognitive and mood disorders. (C) 2013 Elsevier Ltd. All rights reserved.

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