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Behav Brain Res. 2016 Oct 1;312:148-62. doi: 10.1016/j.bbr.2016.06.022. Epub 2016 Jun 15.

A threshold model for opposing actions of acetylcholine on reward behavior: Molecular mechanisms and implications for treatment of substance abuse disorders.

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From the Substance Abuse Research Laboratory, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, United States; From the Division of Clinical Pharmacology, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS 66160, United States. Electronic address:


The cholinergic system plays important roles in both learning and addiction. Medications that modify cholinergic tone can have pronounced effects on behaviors reinforced by natural and drug reinforcers. Importantly, enhancing the action of acetylcholine (ACh) in the nucleus accumbens and ventral tegmental area (VTA) dopamine system can either augment or diminish these behaviors. A threshold model is presented that can explain these seemingly contradictory results. Relatively low levels of ACh rise above a lower threshold, facilitating behaviors supported by drugs or natural reinforcers. Further increases in cholinergic tone that rise above a second upper threshold oppose the same behaviors. Accordingly, cholinesterase inhibitors, or agonists for nicotinic or muscarinic receptors, each have the potential to produce biphasic effects on reward behaviors. Pretreatment with either nicotinic or muscarinic antagonists can block drug- or food- reinforced behavior by maintaining cholinergic tone below its lower threshold. Potential threshold mediators include desensitization of nicotinic receptors and biphasic effects of ACh on the firing of medium spiny neurons. Nicotinic receptors with high- and low- affinity appear to play greater roles in reward enhancement and inhibition, respectively. Cholinergic inhibition of natural and drug rewards may serve as mediators of previously described opponent processes. Future studies should evaluate cholinergic agents across a broader range of doses, and include a variety of reinforced behaviors.


Acetylcholine; Acetylcholinesterase inhibitors; Cocaine; Donepezil; Galantamine; Muscarinic receptor; Nicotinic receptor; Reinforcement (psychology); Rivastigmine; Self-administration

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