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Phasic acetylcholine release and the volume transmission hypothesis: time to move on

Abstract

Traditional descriptions of the cortical cholinergic input system focused on the diffuse organization of cholinergic projections and the hypothesis that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. The ability of ACh to reach the extrasynaptic space (volume neurotransmission), as opposed to remaining confined to the synaptic cleft (wired neurotransmission), has been considered an integral component of this conceptualization. Recent studies demonstrated that phasic release of ACh, at the scale of seconds, mediates precisely defined cognitive operations. This characteristic of cholinergic neurotransmission is proposed to be of primary importance for understanding cholinergic function and developing treatments for cognitive disorders that result from abnormal cholinergic neurotransmission.

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Figure 1: The cortical cholinergic input system.
Figure 2: Cholinergic fibre distribution in the cortex.
Figure 3: Major steps in the synthesis, release and metabolism of ACh, and the main characteristics of wired and volume transmission.

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Acknowledgements

The authors' research was supported by Public Health Service (PHS) grants KO2MH10172, MH080426 and MH080332. W.M.H. was supported by the PHS Training Grant T32 DA007267. We thank S. Baran for comments on a draft of this paper and an anonymous reviewer for suggesting the final title of this paper.

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Sarter, M., Parikh, V. & Howe, W. Phasic acetylcholine release and the volume transmission hypothesis: time to move on. Nat Rev Neurosci 10, 383–390 (2009). https://doi.org/10.1038/nrn2635

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