There is also evidence that extracellular levels of ACh fluctuate in a manner that is not consistent with localized clearance of a synaptic transmitter (Hajnal et al., 1998; Laplante et al., 2004; Mark et al., 1996; Parikh et al., 2004; Reid et al., 1998). However, contrasting observations, including the role of ACh in fast synaptic transmission at the neuromuscular junction and the high level of expression of ACh esterase (a highly efficient degradative enzyme responsible for clearing ACh from the extracellular space), have limited the acceptance of this idea. Ultimately, it is difficult to know how far ACh can diffuse from its site of release and whether volume transmission would allow for rapid transfer of information, suggesting that this is not the only mechanism through which ACh influences neuronal function in the brain. Anatomical studies have identified cortical cholinergic synapses that are structurally similar to those of other point-to-point neurotransmitters, in both rats (Turrini et al., 2001) and humans (Smiley et al., 1997). Effects of ACh on a rapid time-scale likely underlie its role in stimulus-response tasks in which subsecond reactivity is required for appropriate behavioral responses, as in prefrontal cortex-dependent cue detection (Parikh et al., 2007a) or auditory discrimination
