Acetylcholine Sample Clauses

Acetylcholine. Acetylcholine is synthesized from choline and acetyl co-enzyme A by choline acetyltransferase. After depolarization of the presynaptic neuron, it is released in the synaptic cleft and binds to the postsynaptic receptors. To limit its action, acetylcholine is degraded by acetylcholinesterase in the synaptic cleft. The cholinergic system consists of the neurons using acetylcholine as neurotransmitter for transsynaptic communication. The highest density of these neurons is found in the basal forebrain (including the nucleus basalis of Meynert and the substantia innominata) and the brain stem, with a widespread projection to the cerebral cortex.10 Cholinergic neurons can also be found in the peripheral nervous system and are crucial for neuromuscular signal transduction. The autonomic nervous system also contains many cholinergic neurons, influencing for example heart rate, blood pressure and bowel movements. Acetylcholine exerts its action by binding to the postsynaptic receptors, divided in two subtypes. The muscarinic AChRs in the central nervous system (cns), especially the M1 subtype, are mainly located in the cerebral cortex, hippocampus, striatum, nucleus accumbens, dentate gyrus and brainstem and associated with memory, arousal and sleep.11–15 Nicotinic AChRs are mostly found in the cerebral cortex, thalamus, hippocampus, dentate gyrus and striatum and associated with memory.16,17 There are several possible pharmacological approaches for stimulating the cholinergic system to accomplish a potential procognitive effect. To increase the level of ACh in the synaptic cleft, the break-down can be diminished by cholinesterase inhibitors. Another option is to stimulate the postsynaptic neuron with a direct AChR agonist. With these principals in mind, several compounds were developed to influence the cholinergic system. In the second half of the eighties, several M1 AChR agonists were evaluated because of the high density of M1 AChRs in the hippocampus. In general, they had positive cognitive effects, but the cholinergic side effects overshadowed the benefits. This might have been due to a lack of selectivity leading to dominant peripheral cholinergic stimulation.18 This strategy was therefore soon abandoned. The other approach, inhibiting ACh breakdown appeared more hopeful and several cholinesterase inhibitors were developed.19–23 The cholinesterase inhibitor (cei) tacrine was the first to acquire registration in 1995. The registration was supported by mitiga...

Acetylcholine. Nicotinic

Acetylcholine. Lamina III is a projection site of Aβ and Aδ cutaneous afferents (▇▇▇▇▇▇ and ▇▇▇▇▇▇▇▇▇▇ 1991) and is the likely location of interneurons interposed in PAD of cutaneous afferents (Jankowska, ▇▇▇▇▇▇ et al. 1981).Intriguingly, it is also the predominant location of dorsal horn cholinergic interneurons (Olave, Puri et al. 2002) - well positioned to contribute to PAD (▇▇▇▇ 1991; ▇▇▇▇▇▇▇ 1998). Acetylcholine (ACh) and GABA co-exist in a population of dorsal horn interneurons (▇▇▇▇ 1991) and are found in ~25% of the synapses presynaptic to afferent axons (▇▇▇▇▇▇▇ 1998). Thus, there is ample anatomic evidence to support ACh as a transmitter contributing to PAD. Intriguingly, while the early literature did not identify acetylcholine (ACh) as a neurotransmitter in primary afferents (▇▇▇▇▇▇ and ▇▇▇▇▇▇▇▇▇▇ 1991), recent work strongly challenges these studies. First, an alternative splice variant of the ACh synthesis enzyme choline acetyltransferase (ChAT) has been identified. Peripheral ChAT (pChAT) is preferentially localized in peripheral neurons including in dorsal root ganglia (DRG) (Tooyama and Kimura 2000), and has sufficient enzyme activity in the adult rat DRG to produce physiological concentrations of Ach (Bellier and Kimura 2007). PChAT is expressed in both small and large diameter primary afferents (Bellier and Kimura 2007) and immunolabeling studies identify pChAT in myelinated primary afferents that project via dorsal columns to brainstem dorsal column nuclei (Yasuhara, Aimi et al. 2008). DRG neurons have also been shown to express the vesicular ACh transporter (VAChT) preferentially in large-diameter DRG neurons (Tata, De Stefano et al. 2004) as well as the ACh degradative enzyme acetylcholinesterase (AChE) (▇▇▇▇▇▇ and ▇▇▇▇▇▇▇▇▇▇ 1991; Bellier and Kimura 2007). Widespread ChAT labeling in DRG was also observed in mice, including ChAT-GFP BAC transgenic mice (▇▇▇▇▇▇▇, ▇▇▇▇ et al. 2006), and treatment with antisense oligonucleotides reduced labeling (Matsumoto, Xie et al. 2007).