Cholinergics acetylcholine-release modulators

The available data are consistent with the present thesis that cholinergic inputs to cerebral cortex mediate intradendritic events fundamental to conscious activity as a primary role, and that cholinergic modulation of electrophysiological activity may be secondary, even epiphenomenal. Transduction pathways exist whereby muscarinic receptors (and possibly nicotinic receptors acting presynaptically to inhibit acetylcholine release) may lead to actions on the cytoskeleton directly relevant to consciousness. The thesis presented here describes these pathways and also suggests a possible explanation for the diversity of neuromodulators and metabotropic receptors. Accordingly, qualitative aspects of our consciousness would be finely tuned by a number of neurochemicals, prominent among which is acetylcholine. 

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Inhibition of neurotransmitter release mediated by Ai adenosine receptors is a widespread phenomenon. As mentioned in Section 1, it was first described for cholinergic neurons. But presynaptic Ai receptors also inhibit the release of several other neurotransmitters both in CNS and PNS. Table 2 summarizes early relevant studies. As to postganglionic parasympathetic neurons, there is only one study to our knowledge. In that study, carried out in guinea pig atria, no A] receptor-mediated modulation of acetylcholine release was found (Nakatsuka et al. 1995). 

Neurotrophins mediate acetylcholine release from cholinergic neurons (Huh et al., 2008). Brain-derived nerve growth factor (BDNF) is a member of the nerve growth factor family (neurotrophins) that contributes to both pre- and postnatal brain development. BDNF supports the neuronal survival, maintains neuronal activity and plasticity, modulates neurotransmitter release and mediates long-term potentiation... 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl -A (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can he blocked by botulinum toxin. Acetylcholine s action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosome-associated proteins VAMPs, vesicle-associated membrane proteins.

As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary transmitter. Some of the substances identified to date are listed in Table 6-1. Many of these substances are also primary transmitters in the nonadrenergic, noncholinergic nerves described in the text that follows. They appear to play several roles in the function of nerves that release acetylcholine or norepinephrine. In some cases, they provide a faster or slower action to supplement or modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals. 

Receptor-dependent vasodilation may also take place in a more indirect manner through the presynaptic modulation of the release of neurotransmitters, such as norepinephrine and acetylcholine. In addition to its effects on postsynaptic receptors, norepinephrine stimulates the presynaptic a2-receptor, thereby inhibiting further transmitter release. Moreover, the activation of other presynaptic receptors such as the muscarinic cholinergic, dopaminergic, purinergic, serotoninergic, and histaminergic receptors leads to diminished norepinephrine release and subsequent vasodilation. 

The alterations produced by THC and other cannabinoids in biogenic amine levels as well as on uptake, release and synthesis of neurotransmitters and effects on enzymes have been the subject of numerous investigations (for reviews see [8,52,55,114,115]). It is beyond the scope of the present summary to try to analyse and put into a proper perspective the wealth of data published so far. It is our subjective view that the mode of action of cannabi-mimetic compounds is somehow directly associated with prostaglandin metabolism (see, in particular, the series of papers by Burstein [115,116]), and/or reduction of hippocampal acetylcholine turnover observed in rats [117,118]. The latter effect is enantiospecific and follows the known SAR of the cannabinoids. This in vivo selectivity of action suggests that the THC may activate specific transmitter receptors which indirectly modulate the activity of the cholinergic neurons in the septalhippocampal pathway. 

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