Metabolic pathways acetylcholine

Costa, E., Tagliamonte, N., Brunello, N., and Cheney, D.L., Effects of stress on the metabolism of acetylcholine in the cholinergic pathways of extra pyramidal and limbic systems, in Catecholamines and Stress Recent Advances, Usdin, E., Kvetnansky, R., and Kopin, I. J., Eds., Elsevier, New York, 1980, 59. 

With such an extensive knowledge base, what is the present state of our understanding of the mechanisms of this disorder Not unexpectedly, initial studies, primarily in experimental animal models, focused on the known metabolic pathways which involve thiamine. Indeed, the classical studies of Peters in 1930 (Peters, 1969) showed lactate accumulation in the brainstem of thiamine deficient birds with normalization of this in vitro when thiamine was added to the tissue. This led to the concept of the biochemical lesion of the brain in thiamine deficiency. The enzymes which depend on thiamine are shown in Fig. 14.1. They are transketolase, pyruvate and a-ketoglutarate dehydrogenase. Transketolase is involved in the pentose phosphate pathway needed to form nucleic acids and membrane lipids, including myelin. The ketoacid dehydrogenases are key enzymes of the Krebs cycle needed for energy (ATP) synthesis and also to form acetylcholine via Acetyl CoA synthesis. Decrease in activity of this cycle would result in anaerobic metabolism and lead to lactate formation (i.e., tissue acidosis) (Fig. 14.1). 

Several metabolic pathways (e.g. hpid metabohsm, creatine and carnitine synthesis) require methyl groups and these can be snppUed by choline or methionine. During the process of transmethylation, betaine, a tertiary amine, is formed by the oxidation of choline. Betaine can be added to the diet to act as a more direct supply of methyl groups, thus sparing choUne for its other fimctions of lecithin and acetylcholine formation, and methionine for protein synthesis. Betaine occurs in sugar beet. 

The major action of acetylcholine is at post-synaptic membranes, so it is surprising that this transmitter affects phospholipid metabolism in isolated synaptosomes. As Fig. 2 indicates, a fragment of post-synaptic membrane is usually attached to synaptosomes, but this will not have access to the metabolic pathways involved in phospholipid synthesis. Transmission of the nerve impulse involves phospholipid changes in both pre-and post-synaptic membranes. L. E. Hokin (1969) concluded from pre-ganglionic denervation experiments with sympathetic ganglia that there was a pre-synaptic phosphatidic acid effect but that the phosphatidylinositol changes induced by acetylcholine were largely post-synaptic. 

This seventh edition includes discussions of neurotransmitters ranging from acetylcholine through other amines, amino acids, purines, peptides, steroids and lipids Whereas in most cases their metabolism and receptor interactions are known, much current research involves questions of identification of effector pathways, their regulation and control. 

Diacylglycerol, on the other hand, is lipid soluble and remains in the lipid bilayer of the membrane. There it can activate protein kinase C (PKC), a very important and widely distributed enzyme which serves many systems through phosphorylation, including neurotransmitters (acetylcholine, a,- and P-adrenoceptors, serotonin), peptide hormones (insulin, epidermal growth hormone, somatomedin), and various cellular functions (glycogen metabolism, muscle activity, structural proteins, etc.), and also interacts with guanylate cyclase. In addition to diacylglycerol, another normal membrane lipid, phos-phatidylserine, is needed for activation of PKC. The DG-IP3 limbs of the pathway usually proceed simultaneously. 

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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