Cholinergic neurons acetylcholine synthesis

Acetylcholine synthesis and neurotransmission requires normal functioning of two active transport mechanisms. Choline acetyltransferase (ChAT) is the enzyme responsible for ACh synthesis from the precursor molecules acetyl coenzyme A and choline. ChAT is the neurochemical phenotype used to define cholinergic neurons although ChAT is present in cell bodies, it is concentrated in cholinergic terminals. The ability of ChAT to produce ACh is critically dependent on an adequate level of choline. Cholinergic neurons possess a high-affinity choline uptake mechanism referred to as the choline transporter (ChT in Fig. 5.1). The choline transporter can be blocked by the molecule hemicholinium-3. Blockade of the choline transporter by hemicholinium-3 decreases ACh release,... 

Varicosity showing processes of synthesis and storage of acetylcholine within a cholinergic neuron. Also shown are the release of acetylcholine (exocytosis) and the location of acetylcholinesterase, which inactivates acetylcholine. 

The processes involved in neurochemical transmission in a cholinergic neuron are shown in Figure 9.2. The initial substrates for the synthesis of acetylcholine are glucose and choline. Glucose enters the neuron by means of facilitated transport. There is some disagreement as to whether choline enters cells by active or facilitated transport. Pyruvate derived from glucose is transported into mitochondria and converted to acetylcoenzyme A (acetyl-CoA). The acetyl-CoA is transported back into the cytosol. With the aid of the enzyme choline acetyl-transferase, acetylcholine is synthesized from acetyl-CoA and choline. The acetylcholine is then transported into and stored within the storage vesicles by as yet unknown mechanisms. 

Cholinesterase inhibitors cross the blood-brain barrier and decrease enzymatic hydrolysis of acetylcholine in the synaptic cleft, thereby increasing acetylcholine availability for neurotransmission. The rationale for using cholinergic agents to treat Alzheimer s disease stems from evidence of decreased cerebral choline acetyltrans-ferase (the enzyme responsible for acetylcholine synthesis) and cholinergic neuron loss in the nucleus basalis of Meynert, which correlate with plaque formation and cognitive impairment (Arendt et al. 1985 Davies and Maloney 1976 Etienne et al. 1986 Perry et al. 1978b). 

Administration of presynaptically active antagonists, i.e., substances that may trigger the synthesis and increased release of acetylcholine by presynaptic cholinergic neurons. It appears that this approach has not been tested systematically yet. 

Acetylcholine synthesis. Acetylcholine (ACh) is a prominent neurotransmitter, which is formed in cholinergic neurons from two precursors, choline and acetyl coenzyme A (AcCoA) (Fig. 12—8). Choline is derived from dietary and intraneuronal sources, and AcCoA is synthesized from glucose in the mitochondria of the neuron. These two substrates interact with the synthetic enzyme choline acetyltransferase to produce the neurotransmitter ACh. 

Acetylcholine is destroyed too quickly and completely by AChE to be available for transport back into the presynaptic neuron, but the choline that is formed by its breakdown can be transported back into the presynaptic cholinergic nerve terminal by a transporter similar to the transporters for other neurotransmitters discussed earlier in relation to norepinephrine, dopamine, and serotonin neurons. Once back in the presynaptic nerve terminal, this choline can be recycled into acetylcholine synthesis (Fig. 12—8). 

Synthesis of acetylcholine Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by a carrier system that cotransports sodium and can be inhibited by the drug hemicholinium. Choline acetyltransferase (CAT) catalyzes the reaction of choline with acetyl CoA to form acetylcholine in the cytosol. 

Synthesis and release of acetylcholine from the cholinergic neuron... 

Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons (p. 37), except that norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission takes place at numerous beadlike enlargements called varicosities the process involves five steps the synthesis, storage, release, and receptor binding of the norepinephrine, followed by removal of the neurotransmitter from the synaptic gap (Figure 6.3). 

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. 

The rates of synthesis of the neurotransmitters serotonin, acetylcholine, and probably also norepinephrine depend physiologically on the availability to the brain of their precursor molecules, the nutrients tryptophan, choline, and tyrosine, respectively. The brain concentration of each precursor can rapidly be influenced by the diet food ingestion thus readily modifies the synthesis of each of these neurotransmitters in brain. Brain neurons that utilise serotonin, acetylcholine, or norepinephrine are involved in neuronal networks that control a number of body functions and behaviours for example, appetite, food choice, sleep, memory, and mood). Thus dietary constituents are able normally to affect these functions and, when given as large doses of pure nutrients, to serve as treatments for brain diseases involving monoaminergic or cholinergic neurons. 

FIGURE 5.2 (See color insert following page 46.) Presynaptic and postsynaptic regions of the acetylcholine neuron, emphasizing the synthesis and degradation of acetylcholine and the cholinergic receptor suhtypes (Panel [A]) summary of the peripheral nervous system that utilizes acetylcholine as the transmitter (Panel [ B]). 

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