Acetylcholine brain concentrations

Acetylcholine is synthesised in nerve terminals from its precursor choline, which is not formed in the CNS but transported there in free form in the blood. It is found in many foods such as egg yolk, liver and vegetables although it is also produced in the liver and its brain concentration rises after meals. Choline is taken up into the cytoplasm by a high-affinity (Am = 1-5 pM), saturable, uptake which is Na+ and ATP dependent and while it does not appear to occur during the depolarisation produced by high concentrations of potassium it is increased by neuronal activity and is specific to cholinergic nerves. A separate low-affinity uptake, or diffusion (Am = 50 pM), which is linearly related to choline concentration and not saturable, is of less interest since it is not specific to cholinergic neurons. 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Atropine has been found -Ob to reduce markedly the increase in the concentration of total brain acetylcholine In rats later given paraoxon at 0.4 mg/kg. Rats given a dose of paraoxon and than treated with IV lntraperltoneally had brain concentrations of free and total acetylcholine that were essentially the same as those in rats given paraoxon alone, but no tremors or convulsions were observed. These animals survived those given paraoxon alone all died in convulsions within 3-8 min. 

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. 

It was soon found that the administration of choline, by injection or as a constituent of the diet, caused major sequential elevations in serum choline, brain choline, and brain acetylcholine levels. Concentrations of the neurotransmitter were shown to rise within all... 

Most AChR studies were done using skeletal muscle or torpedo tissues. The acetylcholine receptor concentration in the brain is very small, but it is present. Recently, the AChR in the brain has been actively studied using snake postsynaptic neurotoxins. Some of these are rather typical neurotoxins that bind to both skeletal muscles and the brain, and some of them are specific to the brain AChR. Since a brain a-subunit of AChR binds to a-btx, there must be a similarity between the toxin-binding site for the brain AChR and the muscle AChR (McLane et al., 1990 Scheidler et al., 1990). 

Acetylcholine is a neurotransmitter at the neuromuscular junction in autonomic ganglia and at postgangHonic parasympathetic nerve endings (see Neuroregulators). In the CNS, the motor-neuron collaterals to the Renshaw cells are cholinergic (43). In the rat brain, acetylcholine occurs in high concentrations in the interpeduncular and caudate nuclei (44). The LD q (subcutaneous) of the chloride in rats is 250 mg/kg. 

Nicotine increased DA levels both in vivo11,193 and in vitro. 94 196 Nicotine197 and its metabolites198 were found to both release and inhibit the reuptake of DA in rat brain slices, with uptake inhibition occurring at a lower concentration than that required for DA release. In addition, the (-) isomer was more potent than the (+) isomer.197 However, the effects of nicotine upon DA release and uptake were only apparent when brain slices were utilized because nicotine was unable to affect DA when a synaptosomal preparation was utilized.197 These results indicate that nicotine exerts its effects upon the DAT indirectly, most likely via nicotine acetylcholine receptors. This finding was supported by the results of Yamashita et al.199 in which the effect of nicotine on DA uptake was examined in PC 12 and COS cells transfected with rat DAT cDNA. Nicotine inhibited DA uptake in PC 12 cells that possess a nicotine acetylcholine receptor. This effect was blocked by the nicotinic antagonists hexamethonium and mecamylamine. Additionally, nicotine did not influence DA uptake in COS cells, which lack nicotinic acetylcholine receptors. 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

Inhaled nicotine is efficiently delivered to the brain (see chapter by Benowitz, this volume) where it selectively interacts with its central targets, the neuronal nicotinic acetylcholine receptors (nAChRs). The multiple subtypes of uAChR (see chapter by Collins et al, this volume) all bind nicotine but with different affinities, depending on the subunit composition of the uAChR. Binding may result in activation or desensitisation of uAChRs, reflecting the temporal characteristics of nicotine dehvery and local concentration of nicotine. Another level of complexity of the actions of nicotine reflects the widespread and non-uniform distribution of uAChR subtypes within the brain, such that nicotine can influence many centrally regulated functions in addition to the reward systems. In this chapter, we address the consequences of nicotine interactions with nAChRs at the molecular, cellular and anatomical levels. We critically evaluate experimental approaches, with respect to their relevance to human smoking, and contrast the acute and chronic effects of nicotine. 

Studies of brain mechanisms have tended to focus primarily on structures associated with the mesolimbic DA pathway. Ideally, all brain regions with major concentrations of nicotinic acetylcholine receptors should be probed with nicotinic... 

The only known change in neurotransmitter metabolism so far detected is a deficiency of acetylcholine in the brain. This has been shown in post-mortem studies on the brains of patients with Alzheimer s disease. Some success in reducing the symptoms of the disease has been obtained with drugs that inhibit the activity of acetylcholinesterase leading to an increase in the acetylcholine concentration, but the improvement is minimal so that its use is controversial. 

GABA is also present in very high concentrations in the mammalian brain, approximately 500 jUg/g wet weight of brain being recorded for some regions Thus GABA is present in a concentration some 200-1000 times greater than neurotransmitters such as acetylcholine, noradrenaline and 5-HT. 

These amino acid transmitters are predominant, accounting for most of the fast synaptic transmission in the brain. Together they occur in 70-80% of cerebral neurons. The concentration of GABA is for example up to 1000 times greater than that of other transmitters like acetylcholine or dopamine. 

The psychological effects of cannabis are due to cannabinoids such as A -tetrahydrocannabinol (THC) which interact with specific cannabinoid receptors in the brain (Devane et al.,1988 Matsuda et al., 1990). The functions of these receptors are not known but high concentrations are present in sensory and limbic areas, and THC also increases dopamine release from the nucleus accumbens and frontal cortex (Tanda et al., 1987) and decreases the release of acetylcholine (Trzepacz, 2000). 

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