Cholinergic synapse brain

The acute toxicity of organophosphorus (OP) compounds is usually attributed to their irreversible inhibition of acetylchohnesterase (AChE EC 3.1.1.7). The resultant increase in the level of acetylcholine at cholinergic synapses, particularly in brain and... 

When an action potential traveling down the axon of a motoneuron reaches the myoneural endplate, a process occurs that releases acetylcholine into the synaptic cleft and consequently depolarizes the postsynaptic membrane. A similar process probably occurs at cholinergic synapses in the central nervous system. In 1950 Fatt and Katz discovered a spontaneous subthreshold activity (MEPP) of motor nerve endings and were thereby led to the concept that acetylcholine is released in definite units (quanta) of 10 to 10 molecules. Electron microscopy subsequently revealed characteristic vesicles about 40 nm in diameter, clustered near presynaptic membranes. Subcellular fractionation procedures were devised by Whittaker and de Robertis for the isolation of these vesicles from brain homogenates in sucrose density gradients, and it was soon demonstrated that they were indeed concentrated reservoirs of acetylcholine. The hypothesis that the vesicles discharge the quanta of transmitter became irresistible. 

The function of acetylcholinesterase (AChE) is to degrade the neurotransmitter acetylcholine (ACh). "niere is general agreement that the acute toxicity of OP is explained by irreversible inhibition of AChE activity at cholinergic synapses (Chambers and Levi, 1992 McDonough and Shih, 1997 Mileson etal., 1998 Pope, 1999 Taylor, 2001 Casida and Quistad, 2004). Inhibition of AChE (>70%) leads to accumulation of ACh at central and peripheral sites. In the brain, overstimulation of ACh receptors can lead to seizures. Inhibition of the breathing center in the brain results in asphyxiation. In the diaphragm muscle, overstimulation of... 

Breer, H. (1987). Neurochemical aspects of cholinergic synapses in the insect brain. In Arthropod Brain. Its Evolution, Development, Structure and Functions (Gupta, A.P., Ed.), Wiley, New York, pp. 415-437. 

In light of this well-docnmented loss of cholinergic nerve terminals in certain brain areas of AD/SDAT patients, notably in the cerebral cortex and the hippocampns, there is an obvions need for an ACh replacement therapy in these diseases. Ideally, such therapeutic approaches should be selectively targeted at cholinergic synapses in the brain areas containing the degenerating ACh systems. 

The discovery of the loss of the cholinergic neurons and acetylcholine in the brain of Alzheimer s disease patients led to the use of drugs that would enhance the actions of acetylcholine in the brain. Therapeutic agents approved for the treatment of Alzheimer s disease are the cholinesterase inhibitors, drugs that block the breakdown of acetylcholine and increase the availability of the neurotransmitter in synapses (see Chapter 12). These drugs are palliative only and do not cure or prevent neurodegeneration. 

Nicotine is an addictive drug that activates a diverse subset of ionotropic acetylcholine receptors. Most cholinergic actions in brain, both by ionotropic and metabotropic receptors, are modulatory, and very few fast synapses exist that utilize... 

Manzoni O, Bockaert J (1995) Metabotropic glutamate receptors inhibiting excitatory synapses in the CA1 area of rat hippocampus. Eur J Neurosci 7 2518-23 Marchi M, Risso F, Viola C et al (2002) Direct evidence that release-stimulating a7 nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. J Neurochem 80 1071-8... 

---