PRINCIPLES OF TOXICOLOGY - Biology East Borneo

146 NEUROTOXICITY: TOXIC RESPONSES OF THE NERVOUS SYSTEM• Chemicals may disrupt the electrical impulse along the axon, either by harming the myelinsheath or membrane integrity, or by impairing the synthesis or functioning of proteinsessential to axonal transport.• Chemicals may also inhibit the neurotransmitters by blocking their synthesis, release, orbinding to receptors.• General protein synthesis impairment may have an effect not only on neurotransmitterproduction, but also the production of important enzymes which break down neurotransmitterswhen they are no longer needed.We will next consider the mechanisms of electrical and chemical signal transmission through thenervous system in more detail. The reader should keep in mind that proper nervous system functiondepends on all steps in signal transmission working properly, and a disruption in any step may resultin what would be described as a neurotoxic effect.7.1 MECHANISMS OF NEURONAL TRANSMISSIONIn one sense, the nervous system is little more than an enormous network of interconnected nerve cells,or neurons, supported by various other auxilliary cell types. However, this description is deceptive inits simplicity. Neurons come in many shapes, sizes, and functions, but may be generically describedas having dendrites, a cell body, and an axon. The dendrites receive chemical signals from an adjacentneuron. These signals then trigger electrical impulses along the axon and in turn stimulate the releaseof more chemical signals at the terminal boutons. In this way, a stimulus may travel the entire lengthof the human body. The electrical impulse is often maintained along the length of the neuron with theaid of the myelin sheath, which acts as an insulator surrounding the axon. Successive neurons meet ata gap called the synapse, and it is across this gap that the chemical signals, or neurotransmitters, diffusefrom one neuron to the dendrites of the next. Alternatively, neurons may terminate at muscles or glands,releasing neurotransmitters to specialized receptors at these sites.It has been found that these basic features of the nervous system are similar throughout a widetaxonomic range. Most multicellular organisms possess some form of nervous system which includesneurons, neurotransmitters, and electrical signal conduction. This similarity provides us with substantialconfidence in using neurotoxicity test results in animals to predict neurotoxic effects in humans.The Action PotentialElectrical signals are initiated and propagated along the axon by what is called an action potential.The source of this potential is a charge difference across the nerve membrane, created by the movementof sodium (Na + ), potassium (K + ), and chloride (Cl – ) ions. This charge difference is determined by theselective permeability of the membrane, as well as concentration and potential gradients, and activetransport. When the membrane is at rest, the concentration of K + ions is greater inside the cell thanoutside, while the concentrations of Na + and Cl – are greater outside the cell. The concentrations of K +and Cl – ions counterbalance each other, and this balance is maintained against their concentrationgradients by the resulting potential gradient. Thus, in this equilibrium state, the tendency of either ionto diffuse across the membrane and down its concentration gradient is controlled by the imbalancecaused by the potential gradient. Meanwhile, the membrane is relatively impermeable to Na + , andtherefore a net positive charge exists on the outside of the cell relative to the inside (Figure 7.1a).When the cell is stimulated and an action potential is created, the membrane becomes locallypermeable to sodium, and an influx of positive charge occurs. The result is a depolarization of themembrane that is propagated down the axon as current flows ahead of the action potential, depolarizingthe membrane further (Figure 7.1b). Behind the action potential, the membrane permeability againshifts to favor K + movement and to decrease Na + movement. The resulting repolarization from the K +