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Neurotransmission:
The brain is arguably the most fascinating and complex organ of the human body. But, understanding fundamental neuronal anatomy and mechanisms of communication is essential to the study of psychopharmacology, pathogeneses of brain disorders, and the basis of drug addiction and abuse. In 1921, Dr. Otto Loewi of Austria provided strong support for the concept of chemical transmission known as synapses by experimenting with frog hearts. He proved that rather than direct nerve stimulation, chemical substances mediated characteristic changes of function in the heart. He and his successors extended the neuro-chemical mechanism to other organs, muscles, glands. Though the synapse theory has evolved to include processes far more complex than most neuroscientists anticipated, chemicals irrefutably control the behavior of neurons. Neurons are generally composed of many branching dendrites to receive signals; a soma or cell body to store genetic information in the nucleus and for protein synthesis; and a long axon to relay electrochemical signals to other neurons, specifically, at the axonal apex, the terminal button. Chemicals messengers, termed neurotransmitters, such as norepinephrine (NOR) and acetylcholine (ACh), are created in the soma, transported across down the axon via a microtublar network, encapsulated in synaptic vesicles by plasma membranes, and housed in the terminal button ready for release. But, an electrochemical phenomenon must first occur to trigger neurotransmitter release, an action potential. The permeability of axonal plasma membranes and varying concentration of charges substances (ions) cause electrostatic pressures and diffusion gradients in extracellular relative to intraceullar conditions. Organic ions are negatively charges and reside online inside the cell. Since such ions cannot cross the membrane, the internal conditions are negative; in fact, the membrane resting potential is at -70mV. Potassium ions (K+) are concentrated inside the axon. The forces of diffusion cause a potential for K+ to enter the extracellular membrane, but since the extracellular fluid is more positively charged, electrostatic pressure causes it to remain inside the axon. Sodium ions (Na+) are mainly found outside the cell, therefore it is pushed inside the cell by diffusion, and the negative charge inside the cell attracts Na+ molecules. ATP driven Na+-K+ transporters or pumps maintain the electrochemical gradient by pushing three ions of Na+ for every two K+ they push in. Messages are transmitted down the axon by way of an electrochemical event called an action potential. With enough electrical current, Na+ channels open in the axon allowing free flow Na+ inside the cell. There is a rapid change in the membrane potential from -70 mV to +40 mV (depolarization). K+ channels, which require greater depolarization (are less sensitive) and react later than Na+ channels, open and K+ leaves the cell. At the action potential peak, Na+ channels become refractory – blocked and will not re-open until the resting potential is reached – therefore no more Na+ enters the cell. The intracellular positive charge drives out K+ by both diffusion and electrostatic pressure. As the membrane potential returns to its standard value, the K+ channels close. There is a short hyperpolarization and return to resting membrane potential of -70 mV after extra K+ diffuses away. Axons may be covered by a non-continuous myelin sheath that provides intra-axonal insulation, where bare portions are called nodes of Ranvier. The action potential travels uninterrupted down the axon in unmyelinated axons. However, ions in myelinated axons pass through the membrane only at the nodes, for myelin covers the axon from extracellular fluid. By bypassing many Na+-K+ transporters, this process saves significant energy and accelerated the speed of transmission. At each node, a new action potential is triggered. When an action potentials runs down the axon, voltage-dependent calcium (Ca++) channels open, allowing Ca++ to enter the cell. Ca++ subsequently binds to proteins of the synaptic vesicles resting on the release zone of the terminal, where by a process of exocytosis, releases its contents into the synaptic clef – the small area separating the junction the terminal button of one neuron and the membrane (neuronal, muscle, or gland cell). Neurotransmitters bind to special sites on the postsynaptic membrane called postsynaptic receptors. Neurotransmitter-dependent ion channels open causing either excitatory or inhibitory postsynaptic potentials, dependent on the ion species involved. When Na+ channels open, Na+ molecules enter, depolarization occurs, and an excitatory postsynaptic potential (EPSP) is created. Likewise, Ca++ generates EPSPs in addition to key physiological changes in the cell. Inhibitory postsynaptic potentials (IPSP) are due to K+ exit or Cl- entry in to the cell. The postsynaptic potential is quickly terminated by one of two avenues: enzymatic metabolism/deactivation of ACh by ACh-esterase or by reuptake – active transporters on the presynaptic terminal button draw neurotransmitters from the synaptic cleft into the cell.
Shaheen Emmanuel Lakhan © 2005 |
