Neurotransmitter
Neurotransmitter
Neurotransmitter characteristics
Neurotransmitters’ role in memory and learning
Neurotransmitters are chemical agents secreted at the end of axons of nerve cells that diffuse across the synaptic gap and transmit information to adjoining cells such as neurons, muscle cells, and glands by altering their electrical state or activity. There are many neurotransmitters with a variety of structures and functions; two of the principle ones are acetylcho-line and norepinephrine. Since neurotransmitters convey information, anything that affects their behavior affects the function of the organism.
Neurotransmitter function
Neurotransmitters are stored in tiny sac-like structures called vesicles at the end of axons. When an impulse, or nerve signal, reaches the end of the axon, the vesicles release a neurotransmitter into the small space between the adjoining cells (synaptic gap). Neurotransmitters diffuse across the synapse and bind to receptors in the receiving cell that are specific for the neurotransmitter. The kinds of reactions that occur in the receiving cell may vary. The cell may be excited and an action potential is set up and the impulse is transmitted; or the opposite effect may occur, and the cell will be inhibited from transmitting the impulse because it becomes hyperpolarized.
Neurotransmitters function by changing the permeability of the cell membrane to various ions such as sodium and potassium. If an excess of sodium ions flow into the nerve cell, an impulse is generated. If an excess of potassium ions flow out, the impulse is inhibited. Sometimes the receiving cell gets a number of different messages at the same time, and they can cancel one another.
Neurotransmitters coordinate behavior by their effects on receiving cells. The number and kind of neurotransmitter molecules received by the receptor cell, as well as the kind of receptor, determines whether the effect will be to stimulate or inhibit. If neurotransmitters were allowed to operate over a long period of time, the results would be disastrous for the organism since there would be a constant overload of messages being sent. One way in which the problem is solved is through enzymes that break down the neurotransmitter very rapidly. One such enzyme, acetylcholinesterase, can split one acetylcholine molecule every 40 microseconds.
Many organic phosphates, which are poisons, operate by inhibiting acetylcholinesterase, leading to prolonged muscle contractions. Other neurotransmitters, such as norepinephrine and dopamine, are removed when they are taken up again by the vesicles in the axon endings after their release, or they are broken down by monamine oxidase. Some early anti-depressant drugs, such as phenelzine and tranylcypro-mine, were monoamine oxidase (MAO) inhibitors, which allow neurotransmitters, like norepinephrine to have longer action and alleviate symptoms of depression. Significant side effects resulting from the alteration of neurotransmitter degradation has led to a decline in the use of MAO inhibitors in the treatment of clinical depression.
Neurotransmitter characteristics
The number of known neurotransmitters has increased tremendously over the past several years. One of the earliest ones studied was acetylcholine, the most common neurotransmitter found in both invertebrates and vertebrates. It is the stimulating agent for skeletal muscle cells, but is the inhibiting agent for heart muscle cells, which demonstrates that the action of a neurotransmitter is influenced by the target receptor cells.
Norepinephrine, a catecholamine, is a biogenic amine derived from the amino acid tyrosine. It often works in an opposite way from acetylcholine in the autonomic nervous system and is also found in the cerebrum, cerebellum, and spinal cord. Another catecholamine found in the brain is dopamine. It appears to be important in movement and regulating emotional responses. A widely distributed neurotransmitter, serotonin, is found in blood platelets, the lining of the digestive tract, and the brain. It causes very powerful contractions of smooth muscle, and is associated with mood, attention, emotions, and sleep.
Psychoactive drugs like LSD and mescaline mimic the structure and function of serotonin and other biogenic drugs to change the use’s mental state. Some new antidepressants, for example, allow lengthened serotonin activity. One very common drug, Prozac (Fluoxetine), is a selective serotonin reuptake inhibitor (SSRI). As the name implies, the drug inhibits the reuptake of serotonin from synaptic gaps, thus increasing neurotransmitter action in the brain, alleviating depressive symptoms.
Another amino acid derivative, gamma-amino-butyric acid (GABA) is a major inhibitory transmitter in the central nervous system that also seems to play a role in Huntington’s disease. In addition to the naturally occurring neurotransmitters, peptides such as opioids, which kill pain and cause sleepiness, also act as neurotransmitters. Recently, the gases nitric oxide and carbon monoxide have been discovered to be released from neurons. Nitric oxide diffuses to the nerves of the digestive system and governs the relaxation required for the normal movements of digestion.
Neurotransmitters and disease
Learning how neurotransmitters function has given scientists knowledge into the cause of some diseases, the effects of certain substances, and the behavior of organisms. Myasthenia gravis, a disease characterized by muscle weakness and fatigue, is caused by a disturbance in the action of acetylcholine on skeletal muscles; it is treated by drugs that enhance the effect of acetylcholine. The discovery that Parkinson’s disease causes dopa-mine-containing neurons in the brain to degenerate, leading to the characteristic shuffling gait and trembling in its victims, led to the use of levodopa, a compound that replaces dopamine.
Impairment of the dopamine system is also implicated in schizophrenia, a mental disease marked by disturbances in thinking and emotional reactions. Drugs, such as chlorpromazine and clozapine, that block dopamine receptors in the brain have been used to alleviate the symptoms. Depression, which afflicts about 3.5% of the population, is treated with antidepressants that affect norepinephrine and serotonin in the brain by correcting the abnormal excess or inhibition of signals that control mood, thoughts, pain, and other sensations. A new drug, fluoxetine, is a serotonin reuptake inhibitor that appears to establish the level of serotonin required to function at a normal level.
Alzheimer’s disease, which affects an estimated four million Americans, is characterized by memory loss and the eventual inability for self-care. The disease seems to be caused by a loss of cells in the basal forebrain that secrete acetylcholine. Some experimental drugs to alleviate the symptoms have been developed, but presently there is no known treatment for the disease.
Neurotransmitters and drugs
The rise of drug addiction has directed attention to the role of neurotransmitters by attempting to understand how it happens and how it can be counteracted. Cocaine and crack are psychostimulants that affect neurons containing dopamine in the limbic and frontal cortex of the brain; when used they generate a feelings of confidence and power. However, when large amounts are taken, users “crash” and suffer physical and emotional exhaustion as well as depression. Opiates such as heroin and morphine appear to mimic naturally occurring peptide substances in the brain with opiate activity called endorphins. Natural endorphins of the brain kill pain, cause sensations of pleasure, and cause sleepiness. Endorphins released with extensive aerobicexercise, for example, are responsible for the “rush” that long-distance runners experience.
Morphine and heroin are thought to combine with endorphin receptors in the brain, reducing natural endorphin production. As a result, the drugs are needed to replace the naturally produced endorphins and addiction may occur. Treatment often involves using drugs that mimic them, such as nalorphine, naloxone, and naltrexone. Probably the most-used depressant drug, alcohol is believed to cause its effects by interacting with the GABA receptor. Initially anxiety is controlled, but greater amounts reduce muscle control and delay reaction time due to impaired thinking.
Neurotransmitters’ role in memory and learning
One of the most exciting areas of research is the attempt to find out how learning and memory take place. One of the earliest researchers who attempted to explain learning and memory as a function of cellular change was Canadian psychologist Donald O. Hebb. He maintained that repeated firing of axons results in metabolic changes in the pre- and postsynaptic neurons. In other words, learning produces lasting chemical changes in nerve cells.
Aplysia, a marine snail with only 20,000 relatively large neurons, has been used to study the biological basis of learning. A conditioned reflex in Aplysia, has been shown to increase the release of a neurotransmitter that sets up a chain of reactions, one of which also increases the secretion of serotonin from a modulating neuron. In mammals the hippocampus, part of the forebrain, stores long-term memory for weeks before transferring it to the cerebral cortex. The transmitter used for long-term potentiation is the amino acid glutamate, which binds to receptors in the postsynaptic cell. This cell allows calcium to flow in and set up the activation of other molecules known as kinases.
A growing body of evidence implicates dopamine as an important chemical in regulating cell activity involved in working memory. Studies done with aged monkeys show that a deficiency in both dopamine and norepinephrine in the prefrontal cortex can induce a deficit in working memory. Injections of the deficient neurotransmitters restored memory function. Progress in deciphering the operation of the nervous system has helped increase knowledge of the diverse role of the neurotransmitter.
See also Chemoreception.
Resources
BOOKS
Campbell, N., J. Reece, and L. Mitchell. Biology. 5th ed. Menlo Park: Benjamin Cummings, Inc. 2000.
Carey, Joseph, ed. Brain Facts, A Primer on the Brain and the Nervous System. Washington, DC: Society for Neuroscience, 1993.
Raven, Peter H., and George B. Johnson. Biology. 3rd ed. St. Louis: Mosby Year Book, 1992.
KEY TERMS
Action potential— A transient change in the electrical potential across a membrane that results in the generation of a nerve impulse.
Axon— The threadlike projection of a neuron that carries an impulse away from the cell body of the neuron.
Catecholamine— Monoamines such as the neurotransmitters norepinephrine, serotonin, and dopamine that are synthesized from the amino acid, tyrosine, and have similar structures.
Conditioned reflex— A response in which one stimulus, the conditioned one, is associated with and elicits the same response as another stimulus, the unconditioned stimulus.
Dendrites— Branched structures of nerve cell bodies which receive impulses from axons and carry them to the nerve cell body.
Limbic system— Group of nuclei in the lower part of the forebrain involved in certain emotional and behavioral responses.
Monamine oxidase— An enzyme found in the brain and liver that breaks down catecholamines such as norepinephrine, serotonin, and dopamine.
Synapse— Junction between cells where the exchange of electrical or chemical information takes place.
Working memory— Memory that accesses and brings to mind information stored in long-term memory.
PERIODICALS
Fischbach, Gerald D. “Mind and Brain.” Scientific American 3 (1992): 48-57.
Golden, Frederic. “Mental Illness: Probing the Chemistry of the Brain.” Time 157 (January 2001).
Goldman-Rakic, Patricia S. “Working Memory and the Mind.” Scientific American 3 (1992): 110-117.
LeDoux, Joseph E. “Emotion, Memory, and the Brain.” Scientific American 6 (1994): 50-57.
OTHER
Indiana State University. “Biochemistry of Neurotransmitters” <http://web.indstate.edu/thcme/mwking/nerves.html> (October 7, 2006).
McGill University. “The Brain from Top to Bottom: Synapses” <http://www.thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana.html (accessed October 7, 2006).
Mary Finley
Neurotransmitters
NEUROTRANSMITTERS
The idea that nerve cells function as independent units and form a physical contact to facilitate intercellular communication was first proposed by neurobiologists at the turn of the twentieth century. This concept, termed the neuron theory of brain function, is based on the knowledge that the nervous system is not made up of a contiguous labyrinth of intertwining processes but instead represents a collection of neurons, together with their axons and dendrites, that form close functional contacts to permit the transfer of information from one cell to another. The site at which the contact between two neurons is made is called the synapse; and the chemical signal that is used for mediating communication between neurons is the neurotransmitter.
For both the central and peripheral nervous system there are a relatively small number of molecules that fulfill the criteria of a neurotransmitter. These include dopamine (DA), norepinephrine (NE), epinephrine, serotonin, histamine, acetylcholine (Ach), gamma-amino butyric acid (GABA), glycine, and glutamate. During development the nervous system takes on the responsibility for controlling a variety of body functions including movement, consciousness, learning and memory, and sensory processing. A fully competent nervous system is essential for maintaining the integrity of body functions in adulthood while an aging nervous system has often been coupled with an irreversible loss of global function. However, this oversimplified picture of brain aging is far from the truth. Research conducted since the early 1980s has indicated that an age-related decline in neurotransmitter function is not a global phenomenon. Instead, studies have reported that just as organisms age at different rates, so do the different neurotransmitter systems in their bodies; and that wide differences in neurotransmitter levels exist in the brain between individuals of like age. This divergence between biological and chronological old age is most obvious in the human population but is also found in aged rodents and nonhuman primates. Functional variability with age is tied closely to the variability in the biochemical and anatomical changes found in different neurotransmitter systems of the brain and is unquestionably linked to genetic and environmental factors that influence the "rate" at which we age. Thus, the degree to which age-related anatomical and biochemical changes occur in neurotransmitter systems of the brain can be described as variable at best.
When investigating age-related alterations in neurotransmitter function it is important to realize that a decline of a particular neurotransmitter does not always equate with a loss in physiological function. Previous studies have reported that age-related changes in the brain cannot be represented by simple cell loss that leads to functional decline. Rather, it is understood that the aging brain represents a composite of various adaptive and compensatory responses, which work together to maintain and repair the brain's neural networks in response to naturally occurring cell loss or neurochemical deficits that are brain region, cell type, and species specific. In addition, it is important to distinguish between changes in neurotransmitter systems that are seen in normal aging with that characteristic of the diseased state. While it was once believed that neurodegenerative diseases such as Alzheimer's and Parkinson's disease were part of an accelerated aging process it is now known that the neuropathology of the diseased brain represents extensive neuronal degeneration and cell death that goes beyond normal aging. In fact anatomical studies with sophisticated neuronal counting techniques indicate that the degree of neuron loss in the aged brain is quite low and age-related changes ascribed to neurotransmitter neurons may not affect our activities of daily living until we are well into our late seventies or eighties.
If global neurodegeneration and cell death are not characteristic of neurotransmitter neurons then what are the changes seen in neurotransmitter neurons with increased age? To answer this question we must consider that changes can occur in either the presynaptic or postsynaptic components involved in information transfer. Age-related changes in the presynaptic components can include changes in neurotransmitter synthesis, storage, synaptic release, and neurotransmitter re-uptake. Changes in postsynaptic components include changes in neurotransmitter receptors (protein complexes that bind neurotransmitters), secondary messenger systems (responsible for transfer of information into neurons), and enzymes involved in neurotransmitter degradation. The following is a brief overview of the age-related changes that have been described for the four most common neurotransmitters found in the central and peripheral nervous system.
Acetylcholine
The neurotransmitter acetylcholine is important for communication in a number of brain regions, particularly the hippocampus, striatum, and cerebral cortex. It is also the neurotransmitter used to transmit information at the neuromuscular junction. Acetylcholine is synthesized presynaptically by the enzyme choline acetyltransferase (CAT). Absolute levels of CAT and its activity decline with age, ranging from a 20 to 30 percent decline in the hippocampus and striatum and about a 10 percent decline in the cerebral cortex. Within these same anatomical regions there is evidence of some neuron cell loss, but it does not necessarily account for total decline in neurotransmitter production. It is interesting that the loss of CAT activity can be reversed or attenuated. For example, increased production of neurotrophic factors (which themselves are regulated by exercise and diet) influence CAT activity and acetylcholine production. In addition to these presynaptic changes, postsynaptic alterations have also been documented. For example, the muscarinic acetylcholine receptor, the synaptic receptor protein that binds acetylcholine, has been shown to decline by similar degrees in areas where CAT activity is also diminished. However, it remains to be determined whether this is the cause of the neurotransmitter deficiency or a consequence in response to presynaptic changes. Despite the fact that global neuron cell death may not underlie specificity of neurotransmitter system decline, some studies, but not all, have suggested that altered cholinergic neurotransmission may also be accompanied by a decline in the number or size (atrophy) of cholinergic neurons, including those in the nucleus basalis. The best example of a neurodegenerative disease associated with the loss of cholinergic neurons is Alzheimer's disease.
Dopamine
Dopamine is the primary neurotransmitter in the basal ganglia (i.e., striatum, substantia nigra) and to a lesser extent in the cerebral cortex. In normal aging there are presynaptic alterations including decline of dopamine in the striatum, decreased dopamine metabolites (indicated by decreased dopamine biosynthesis), as well as postsynaptic alterations including decreased dopamine receptors. As summarized in the review by Morgan and Finch, the decline in the DA content and TH activity of the substantia nigra and striatum of aged rodents is not a consistent finding across rodent species and is generally smaller than that reported for nonhuman primate and postmortem human brains. Similarly, for dopamine cell loss, while it has been reported that normal aging is not associated with a significant decline in the total number of DA neurons of the substantia nigra in aged mice, controversy exists as to the degree DA cell loss occurs in the substantia nigra of nonhuman primates and man. It is interesting that despite the fact that there are presently five different classes of dopamine receptors, the decline in the D2 receptor is the only one that has been reported to show an age-related decline across species. The reasons for this variability are yet unclear. Other age changes seen in the dopaminergic system included decreased dopamine transporter (responsible for uptake of dopamine from the synapse) and increased monoamine oxidase B (an enzyme that breaks down dopamine resulting in reduced effective synaptic levels of dopamine). The prime example of a neurogenerative disease associated with the loss of dopamine neurons is Parkinson's disease.
GABA and glutamate
GABA and glutamate are both metabolic intermediates and neurotransmitters. GABA is considered the major inhibitory neurotransmitter in the brain, whereas glutamate is considered an excitatory neurotransmitter that promotes a postsynaptic stimulatory response. In the aged brain glutamic acid decarboxylase (GAD), the enzyme that converts glutamate into GABA, falls 20–30 percent in the cortex and thalamus of postmortem human brain, and there is a decrease in GABA receptor binding sites and GAD mRNA levels in the aged rodent brain. Similarly, previous studies have reported an age-related decrease in glutamate receptors in the hippocampus of aged rats, mice, and nonhuman primates while no change in glutamate receptor binding sites has been found in postmortem human brains. Huntington's disease is the classic example of a neurodegenerative disease linked to the loss of GABA neurons in the striatum.
To summarize, while there is little doubt that degenerative changes occur in neurons of the aged brain the severity of these changes vary from person to person, and the question of cause and effect remains elusive. In addition, previous studies have shown that age-related changes in the neurotransmitter systems of the brain are not a global phenomenon of normal aging but are brain region, cell type, and species specific. Species variability is well documented in the gerontologic literature, and we must be cautious in our interpretations when comparing data across animal species or when comparing cellular changes in animals and human aging. Lastly, it is no longer possible to associate brain aging with the loss of function and structure without taking into consideration the compensatory or plastic nature of the nervous system. Rather, it is understood that the aging brain represents a composite of various adaptive and compensatory responses, which work together to maintain neurotransmitter levels in the brain and repair the brain's neural networks in response to naturally occurring cell loss or neurochemical changes that are brain region specific.
Thomas H. McNeill Michael Jakowec
See also Neurochemistry.
BIBLIOGRAPHY
Collier, T. J., and Coleman, P. D. "Divergence of Biological and Chronological Aging: Evidence from Rodent Studies." Neurobiology of Aging 12 (1991): 685–693.
Finch, C. E., and Roth, George S. "Biochemistry of Aging." In Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Edited by G. J. Siegel, B. W. Agranoff, R. W. Albers, S. K. Fisher, and M. D. Uhler. Philadelphia: Lippincott-Raven, 1999. Pages 614–633.
Morgan, D. G., and Finch, C. E. "Dopaminergic Changes in Basal Ganglia: A Generalized Phenomenon of Aging in Mammals." Annals of the New Academy of Science 515 (1988): 145–160.
Wang, E., and Snyder, D. S. Handbook of the Aging Brain, San Diego, Calif.: Academic Press, 1998.
NORMAL AGING
See Physiological changes
Neurotransmitter
Neurotransmitter
Neurotransmitters are chemical agents secreted at the end of axons of nerve cells that diffuse across the synaptic gap and transmit information to adjoining cells such as neurons, muscle cells, and glands , by altering their electrical state or activity. There are many neurotransmitters with a variety of structures and functions; two of the principle ones are acetylcholine and norepinephrine. Since the neurotransmitters convey information, anything that affects their behavior affects the function of the organism .
Function of neurotransmitters
The neurotransmitters are stored in tiny sac-like structures called vesicles at the end of axons. When an impulse, or nerve signal, reaches the end of the axon, the vesicles release a neurotransmitter into the small space between the adjoining cells (synaptic gap). Neurotransmitters diffuse across the synapse and bind to receptors in the receiving cell that are specific for the neurotransmitter. The kinds of reactions that occur in the receiving cell may vary. The cell may be excited and an action potential is set up and the impulse is transmitted; or the opposite effect may occur, and the cell will be inhibited from transmitting the impulse because it becomes hyperpolarized. Neurotransmitters function by changing the permeability of the cell membrane to various ions such as sodium and potassium. If an excess of sodium ions flow into the nerve cell, an impulse is generated. If an excess of potassium ions flow out, the impulse is inhibited. Sometimes the receiving cell receives a number of different messages at the same time, and they can cancel one another out. By their effects on the receiving cells, neurotransmitters coordinate behavior. The number and kind of neurotransmitter molecules received by the receptor cell, as well as the kind of receptor, determines whether the effect will be to stimulate or to inhibit. If neurotransmitters were allowed to operate over a long period of time, the results would be disastrous for the organism since there would be a constant overload of messages being sent. One way in which the problem is solved is through enzymes which break down the neurotransmitter very rapidly. One enzyme , acetylcholinesterase, can split one acetylcholine molecule every 40 microseconds. Many organic phosphates, which are poisons, operate by inhibiting acetylcholinesterase which leads to prolonged muscle contractions. Other neurotransmitters, such as norepinephrine and dopamine , are removed when they are taken up again by the vesicles in the axon endings after their release, or they are broken down by monamine oxidase. Some of the first anti-depressant drugs created were monoamine oxidase inhibitors (MAO inhibitors) such as phenelzine or tranylcypromine. MAO inhibitors inhibit the action of monoamine oxidase, thus allowing neurotransmitters, like norepinephrine, to have longer action. In this way, MAO inhibitor antidepressants are believed to alleviate symptoms of depression . Significant side effects resulting from the alteration of neurotransmitter degradation has led to a decline in the use of MAO inhibitors in the treatment of clinical depression.
Characteristics of neurotransmitters
The number of known neurotransmitters has increased tremendously over the past several years. One of the earliest ones studied was acetylcholine, the most common neurotransmitter found in both invertebrates and vertebrates . It is the stimulating agent for skeletal muscle cells, but is the inhibiting agent for heart muscle cells, which demonstrates that the action of a neurotransmitter is influenced by the target receptor cells. Norepinephrine, a catecholamine, is an example of a biogenic amine, which is derived from the amino acid tyrosine. It often works in an opposite way from acetylcholine in the autonomic nervous system and is also found in the cerebrum, cerebellum and spinal cord. Another catecholamine found in the brain is dopamine. It appears to be important in movement and regulating emotional responses. A widely distributed neurotransmitter, serotonin, is found in blood platelets, the lining of the digestive tract, and the brain. It causes very powerful contractions of smooth muscle, and is associated with mood, attention, emotions, and sleep . LSD and mescaline, psychoactive drugs, mimic the structure and function of serotonin and other biogenic drugs to change the mental state of the user. Some new anti-depression drugs, for example, allow lengthened serotonin activity. One very common drug, Prozac (Fluoxetine), is a selective serotonin re-uptake inhibitor (SSRI). As the name implies, the drug inhibits the re-uptake of serotonin neurotransmitter from synaptic gaps, thus increasing neurotransmitter action. In the brain, then, the increased serotonin activity alleviates depressive symptoms. One of the other amino acid derivatives, GABA (gamma-aminobutyric acid) is a major inhibitory transmitter in the central nervous system and it seems to play a role in Huntington's disease . In addition to the well known neurotransmitter, there are peptides, such as the opioids involved in killing pain and causing sleepiness, that act as neurotransmitters. Recently, certain gases, nitric oxide and carbon monoxide , have been discovered to be released from neurons. Nitric oxide has been found to diffuse to the nerves of the digestive system and govern the relaxation required for the normal movements of digestion.
Neurotransmitters and disease
Interest in the neurotransmitter is based on evidence that knowledge of how they function provides insight into the cause of some diseases, the effects of certain substances, and the behavior of organisms. Myasthenia gravis, which is a disease characterized by weakness of muscles and fatigue, is caused by a disturbance in the action of acetylcholine on skeletal muscles and is now treated by drugs that enhance the effect of acetylcholine. The discovery that dopamine-containing neurons in the brain of Parkinson's disease victims degenerate, which results in the shuffling gait and trembling characteristic of the disease, led to the use of levodopa, a compound that replaces dopamine.
Impairment of the dopamine system is also implicated in schizophrenia , a mental disease marked by disturbances in thinking and emotional reactions. Drugs, such as chlorpromazine and clozapine, that block dopamine receptors in the brain have been used to alleviate the symptoms and help patients return to a normal social setting. Depression, which afflicts about 3.5% of the population, is treated with antidepressants that affect norepinephrine and serotonin in the brain. The antidepressants help correct the abnormal excess or inhibition of signals that control mood, thoughts, pain, and other sensations. A new drug, fluoxetine, is a serotonin reuptake inhibitor which appears to establish the level of serotonin required to function at a normal level.
Alzheimer disease , which affects an estimated four million Americans, is characterized by memory loss and the eventual inability for self-care. The disease seems to be caused by a loss of cells in the basal forebrain which secrete acetylcholine. Some experimental drugs to alleviate the symptoms have been developed, but presently there is no known treatment for the disease.
Neurotransmitters and drugs
The rise of drug addiction has directed attention to the role of neurotransmitters by attempting to understand how it happens and how it can be counteracted. Cocaine and crack are psychostimulants that affect neurons containing dopamine in the limbic and frontal cortex of the brain; when they are used they generate a feelings of confidence and power. However, when large amounts are taken, people "crash" and suffer from physical and emotional exhaustion as well as depression. Opiates such as heroin and morphine appear to mimic naturally-occurring peptide substances in the brain with opiate activity called endorphins. Natural endorphins of the brain act to kill pain, cause sensations of pleasure, and cause sleepiness. Endorphins released with extensive aerobic exercise , for example, are responsible for the "rush" that long-distance runners experience.
It is believed that morphine and heroin combine with the endorphin receptors in the brain, resulting in reduced natural endorphin production. As a result, the drugs are needed to replace the naturally produced endorphins and addiction may occur. Attempts to counteract the effects involve using drugs that mimic them, such as nalorphine, naloxone, and naltrexone. One of the depressant drugs in widest use, alcohol , is believed to cause its effects by interacting with the GABA receptor. Initially anxiety is controlled, but greater amounts reduce muscle control and delay reaction time due to impaired thinking.
Neurotransmitters' role in memory and learning
One of the most exciting areas of research is the attempt to find out how learning and memory take place. One of the earliest researchers who attempted to explain learning and memory as a function of cellular change was the Canadian psychologist, Donald O. Hebb. He maintained that repeated firing of axons results in metabolic changes in the presynaptic and post synaptic neurons. In other words, learning produces lasting chemical changes in nerve cells.
Aplysia, a marine snail with only 20,000 relatively large neurons, has been used in studies to determine the biological basis of learning. A conditioned reflex in Apylsia has been shown to cause an increase in the release of a neurotransmitter that sets up a chain of reactions, one of which also increases the secretion of serotonin from a modulating neuron . In mammals , the hippocampus, part of the forebrain, stores long term memory for weeks before transferring it to the cerebral cortex. The transmitter used for long term potentiation is the amino acid, glutamate, which binds to receptors in the postsynaptic cell. This cell allows calcium to flow in and set up the activation of other molecules known as kinases. A growing body of evidence implicates the role of dopamine as one of the most important chemicals that regulate cell activity involved in working memory. Studies done with aged monkeys show that a deficiency in both dopamine and norepinephrine in the prefrontal cortex can induce a deficit in working memory. Injections of the deficient neurotransmitters restored memory function. Progress in deciphering the operation of the nervous system has helped to increase knowledge of the diverse role of the neurotransmitter.
See also Chemoreception.
Resources
books
BSCS Revision Team. Biological Science, A Molecular Approach. Lexington, MA: D.C. Heath & Co., 1990.
Campbell, Neil A. Biology. Menlo Park, CA: Benjamin/Cummings, 1987.
Campbell, N., J. Reece, and L. Mitchell. Biology. 5th ed. Menlo Park: Benjamin Cummings, Inc. 2000.
Carey, Joseph, ed. Brain Facts, A Primer on the Brain and theNervous System. Washington, DC: Society for Neuroscience, 1993.
Holtzman, Eric, and Alex B. Novikoff. Cells and Organelles. Philadelphia: Saunders College Publishing, 1984.
Kuffler, Stephen W., and John G. Nicholls. From Neuron toBrain. Sunderland, MA: Sinauer Associates, 1976.
Purves, Dale. Body and Brain, A Trophic Theory of Neural Connections. Cambridge, MA: Harvard University Press, 1988.
Raven, Peter H., and George B. Johnson. Biology. 3rd ed. St. Louis: Mosby Year Book, 1992.
periodicals
Fischbach, Gerald D. "Mind and Brain." Scientific American 3 (1992): 48-57.
Golden, Frederic. "Mental Illness: Probing the Chemistry of the Brain." Time 157 (January 2001).
Goldman-Rakic, Patricia S. "Working Memory and the Mind." Scientific American 3 (1992): 110-117.
LeDoux, Joseph E. "Emotion, Memory, and the Brain." Scientific American 6 (1994): 50-57.
Mary Finley
KEY TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .- Action potential
—A transient change in the electrical potential across a membrane which results in the generation of a nerve impulse.
- Axon
—The threadlike projection of a neuron that carries an impulse away from the cell body of the neuron.
- Catecholamine
—Monoamines such as the neurotransmitters norepinephrine, serotonin, and dopamine that are synthesized from the amino acid, tyrosine, and have similar structures.
- Conditioned reflex
—A response in which one stimulus, the conditioned one, is associated with and elicits the same response as another stimulus, the unconditioned stimulus.
- Dendrites
—Branched structures of nerve cell bodies which receive impulses from axons and carry them to the nerve cell body.
- Limbic system
—Group of nuclei in the lower part of the forebrain involved in certain emotional and behavioral responses.
- Monamine oxidase
—An enzyme found in the brain and liver which breaks down catecholamines such as norepinephrine, serotonin and dopamine.
- Synapse
—Junction between cells where the exchange of electrical or chemical information takes place.
- Working memory
—Memory that accesses and brings to mind information stored in longterm memory.
neurotransmitters
Du Bois Reymond, in 1877, declared that chemical or electrical transmission were the only two real alternatives, although there was no data to decide unequivocally between the two. In 1904 Elliot suggested that adrenaline might be the transmitter in the sympathetic nervous system, and in the next year a nicotine-like substance was postulated by Langley as the transmitter in motor nerves to muscles. Dixon, in 1907, tried to extract from a heart the neurotransmitter released by the vagus, measuring the effect of the extract on another heart, but reached no conclusions. It was 1921 before Loewi performed the celebrated experiment in which two beating frog hearts were superfused in series, the perfusate of the first flowing over the second. Stimulation of the vagus nerve to the first heart caused its beat to slow and, after a brief interval, the second heart slowed too. While this experiment did not prove that the substance flowing over from the first heart was released from the vagus nerve, clearly something chemical rather than electrical slowed the second heart.
In the 1930s Dale and his school in England showed that acetylcholine was the transmitter at motor nerve endings in skeletal muscle (neuromuscular junctions) and Cannon and his colleagues in the US demonstrated that an adrenaline-like substance was the transmitter in the sympathetic nervous system. These discoveries depended on the development of sensitive bioassays for transmitter substances. Dale was not convinced that the sympathetic neurotransmitter was adrenaline itself, because he demonstrated subtle differences between the responses to the transmitter and to adrenaline. Von Euler, in 1946, finally showed that the sympathetic neurotransmitter was noradrenaline (non-methylated adrenaline).
After this period there was a lull in which many thought that acetylcholine and noradrenaline were the only two neurotransmitters. After all, the transmitter at the neuromuscular junction in skeletal muscle, in the synapses in ganglia of the autonomic nervous system, and at the ends of parasympathetic nerve fibres was shown to be acetylcholine, and noradrenaline was the transmitter at sympathetic nerve endings. So all types of synapse appeared to be accounted for. There was also evidence that acetylcholine was a transmitter in the brain. Furthermore, by then, criteria for showing that an agent was a neurotransmitter had been laid down and these were quite difficult to fulfill, especially in complex situations like the neural pathways in the brain. These five criteria are demonstrations that show:(i) the putative transmitter is released when the nerve trunk is stimulated;(ii) application of the transmitter to the post-synaptic structure causes the same effect as nerve stimulation;(iii) the nerve fibres have a mechanism for making, storing, and releasing the transmitter;(iv) a mechanism is present for rapidly terminating the actions of the neurotransmitter; and(v) an appropriate antagonist is equally effective at blocking both neurotransmission and exogenous application of the neurotransmitter.
Consider how these criteria are met for acetylcholine and for noradrenaline. We have already seen that these two substances were detected by sensitive bioassays in perfusates from neuronally-stimulated systems. To meet the second criterion it is necessary to show identity of action of the neurotransmitter and exogenously-applied transmitter substance. While this was straightforward with acetylcholine, Dale's insistence that adrenaline was not the neurotransmitter was based on differences between the responses to adrenaline and to nerve stimulation. This was an essential step leading to the discovery of noradrenaline.
The third criterion is satisfied because nerves that release acetylcholine (cholinergic nerves) have an enzyme (choline acetyltransferase) in the nerve terminals that synthesizes acetylcholine from choline, while noradrenergic nerves have a series of enzymes that synthesize noradrenaline from the amino acid tyrosine. The enzymes are produced in the nerve cell bodies and pass down the axon to the nerve terminals in the so-called axoplasmic flow (they can travel a considerable distance — for example, from the spinal cord to the foot muscles).
With respect to the fourth criterion: after release of acetylcholine from the nerve terminals it is attacked by acetylcholine esterase, which breaks down the neurotransmitter to choline and an acetate group, thus quickly terminating its action at the muscle membrane receptors. The choline is taken up into the terminal and recycled.
The mechanism for terminating transmitter action is different in the noradrenergic system. Seventy per cent of the released noradrenaline is taken back up into the nerve terminals and stored for later reuse. The rest is metabolized either extracellularly or after uptake into the end organ.
We have seen earlier that there are specific antagonists for acetylcholine, which also antagonize the effects of cholinergic stimulation. Similarly there are antagonists, such as the b-blockers, which block both noradrenaline and noradrenergic stimulation, thus meeting the fifth criterion.
In 1934 Dale enunciated a principle which stated that a nerve liberates the same neurotransmitter at all its terminations. Thus if a nerve branches, each branch will release the same neurotransmitter. This principle has remained a truism and it would be difficult to imagine a nerve cell that could exclusively send a different set of synthetic enzymes, in the axoplasmic flow, down different branches. However, until relatively recently it was assumed that any one nerve produced only one type of neurotransmitter. As usual in science, advances arose when observations were made which failed to fit the established dogma. It was recognized that in some systems antagonists that were able to block exogenously applied transmitter were not able to block nerve stimulation completely. There was a residual activity with nerve stimulation that was resistant to the block. The term NANC transmission was coined, standing for ‘nonadrenergic non-cholinergic transmission’. As the responses to nerve stimulation were partially blocked by antagonists with known specificities, the corollary was that the nerve must liberate more than one transmitter, but would do so from all its branches. Thus the concept of co-transmission was born, in which nerve stimulation could, in some instances, co-release more than one transmitter. In the peripheral autonomic nervous system — at the site where the nerves reach the tissue that they act upon — a great number of NANC transmitters have been claimed including, among others, ATP, VIP (vasoactive intestinal peptide), 5-HT, GABA, and dopamine. Undoubtedly some of these substances are transmitters, but few have yet met all the five criteria required to confirm their bona fides.
What advantages might accrue from co-transmission? First, the small molecular weight transmitters (amine transmitters) and one of the peptide transmitters are likely to have very different kinetics (fast and slow effects). Secondly, the receptor targets for the two transmitters may have different locations, for example one on the end organ and the other on the nerve terminal itself, allowing feedback control and finally ‘traffic neuromodulation’. This last results from the different ways in which the peptide transmitters and amine transmitters are handled. The ‘machinery’ needed to synthesize peptides like VIP is considerable. Consequently, these transmitters are synthesized in the nerve cell body and pass to the terminal in the axoplasmic flow, where they are stored ready for release. If there is heavy traffic in the nerve then the supply of the peptide neurotransmitter will soon be depleted. It is more difficult to deplete the supply of amine transmitters, which are made in the nerve terminal itself, so the ratio of the two transmitters released by nerve impulses will change.
While the criteria for proving that a chemical agent acts as a neurotransmitter in the periphery are not easy to achieve, the technical difficulties in the brain and spinal cord are much greater. Here there is a mass of neural tissue with intricate interconnections and ramifications within the brain, as well as the connections made with incoming and outgoing neural pathways. However, there is overwhelming evidence for many neurotransmitters in the central nervous system, even though not all the five criteria above have been satisfied. Histochemical methods have been used to demonstrate the localization of neurotransmitters in particular types of nerve cells, coupled with electrophysiological methods in which the physiology of a single identified cell is studied with microelectrodes. Finally, it is now possible to suck a few nanolitres of intracellular substance (cytosol) from a single, identified neuron in a brain slice and to determine which genes are activated, including those coding for proteins associated with neurotransmission (receptors, enzymes, etc.). Useful information can also be obtained by a study of disease states. For example, there can be no doubt that a lack of dopamine transmission gives rise to Parkinson's disease. Evidence from post-mortem brains and comparison of the dopamine concentrations in normal and diseased brains locates the dopaminergic pathways involved in the disease.
A potential forty neurotransmitters have been postulated to exist in the brain, of which ten are of the amine type with a small molecular weight. The amine types include acetylcholine, noradrenaline, dopamine, 5-HT, and histamine, and there are also excitatory and inhibitory amino acids. Glutamate and aspartate are the principal fast-acting excitatory transmitters in the brain, while GABA and glycine are the main inhibitory transmitters. Initially there was great reluctance to accept that these simple amino acids could act as neurotransmitters. Identified neurons were excited or inhibited when these amino acids were squirted onto them from very fine micropipettes. However, the presence of a pharmacological response does not prove physiological relevance. The development of selective agonists and antagonists has, subsequently, established that the four amino acids are true neurotransmitters. The remaining thirty-odd neurotransmitters in the central nervous system are mainly peptides, but much more evidence is needed before their true roles are unravelled.
Alan W. Cuthbert
See also autonomic nervous system; neuromuscular junction; peptides; synapse.
Neurotransmitters
Neurotransmitters
Neurotransmitters are chemical messengers produced by the nervous systems of higher organisms in order to relay a nerve impulse from one cell to another cell. The two cells may be nerve cells, also called neurons, or one of the cells may be a different type, such as a muscle or gland cell. A chemical messenger is necessary for rapid communication between cells if there are small gaps of 20 to 50 nanometers (7.874 × 10−7–19.69 ×10−7 inches), called synapses or synaptic clefts, between the two cells. The two cells are referred to as either presynaptic or postsynaptic. The term "presynaptic" refers to the neuron that produces and releases the neurotransmitter, whereas "postsynaptic" refers to the cell that receives this chemical message.
Neurotransmitters include small molecules with amine functional groups such as acetylcholine , certain amino acids, amino acid derivatives, and peptides. Through a series of chemical reactions, the amino acid tyrosine is converted into the catecholamine neurotransmitters dopamine and norepinephrine or into the hormone epinephrine. Other neurotransmitters that are amino acid derivatives include γ -aminobutyric acid, made from glutamate, and serotonin, made from the amino acid tryptophan.
Peptide neurotransmitters include the enkephalins, the endorphins, oxytocin, substance P, vasoactive intestinal peptide, and many others. The gaseous free radical nitric oxide is one of the more recent molecules to be added to the list of possible neurotransmitters. It is commonly believed that there may be fifty or more neurotransmitters. Although there are many
different neurotransmitters, there is a common theme by which they are released and exert their actions. In addition, there is always a mechanism for termination of the chemical message.
General Mechanism of Action
Neurotransmitters are formed in a presynaptic neuron and stored in small membrane-bound sacks, called vesicles , inside this neuron. When this neuron is activated, these intracellular vesicles fuse with the cell membrane and release their contents into the synapse, a process called exocytosis.
Once the neurotransmitter is in the synapse, several events may occur. It may (1) diffuse across the synapse and bind to a receptor on the postsynaptic membrane, (2) diffuse back to the presynaptic neuron and bind to a presynaptic receptor causing modulation of neurotransmitter release, (3) be chemically altered by an enzyme in the synapse, or (4) be transported into a nearby cell. For the chemical message to be passed to another cell, however, the neurotransmitter must bind to its protein receptor on the postsynaptic side. The binding of a neurotransmitter to its receptor is a key event in the action of all neurotransmitters.
Mechanism of Fast-Acting Neurotransmitters
Some neurotransmitters are referred to as fast-acting since their cellular effects occur milliseconds after the neurotransmitter binds to its receptor. These neurotransmitters exert direct control of ion channels by inducing a conformational change in the receptor, creating a passage through which ions can flow. These receptors are often called ligand -gated ion channels since the channel opens only when the ligand is bound correctly. When the channel opens, it allows for ions to pass through from their side of highest concentration to their side of lowest concentration. The net result is depolarization if there is a net influx of positively charged ions or hyperpolarization if there is a net inward movement of negatively charged ions. Depolarization results in a continuation of the nerve impulse, whereas hyperpolarization makes it less likely that the nerve impulse will continue to be transmitted.
The first ligand-gated ion channel whose structure and mechanism were studied in detail was the nicotinic acetylcholine receptor of the neuromuscular junction. This receptor contains five protein subunits, each of which spans the membrane four times. When two acetylcholine molecules bind to this receptor, a channel opens, resulting in sodium and potassium ions being transported at a rate of 107 per second. Acetylcholine's action at these receptors is said to be excitatory due to the resulting depolarization. Other receptors for fast transmitters have a similar amino acid sequence and are believed to have a similar protein structure. Glycine and γ -aminobutyric acid (GABA) also act on ligand-gated ion channels and are fast-acting. However, they cause a net influx of chloride ions, resulting in hyperpolarization; thus, their action is inhibitory .
Mechanism of Slow-Acting Neurotransmitters
Slower-acting neurotransmitters act by binding to proteins that are sometimes called G-protein-coupled receptors (GPCRs). These receptors do not form ion channels upon activation and have a very different architecture than the ion channels. However, the timescale for activation is often relatively fast, on the order of seconds. The slightly longer time frame than that for fast-acting neurotransmitters is necessary due to additional molecular interactions that must occur for the postsynaptic cell to become depolarized or hyperpolarized. The protein structure of a GPCR is one protein subunit folded so that it transverses the membrane seven times. These receptors are referred to as G-coupled protein receptors because they function through an interaction with a GTP -binding protein, called G-protein for short.
The conformational change produced when a neurotransmitter binds to a GPCR causes the G-protein to become activated. Once it becomes activated, the protein subunits dissociate and diffuse along the intracellular membrane surface to open or close an ion channel or to activate or inhibit an enzyme that will, in turn, produce a molecule called a second messenger. Second messengers include cyclic AMP , cyclic GMP , and calcium ions and phosphatidyl inositol. They serve to activate enzymes known as protein kinases. Protein kinases in turn act to phosphorylate a variety of proteins within a cell, possibly including ion channels. Protein phosphorylation is a common mechanism used within a cell to activate or inhibit the function of various proteins.
Termination of Transmission
For proper control of neuronal signaling, there must be a means of terminating the nerve impulse. In all cases, once the neurotransmitter dissociates from the receptor, the signal ends. For a few neurotransmitters, there are enzymes in the synapse that serve to chemically alter the neurotransmitter, making it nonfunctional. For instance, the enzyme acetylcholinesterase hydrolyzes acetylcholine. Other neurotransmitters, such as catecholamines and glutamate, undergo a process called reuptake. In this process, the neurotransmitter is removed from the synapse via a transporter protein. These proteins are located in presynaptic neurons or other nearby cells.
Drugs of Abuse
The actions of neurotransmitters are important for many different physiological effects. Many drugs of abuse either mimic neurotransmitters or otherwise alter the function of the nervous system. Barbiturates act as depressants with effects similar to those of anesthetics. They seem to act mainly by enhancing the activity of the neurotransmitter GABA, an inhibitory neurotransmitter. In other words, when barbiturates bind to a GABA receptor, the inhibitory effect of GABA is greater than before. Opiates such as heroin bind to a particular type of opiate receptor, resulting in effects similar to those of naturally occurring endorphins. Amphetamines can displace catecholamines from synaptic vesicles and block reuptake of catecholamines in the synapse, prolonging the action of catecholamine neurotransmitters.
see also Acetylcholine; Dopamine; Hydrolysis; Ion Channels; Norepinephrine.
Jennifer L. Powers
Bibliography
Changeux, Jean-Pierre (1993). "Chemical Signaling in the Brain." Scientific American 269(5):58.
Garrett, Reginald H., and Grisham, Charles M. (1995). "Excitable Membranes, Neurotransmission, and Sensory Systems." In Molecular Aspects of Cell Biology. Philadelphia: Saunders.
Powledge, Tabitha M. (2002). "Beating Abuse." Scientific American 286(1):20.
Internet Resources
"Hallucinogens." Available from <http://www.pharmcentral.com>.
"Narcotics." Available from <http://www.pharmcentral.com>.
"Neurotransmitters." Available from <http://www.pharmcentral.com>.
"Sedatives." Available from <http://www.pharmcentral.com>.
"Stimulants." Available from <http://www.pharmcentral.com>.
Neurotransmitters
Neurotransmitters
Mechanism of impulse transmission
Neurotransmitters, mental disorders, and medications
Definition
Neurotransmitters are chemicals located and released in the brain to allow an impulse from one nerve cell to pass to another nerve cell.
Description
There are approximately 50 neurotransmitters identified. There are billions of nerve cells located in the brain, which do not directly touch each other. Nerve cells communicate messages by secreting neurotransmitters. Neurotransmitters can excite or inhibit neurons (nerve cells). Some common neurotransmitters are ace-tylcholine, norepinephrine, dopamine , serotonin and gamma aminobutyric acid (GABA). Acetylcholine and norepinephrine are excitatory neurotransmitters while dopamine, serotonin, and GABA are inhibitory.
Mechanism of impulse transmission
Each neurotransmitter can directly or indirectly influence neurons in a specific portion of the brain, thereby affecting behavior. A nerve impulse travels through a nerve in a long, slender cellular structure called an axon, and it eventually reaches a structure called the presynaptic membrane, which contains neurotransmitters to be released in a free space called the synaptic cleft. Freely flowing neurotransmitter molecules are picked up by receptors (structures that appear on cellular surfaces that pick up molecules
that fit into them like a “lock and key”) located in a structure called the postsynaptic membrane of another nearby neuron. Once the neurotransmitter is picked up by receptors in the postsynaptic membrane, the molecule is internalized in the neuron and the impulse continues. This process of nerve cell communication is extremely rapid.
Once the neurotransmitter is released from the neurotransmitter vesicles of the presynaptic membrane, the normal movement of molecules should be directed to receptor sites located on the postsynaptic membrane. However, in certain disease states, the flow of the neurotransmitter is defective. For example, in depression , the flow of the inhibitory neurotransmitter serotonin is defective, and molecules flow back to their originating site (the presynaptic membrane) instead of to receptors on the postsynaptic membrane that will transmit the impulse to a nearby neuron.
The mechanism of action and localization of neu-rotransmitters in the brain has provided valuable information concerning the cause of many mental disorders, including clinical depression and chemical dependency, and in researching medications that allow normal flow and movement of neurotransmitter molecules.
Neurotransmitters, mental disorders, and medications
Schizophrenia
Impairment of dopamine-containing neurons in the brain is implicated in schizophrenia , a mental disease marked by disturbances in thinking and emotional reactions. Medications that block dopamine receptors in the brain, such as chlorpromazine and clozapine , have been used to alleviate the symptoms and help patients return to a normal social setting.
Depression
In depression, which afflicts about 3.5% of the population, there appears to be abnormal excess or inhibition of signals that control mood, thoughts, pain, and other sensations. Depression is treated with antidepressants that affect norepinephrine and serotonin in the brain. The antidepressants help correct the abnormal neurotransmitter activity. A newer drug, fluoxetine (Prozac), is a selective serotonin reuptake inhibitor (SSRI) that appears to establish the level of serotonin required to function at a normal level. As the name implies, the drug inhibits the re-uptake of serotonin neurotransmitter from synaptic gaps, thus increasing neurotransmitter action. In the brain, then, the increased serotonin activity alleviates depressive symptoms.
Alzheimer’s disease
Alzheimer’s disease, which affects an estimated four million Americans, is characterized by memory loss and the eventual inability for self-care. The disease seems to be caused by a loss of cells that secrete acetyl-choline in the basal forebrain (region of brain that is the control center for sensory and associative information processing and motor activities). Some medications to alleviate the symptoms have been developed, but presently there is no known treatment for the disease.
Generalized anxiety disorder
People with generalized anxiety disorder (GAD) experience excessive worry that causes problems at work and in the maintenance of daily responsibilities. Evidence suggests that GAD involves several neurotransmitter systems in the brain, including norepinephrine and serotonin.
Attention-deficit/hyperactivity disorder
People affected by attention-deficit/hyperactivity disorder (ADHD) experience difficulties in the areas of attention, overactivity, impulse control, and
KEY TERMS
Acetylcholine —A naturally occurring chemical in the body that transmits nerve impulses from cell to cell. Generally, it has opposite effects from dopamine and norepinephrine; it causes blood vessels to dilate, lowers blood pressure, and slows the heartbeat. Central nervous system well-being is dependent on a balance among acetylcholine, dopamine, serotonin, and norepinephrine.
Catecholamine —A group of neurotransmitters synthesized from the amino acid tyrosine and released by the hypothalamic-pituitary-adrenal system in the brain in response to acute stress. The catechol-amines include dopamine, serotomin, norepinephrine, and epinephrine.
Dopamine —A chemical in brain tissue that serves to transmit nerve impulses (is a neurotransmitter) and helps to regulate movement and emotions.
GABA —Gamma-aminobutyric acid, an inhibitory neurotransmitter in the brain.
Norepinephrine —A neurotransmitter in the brain that acts to constrict blood vessels and raise blood pressure. It works in combination with serotonin.
Serotonin —A widely distributed neurotransmitter that is found in blood platelets, the lining of the digestive tract, and the brain, and that works in combination with norepinephrine. It causes very powerful contractions of smooth muscle, and is associated with mood, attention, emotions, and sleep. Low levels of serotonin are associated with depression.
Synaptic cleft —An area between nerve cells which can contain neurotransmitters.
distractibility. Research shows that dopamine and norepinephrine imbalances are strongly implicated in causing ADHD.
Others
Substantial research evidence also suggests a correlation of neurotransmitter imbalance with disorders such as borderline personality disorders , schizotypal personality disorder , avoidant personality disorder , social phobia , histrionic personality disorder , and somatization disorder .
Drug addictions
Cocaine and crack cocaine are psychostimulants that affect neurons containing dopamine in the areas of the brain known as the limbic and frontal cortex. When cocaine is used, it generates a feeling of confidence and power. However, when large amounts are taken, people “crash” and suffer from physical and emotional exhaustion as well as depression.
Opiates, such as heroin and morphine, appear to mimic naturally occurring peptide substances in the brain that act as neurotransmitters with opiate activity called endorphins. Natural endorphins of the brain act to kill pain, cause sensations of pleasure, and cause sleepiness. Endorphins released with extensive aerobic exercise, for example, are responsible for the “rush” that long-distance runners experience. It is believed that morphine and heroin combine with the endorphin receptors in the brain, resulting in reduced natural endorphin production. As a result, the drugs are needed to replace the naturally produced endorphins and addiction occurs. Attempts to counteract the effects of the drugs involve using medications that mimic them, such as nalorphine, naloxone, and naltrexone .
One of the depressant drugs in widest use, alcohol, is believed to cause its effects by interacting with the GABA receptor. Initially anxiety is controlled, but greater amounts reduce muscle control and delay reaction time due to impaired thinking.
Resources
BOOKS
Tasman, Allan, Kay Jerald, MD, Jeffrey A. Lieberman, MD, eds. Psychiatry. 1st ed. Philadelphia: W. B. Saun-ders Company, 1997.
Laith Farid Gulli, M.D.
Mary Finley
Neurotransmitters
Neurotransmitters
The forensic investigation of an accident or death is not always aided by the presence of physically obvious signs, such as a stab wound or gunshot wound. Injury or death inflicted by toxic agents may have less subtle physical effects. Toxins can interfere with the normal physiological functions of the body. Then, their presence is forensically evident by a physiological change in the norm. One example is agents that disrupt the action of neurotransmitters.
Neurotransmitters are chemicals released in minute amounts from the terminals of nerve cells in response to the arrival of an action potential. There are now more than 300 known neurotransmitters and they act either locally in point-to-point signal transmission (e.g., the motor nerve of a neuromuscular junction) or at a distal site (e.g., the hypothalamic releasing hormones acting on the anterior pituitary). Locally acting neurotransmitters relay the electrical signal traveling along a neuron as chemical information across the neuronal junction, or synapse, that separates one neuron from another neuron or a muscle. Neurons communicate with peripheral tissues, such as muscles, glands etc., or with each other, largely by this chemical means rather than by direct electrical transmission.
Neurotransmitters are stored in the bulbous end of the nerve cell's axon. When an electrical impulse traveling along an axon reaches the junction, the neurotransmitter is released and diffuses across the synaptic gap, a distance of as little as 25 nanometers (nm) or as great as 100 micrometers (mm). The interaction of the neurotransmitter with the postsynaptic receptor of the target cell generates either an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP). Transmitters that lead to EPSPs appear to open large, non-specific membrane channels, permitting the simultaneous movement of Na+, K+ and Cl-. IPSPs are caused by Cl- flux only.
Neurotransmitters include such diverse molecules as acetylcholine, noradrenalin, serotonin, dopamine, γ-aminobutyric acid, glutamate, glycine and numerous other small monoamines and amino acids. There are also small peptides, which appear to act as chemical messengers in the nervous system. They include substance P, vasopressin, oxytocin, endorphins, angiotensin, and many others. A rather unusual but interesting neurotransmitter is the gas nitric oxide. This diverse range of chemical neurotransmitters may suggest that chemical coding could play as important a part in communication between neurons as do the strict point-to-point connections of neural circuitry.
Acetylcholine is one of the neurotransmitters functioning in the peripheral nervous system. It is released by all motor nerves to control skeletal muscles and also by autonomic nerves controlling the activity of smooth muscle and glandular functions in many parts of the body. Norepinephrine is released by sympathetic nerves controlling smooth muscle, cardiac muscle, and glandular tissues. In these tissues acetylcholine and norepinephrine often exert diametrically opposed actions.
The neurotransmitters used by the majority of fast, point-to-point neural circuits in the central nervous system (CNS) are amino acids. Of these, the inhibitory substance γ-aminobutyric acid (GABA) is well characterized and it is present in all regions of the brain and spinal cord. GABA rapidly inhibits virtually all CNS neurons when applied locally by increasing cell permeability to chloride ions, thus stabilizing resting membrane potential near the chloride equilibrium level. Although GABAergic (GABA-producing) neurons also exist in the spinal cord, another inhibitory amino acid, glycine, predominates in this region of the CNS. Glycine is present in small inhibitory interneurons in the spinal cord gray matter and mediates the inhibition of most spinal neurons. The amino acids L-glutamate and L-asparagine depolarize neurons by activating membrane sodium channels and are ubiquitously distributed, appearing as the most common excitatory transmitters for interneurons in the CNS.
In contrast to the point-to-point signaling in which amino acids are involved, the monoamines are mainly associated with the more diffuse neural pathways in the CNS. The monoamines are present in small groups of neurons, primarily located in the brain stem, with elongated and highly branched axons. These diffuse ascending and descending monoaminergic innervations impinge on very large terminal fields and there is evidence that the monoamines may be released from many points along the varicose terminal networks of monoaminergic neurons. Most monoamines released in this way occur at nonsynaptic sites and a very large number of target cells may be affected by the diffuse release of these substances, which are therefore thought to perform modulatory functions of various types.
One of the most remarkable developments was the realization that most peptide hormones of the endocrine and neuroendocrine systems also exist in neurons. These are by far the largest group of potential chemical messengers. For example, the opioid peptides (endorphins) have attracted enormous interest because of their morphine-like properties. They are consequently of considerable interest in the understanding of pain. Endorphins represent a family of chemical messengers found in all regions of the CNS including the pituitary (e.g., beta-endorphin and dynorphin) and the peripheral enteric nervous system. Their presence in regions such as the basal ganglia and the eye's retina, where it is unlikely that they have any connection with pain pathways, suggests that they may also have other diverse functions. There is still much to be learned about the possible functions of neuropeptides in the CNS. In all cases so far examined the peptides seem to be capable of being released by a specialized secretory mechanism from stimulated CNS neurons. They can exert powerful effects on the CNS. For example, the direct administration of small amounts of peptide to the brain can elicit a variety of behavioral responses, including locomotor activity (substance P), analgesia (endorphins), drinking behavior (angiotensisn II), female sexual behavior (LHRH), and improved retention of learned tasks (vasopressin).
An interesting and novel neurotransmitter identified in the 1980s is nitric oxide (NO). This is a highly reactive naturally occurring gas generated in the body from arginine and has the alternative name "epithelium-derived-relaxing factor." Synthesis of NO in blood vessel epithelia occurs in response to the distortion of blood vessels by blood flow. The gas then rapidly diffuses into the surrounding muscle layers, causing them to relax. It, therefore, has vasodilatory (dilation of blood vessels) properties and as a neurotransmitter occurs in a number of nerve networks. For example, it is known to be active in the dilation of arteries supporting the penis and in the relaxation of muscles of the corpora cavernosa (the two chambers filled with spongy tissue which run the length of the penis). NO released from stomach nerves causes the stomach to relax in order to accommodate food. Intestinal nerves also induce the relaxation of the intestinal muscle by releasing NO. In addition, nervous activity in the cerebellum is increased by NO and it appears that NO is an important neurotransmitter associated with memory. Despite its usefulness, nitric oxide can have a toxic effect on body cells and has been implicated in Huntington's disease and Alzheimer's disease.
see also Death, cause of; Nervous system overview; Toxicology.
Neurotransmitters
Neurotransmitters
Definition
Neurotransmitters are chemicals located and released in the brain to allow an impulse from one nerve cell to pass to another nerve cell.
Description
There are approximately 50 neurotransmitters identified. There are billions of nerve cells located in the brain, which do not directly touch each other. Nerve cells communicate messages by secreting neurotransmitters. Neurotransmitters can excite or inhibit neurons (nerve cells). Some common neurotransmitters are acetylcholine, norepinephrine, dopamine, serotonin and gamma aminobutyric acid (GABA). Acetylcholine and norepinephrine are excitatory neurotransmitters while dopamine, serotonin, and GABA are inhibitory. Each neurotransmitter can directly or indirectly influence neurons in a specific portion of the brain, thereby affecting behavior.
Mechanism of impulse transmission
A nerve impulse travels through a nerve in a long, slender cellular structure called an axon, and it eventually reaches a structure called the presynaptic membrane, which contains neurotransmitters to be released in a free space called the synaptic cleft. Freely flowing neurotransmitter molecules are picked up by receptors (structures that appear on cellular surfaces that pick up molecules that fit into them like a "lock and key") located in a structure called the postsynaptic membrane of another nearby neuron. Once the neurotransmitter is picked up by receptors in the postsynaptic membrane, the molecule is internalized in the neuron and the impulse continues. This process of nerve cell communication is extremely rapid.
Once the neurotransmitter is released from the neurotransmitter vesicles of the presynaptic membrane, the normal movement of molecules should be directed to receptor sites located on the postsynaptic membrane. However, in certain disease states, the flow of the neurotransmitter is defective. For example, in depression, the flow of the inhibitory neurotransmitter serotonin is defective, and molecules flow back to their originating site (the presynaptic membrane) instead of to receptors on the postsynaptic membrane that will transmit the impulse to a nearby neuron.
The mechanism of action and localization of neurotransmitters in the brain has provided valuable information concerning the cause of many mental disorders, including clinical depression and chemical dependency, and in researching medications that allow normal flow and movement of neurotransmitter molecules.
Neurotransmitters, mental disorders, and medications
Schizophrenia
Impairment of dopamine-containing neurons in the brain is implicated in schizophrenia , a mental disease marked by disturbances in thinking and emotional reactions. Medications that block dopamine receptors in the brain, such as chlorpromazine and clozapine , have been used to alleviate the symptoms and help patients return to a normal social setting.
Depression
In depression, which afflicts about 3.5% of the population, there appears to be abnormal excess or inhibition of signals that control mood, thoughts, pain, and other sensations. Depression is treated with antidepressants that affect norepinephrine and serotonin in the brain. The antidepressants help correct the abnormal neurotransmitter activity. A newer drug, fluoxetine (Prozac), is a selective serotonin reuptake inhibitor (SSRI) that appears to establish the level of serotonin required to function at a normal level. As the name implies, the drug inhibits the re-uptake of serotonin neurotransmitter from synaptic gaps, thus increasing neurotransmitter action. In the brain, then, the increased serotonin activity alleviates depressive symptoms.
Alzheimer's disease
Alzheimer's disease , which affects an estimated four million Americans, is characterized by memory loss and the eventual inability for self-care. The disease seems to be caused by a loss of cells that secrete acetylcholine in the basal forebrain (region of brain that is the control center for sensory and associative information processing and motor activities). Some medications to alleviate the symptoms have been developed, but presently there is no known treatment for the disease.
Generalized anxiety disorder
People with generalized anxiety disorder (GAD) experience excessive worry that causes problems at work and in the maintenance of daily responsibilities. Evidence suggests that GAD involves several neurotransmitter systems in the brain, including norepinephrine and serotonin.
Attention-deficit/hyperactivity disorder
People affected by attention-deficit/hyperactivity disorder (ADHD) experience difficulties in the areas of attention, overactivity, impulse control, and distractibility. Research shows that dopamine and norepinephrine imbalances are strongly implicated in causing ADHD.
Others
Substantial research evidence also suggests a correlation of neurotransmitter imbalance with disorders such as borderline personality disorders , schizotypal personality disorder , avoidant personality disorder , social phobia , histrionic personality disorder , and somatization disorder .
Drug addictions
Cocaine and crack cocaine are psychostimulants that affect neurons containing dopamine in the areas of the brain known as the limbic and frontal cortex. When cocaine is used, it generates a feeling of confidence and power. However, when large amounts are taken, people "crash" and suffer from physical and emotional exhaustion as well as depression.
Opiates, such as heroin and morphine, appear to mimic naturally occurring peptide substances in the brain that act as neurotransmitters with opiate activity called endorphins. Natural endorphins of the brain act to kill pain, cause sensations of pleasure, and cause sleepiness. Endorphins released with extensive aerobic exercise, for example, are responsible for the "rush" that long-distance runners experience. It is believed that morphine and heroin combine with the endorphin receptors in the brain, resulting in reduced natural endorphin production. As a result, the drugs are needed to replace the naturally produced endorphins and addiction occurs. Attempts to counteract the effects of the drugs involve using medications that mimic them, such as nalorphine, naloxone, and naltrexone .
Alcohol is one of the depressant drugs in widest use, and is believed to cause its effects by interacting with the GABA receptor. Initially anxiety is controlled, but greater amounts reduce muscle control and delay reaction time due to impaired thinking.
Resources
BOOKS
Tasman, Allan, Kay Jerald, MD, Jeffrey A. Lieberman, MD, eds. Psychiatry. 1st ed. Philadelphia: W. B. Saunders Company, 1997.
Laith Farid Gulli, M.D.
Mary Finley
Neurotransmitters
Neurotransmitters
Definition
Neurotransmitters are chemicals that allow the movement of information from one neuron across the gap between it and the adjacent neuron. The release of neurotransmitters from one area of a neuron and the recognition of the chemicals by a receptor site on the adjacent neuron causes an electrical reaction that facilitates the release of the neurotransmitter and its movement across the gap.
Description
The transmission of information from one neuron to another depends on the ability of the information to traverse the gap (also known as the synapse) between the terminal end of one neuron and the receptor end of an adjacent neuron. The transfer is accomplished by neurotransmitters.
In 1921, an Austrian scientist named Otto Loewi discovered the first neurotransmitter. He named the compound "vagusstoff," as he was experimenting with the vagus nerve of frog hearts. Now, this compound is known as acetylcholine.
Neurotransmitters are manufactured in a region of a neuron known as the cell body. From there, they are transported to the terminal end of the neuron, where they are enclosed in small membrane-bound bags called vesicles (the sole exception is nitric oxide, which is not contained inside a vesicle, but is released from the neuron soon after being made). In response to an action potential signal, the neurotransmitters are released from the terminal area when the vesicle membrane fuses with the neuron membrane. The neurotransmitter chemical then diffuses across the synapse.
At the other side of the synapse, neurotransmitters encounter receptors. An individual receptor is a transmembrane protein, meaning part of the protein projects from both the inside and outside surfaces of the neuron membrane, with the rest of the protein spanning the membrane. A receptor may be capable of binding to a neurotransmitter, similar to the way a key fits into a lock. Not all neurotransmitters can bind to all receptors; there is selectivity within the binding process.
When a receptor site recognizes a neurotransmitter, the site is described as becoming activated. This can result in depolarization or hyperpolarization, which acts directly on the affected neurons, or the activation of another molecule (second messenger) that eventually alters the flow of information between neurons.
Depolarization stimulates the release of the neuro-transmitter from the terminal end of the neuron. Hyperpolarization makes it less likely that this release will occur. This dual mechanism provides a means of control over when and how quickly information can pass from neuron to neuron. The binding of a neurotransmitter to a receptor triggers a biological effect. However, once the recognition process is complete, its ability to stimulate the biological effect is lost. The receptor is then ready to bind another neurotransmitter.
Neurotransmitters can also be inactivated by degradation by a specific enzyme (e.g., acetylcholinesterase degrades acetylcholine). Cells known as astrocytes can remove neurotransmitters from the receptor area. Finally, some neurotransmitters (norepinephrine, dopamine, and serotonin) can be reabsorbed into the terminal region of the neuron.
Since Loewi's discovery of acetylcholine, many neurotransmitters have been discovered, including the following partial list:
- Acetylcholine: Acetylcholine is particularly important in the stimulation of muscle tissue. After stimulation, acetylcholine degrades to acetate and choline, which are absorbed back into the first neuron to form another acetylcholine molecule. The poison curare blocks transmission of acetylcholine. Some nerve gases inhibit the breakdown of acetylcholine, producing a continuous stimulation of the receptor cells, and spasms of muscles such as the heart.
- Epinephrine (adrenaline) and norepinephrine: These compounds are secreted principally from the adrenal gland. Secretion causes an increased heart rate and the enhanced production of glucose as a ready energy source (the "fight or flight" response).
- Dopamine: Dopamine facilitates critical brain functions and, when unusual quantities are present, abnormal dopamine neurotransmission may play a role in Parkinson's disease , certain addictions, and schizophrenia.
- Serotonin: Synthesized from the amino acid tryptophan, serotonin is assumed to play a biochemical role in mood and mood disorders, including anxiety, depression , and bipolar disorder.
- Aspartate: An amino acid that stimulates neurons in the central nervous system , particularly those that transfer information to the area of the brain called the cerebrum.
- Oxytocin: A short protein (peptide) that is released within the brain, ovary, and testes. The compound stimulates the release of milk by mammary glands, contractions during birth, and maternal behavior.
- Somatostatin: Another peptide, which is inhibitory to the secretion of growth hormone from the pituitary gland, of insulin, and of a variety of gastrointestinal hormones involved with nutrient absorption.
- Insulin: A peptide secreted by the pancreas that stimulates other cells to absorb glucose.
As exemplified above, neurotransmitters have different actions. In addition, some neurotransmitters have different effects depending upon which receptor to which they bind. For example, acetylcholine can be stimulatory when bound to one receptor and inhibitory when bound to another receptor.
Resources
BOOKS
Alberts, B., A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter. Molecular Biology of the Cell. New York: Garland Publishers, 2002.
OTHER
King, M. W., Indiana State University. Biochemistry of Neurotransmitters. <http://www.indstate.edu/theme/mwking/nerves.html> (January 20, 2004).
Washington State University. "Neurotransmitters and Neuroactive Peptides." Neuroscience for Kids. <http://faculty.washington.edu/chudler.chnt1.html> (January 22, 2004).
Brian Douglas Hoyle, PhD
Neurotransmitter
Neurotransmitter
Chemical substances or molecules which aid in message transmission between neurons.
Communication at the synapses between neurons relies on chemicals called neurotransmitters. Secreted from a part of one neuron (the axon) into the synaptic gap between two others, neurotransmitters diffuse across this space and combine with specific proteins on the surface of the receiving cell, triggering an electrochemical response in the target cell. Afterward, neurotransmitters are either destroyed or reabsorbed back into the neuron for storage and reuse. The release of neurotransmitters by a neuron has three main functions: 1) exciting a second neuron, thus causing it to depolarize; 2) inhibiting a second neuron, which prevents it from depolarizing; and 3) stimulating a muscle fiber to contract.
More than 50 different neurotransmitters have been identified, and more are constantly being discovered. Researchers have proposed that almost all drugs work through interaction with neurotransmitters. Important neurotransmitters include acetylcholine (ACh), which is used by motor neurons in the spinal cord; the catecholamines (including norepinephrine and dopamine), which are important in the arousal of the sympathetic nervous system ; serotonin, which affects body temperature, sensory perception , and the onset of sleep ; and a group of transmitters called endorphins, which are involved in the relief of pain . In recent years, it has been recognized that biochemical imbalances in the brain play an important role in mental illness . Low levels of norepinephrine characterize some varieties of depression , for example, and an imbalance of dopamine is considered a factor in schizophrenia .