Factors affecting synaptic transmission

Several factors influence synaptic transmission of electrical impulses:

• pH of the interstitial fluid

• Drugs, toxins, and diseases

Neurons are very sensitive to changes in the pH of the interstitial fluid surrounding them. Normally, the pH of arterial blood is 7.4. Under conditions of alkalosis, in which pH increases, the excitability of neurons also increases, rendering them more likely to generate action potentials. This inappropriate stimulation of the nervous system may lead to seizures, particularly in epileptics predisposed to them. Under conditions of acidosis, in which pH decreases, the excitability of neurons is depressed, rendering them less likely to generate action potentials. This lack of nervous system stimulation may lead to a comatose state. Severe diabetic acidosis or acidosis associated with end-stage renal failure will often lead to coma.

Neuronal function depends on a constant supply of oxygen. Hypoxia, a decrease in oxygen availability, depresses neuronal activity. Interruption of blood flow to the brain for only a few seconds leads to unconsciousness. A prolonged lack of blood flow, which is characteristic of stroke, leads to permanent brain damage in the affected area.

Many drugs, toxins, and diseases exert their clinical effects by altering some phase of synaptic activity. These effects may occur by means of:

• Altered release of a neurotransmitter

• Altered interaction of a neurotransmitter with its receptor

• Altered removal of a neurotransmitter from the synaptic cleft

• Replacement of a deficient neurotransmitter

Altered release. Tetanus is an infectious disease caused by the bacterium Clostridium tetani. This bacterium produces a neurotoxin active on inhibitory synapses in the spinal cord. Motor neurons, which supply skeletal muscle and cause contraction, have cell bodies that lie in the spinal cord. Under normal circumstances, these motor neurons receive excitatory and inhibitory inputs from various sources. The balance of these inputs results in the appropriate degree of muscle tone or muscle contraction. Tetanus toxin prevents the release of gamma amino butyric acid (GABA), an important neurotrans-mitter active at these inhibitory synapses. Eliminating inhibitory inputs results in unchecked or unmodulated excitatory input to the motor neurons. The resulting uncontrolled muscle spasms initially occur in the muscles of the jaw, giving rise to the expression lockjaw. The muscle spasms eventually affect the respiratory muscles, thus preventing inspiration and leading to death due to asphyxiation.

Altered interaction of a neurotransmitter with its receptor. Interaction of a neurotransmitter with its receptor may be altered pharmacologically in several ways. One such mechanism involves administration of antagonists — drugs that bind to a given receptor and prevent the action of the neurotransmitter but, by classical definition, initiate no other effect. An interesting clinical example of this form of therapy involves schizophrenia, a severe mental disorder characterized by delusions, hallucinations, social withdrawal, and disorganized speech and behavior. Although the precise cause of schizophrenia is unknown, its pathophysiology appears to involve neuronal pathways that release excessive amounts of the neurotransmitter dopamine. Antipsychotic drugs, such as Thorazine® (chlorpromazine) and Haldol® (haloperidol), minimize symptoms of schizophrenia by blocking dopamine receptors and thus preventing excess dopamine from exerting its effects.

An agonist is a drug that binds to a given receptor and stimulates it. In other words, agonists mimic the effect of endogenous neurotransmitters. Albuterol, the active ingredient in medications such as Ventolin ®, is a b2-adr-energic receptor agonist that mimics the effect of the neurotransmitter, epi-nephrine. Because stimulation of these receptors in the lungs causes the airways to dilate, albuterol is effective in reversing the bronchospasm and dyspnea (difficulty in breathing) associated with asthma.

Another mechanism by which neurotransmitter/receptor interaction may be altered involves administering drugs that facilitate binding of the neurotransmitter to its receptor. Once again, the neurotransmitter used as an example is GABA, the most prevalent inhibitory neurotransmitter in the nervous system. It not only contributes to regulation of skeletal muscle tone by inhibiting activity of motor neurons, but is also involved in the regulation of mood and emotions by acting as a CNS depressant. The benzodiazepines, antianxiety drugs that include Valium® (diazepam) and Ativan® (lorazepam), act by binding to a specific site on the GABA receptor. This binding causes a conformational change in the receptor protein that enhances the binding of GABA. As more GABA binds to the receptors, its effectiveness in the CNS is increased and anxiety is decreased.

Altered removal of a neurotransmitter from the synaptic cleft. The third mechanism by which drugs may alter synaptic activity involves changes in neurotransmitter reuptake or degradation. A very well known example of a drug in this category is Prozac® (fluoxetine), which is used to treat depression. The complete etiology is unknown, but it is widely accepted that depression involves a deficiency of monoamine neurotransmitters (e.g., norepinephrine and serotonin) in the CNS. Prozac, a selective serotonin reuptake inhibitor, prevents removal of serotonin from the synaptic cleft. As a result, the concentration and activity of serotonin are enhanced.

Replacement of a deficient neurotransmitter. Finally, synaptic activity may be altered by replacement of a deficient neurotransmitter, a form of drug therapy effective in treatment of Parkinson's disease. The pathophys-iology of Parkinson's involves progressive destruction of dopaminergic (dopamine-releasing) neurons, resulting in a deficiency of dopamine in certain areas in the brain. In addition to neuronal pathways involved in regulation of mood and emotion, dopamine is released by neurons that inhibit skeletal muscle contraction. Because motor neurons normally receive excitatory and inhibitory inputs, the inhibition provided by the dopaminergic pathways results in smooth, precise muscle contractions. In the patient with Parkinson's disease, this loss of inhibition leads to increased muscle tone, or muscle rigidity, and resting tremors.

These symptoms are alleviated by administering levodopa (L-dopa), a precursor for dopamine. L-dopa is taken up by the axon terminals of dopam-inergic neurons and used to form dopamine. Interestingly, in some patients, a side effect of dopamine replacement therapy is the development of symptoms characteristic of schizophrenia. (Recall that this mental disorder is caused by overactive dopaminergic neurons.) On the other hand, drugs used to treat schizophrenia — dopamine receptor antagonists — may elicit symptoms of Parkinson's disease.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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