Neuroscience
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Cellular and Molecular Neurobiology
12. Biogenic Amine Neurotransmitters |
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Neuroscience
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Cellular and Molecular Neurobiology
12. Biogenic Amine Neurotransmitters |
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Schizophrenia. The DA theory of schizophrenia is based on the observation that DA antagonists are effective antipsychotic drugs. Their capacity to inhibit DA receptors correlates well with their antipsychotic efficacy. Currently, clinical studies are attempting to develop DA antagonists with specific DA receptor subtype efficacy that will most effectively decrease the antipsychotic symptoms without influencing other DA actions, such as movement control. As mentioned in the anatomy section, an overactivity of the mesolimbic DA system appears especially prominent in schizophrenia.
Disorders of Movement Control. It is now well accepted that decreased DA in the substantia nigra and striatum is the critical lesion in Parkinson's disease. Autopsy shows that nearly all DA is lost during the course of this disease, apparently due to the degeneration of DA neurons. l-DOPA is used to treat this disease's symptoms because it can be converted to DA by AADC in the cells in the vicinity of the degenerated nerve endings to replace the missing endogenous DA. Some preparations of l-DOPA include a pherpheral AADC inhibitor so that more of the l-DOPA will be available for transport into the CNS. Conversion of l-DOPA into DA in the blood prevents its transport into the CNS. Other drugs that are effective in treating Parkinson's symptoms are DA agonists, as well as MAO and COMT inhibitors.
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Autonomic or Smooth Muscle Dysfunction. Drugs that interact with NE receptors are widely used to treat disorders involving autonomic or smooth muscle dysfunction such as asthma, coronary heart disease, angina pectoris, ventricular arrhythmias, migraine and hyperthyroidism. (See Table VI).
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Affective Disorders. Low levels of 5-HT and metabolites are associated with depression and especially a type of depression that is more likely to lead to suicide. Several studies have shown reduced 5-HT in brains of suicide victims as well as a low 5HIAA in CSF of depressed patients who have high incidence of suicide attempts. Recent studies indicate that this type of 5-HT influence may start early in life; low levels of 5HIAA have been found in children and adolescents with disruptive behavioral disorders. Some of the drugs that are effective antidepressant treatments are nonspecific with respect to their relative influence on NE versus 5-HT disposition, thus it has been difficult to know for certain which monoamine is responsible for the treatment effects. More recently selective serotonin reuptake inhibitors (termed SSRIs) have been introduced for the treatment of depression that are among the more effective drugs available for this purpose.
Obsessive Compulsive Disorder. 5-HT dysfunction has been associated with obsessive compulsive disorder. Accordingly, selective 5-HT uptake blockers are used as a therapy for this condition.
Aggression. Although controversial, 5-HT reuptake blockers are used for the treatment of aggression.
Eating Disorders. Also controversial is the use of the drug fenfluramine to treat eating disorders because of the toxic effects that occur in some individuals. Fenfluramine blocks 5-HT reuptake into nerve terminals.
Schizophrenia. A number of recently introduced antipsychotic drugs are producing favorable results in treating the symptoms of schizophrenia. These drugs are interesting pharmacologically in that they block both DA and 5-HT receptors as well as ACh and HA (Table VII, Olanzapine).
Migraine Headaches. 5-HT1 agonists are used for the treatment of migraine headache.
Insomnia. The role of 5-HT in sleep regulation has lead to the hypothesis that reduced levels 5-HT may induce insomnia. Some clinicians are treating patients with 5-HT uptake blockers for this ailment.
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Insomnia. The most popular treatment for insomnia is the use of over the counter CNS acting antihistamines.
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See the Table of Drugs that Interact with Monoamines.
Which of the following can be administered orally to increase dopamine levels in the CNS? (NOTE: Thre is more than one correct answer.)
A. Dopamine
B. Tyrosine
C. Acetyl coenzyme A
D. l-DOPA
E. l-DOPA plus an aromatic L-amino acid decarboxylase inhibitor
Which of the following can be administered orally to increase dopamine levels in the CNS? (NOTE: Thre is more than one correct answer.)
A. Dopamine This answer is INCORRECT.
Dopamine, because it is a charged compound, does not enter the CNS.
B. Tyrosine
C. Acetyl coenzyme A
D. l-DOPA
E. l-DOPA plus an aromatic L-amino acid decarboxylase inhibitor
Which of the following can be administered orally to increase dopamine levels in the CNS? (NOTE: Thre is more than one correct answer.)
A. Dopamine
B. Tyrosine This answer is INCORRECT.
Although tyrosine hydroxylase is the rate-limiting step in the synthesis of all catecholamines, there is sufficient tyrosine available to cells that tyrosine availability is not a factor in determining how much catecholamine is synthesized. It is the activation of tyrosine hydroxylase that leads to increased catecholamine synthesis.C. Acetyl coenzyme A
D. l-DOPA
E. l-DOPA plus an aromatic L-amino acid decarboxylase inhibitor
Which of the following can be administered orally to increase dopamine levels in the CNS? (NOTE: Thre is more than one correct answer.)
A. Dopamine
B. Tyrosine
C. Acetyl coenzyme A This answer is INCORRECT.
Acetyl coenzyme A not involved in the biosynthesis of monoamines.D. l-DOPA
E. l-DOPA plus an aromatic L-amino acid decarboxylase inhibitor
Which of the following can be administered orally to increase dopamine levels in the CNS? (NOTE: Thre is more than one correct answer.)
A. Dopamine
B. Tyrosine
C. Acetyl coenzyme A
D. l-DOPA This answer is CORRECT!
Because tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of all monoamines, the administration of the product of the tyrosine hydroxylase catalyzed reaction, DOPA, bypasses the rate limiting step. Because L-DOPA can easily cross the blood brain barrier, it has access to aromatic L-amino acid decarboxylase in both monoamine and non-monoamine cells in the CNS. For this reason it is an effective means to increase monoamines in the CNS. Consequently, L-DOPA is one of the drugs used to treat Parkinson's disease, a disease in which dopamine neurons die.E. l-DOPA plus an aromatic L-amino acid decarboxylase inhibitor
Which of the following can be administered orally to increase dopamine levels in the CNS? (NOTE: Thre is more than one correct answer.)
A. Dopamine
B. Tyrosine
C. Acetyl coenzyme A
D. l-DOPA
E. l-DOPA plus an aromatic L-amino acid decarboxylase inhibitor This answer is CORRECT!
Because L-DOPA can be converted to dopamine by the liver and kidney, much of the L-DOPA administered never reaches the CNS because it is converted to dopamine as it passes through the liver and kidney. To circumvent this, L-DOPA is administered in combination with an inhibitor of the liver and kidney L-aromatic amino acid decarboxylase. This combination is termed Carbidopa. Because the decarboxylase inhibitor is unable to cross the blood brain barrier it does not inhibit the conversion of L-DOPA to dopamine in the CNS.
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Contact the author(s) at: nba_course@uth.tmc.edu
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The University of Texas Health Science Center at Houston
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