by Keith A. Trujillo, Ph.D. and Andrea B. Chinn
Last Revised 10/2/96
Psychomotor stimulants are a group of drugs, including cocaine, amphetamine, methylphenidate, ephedrine and cathinone that produce wakefullness and arousal and stimulate behavior. Their current clinical use is limited to treatment of specific sleep disorders such as narcolepsy, and certain childhood behavioral problems such as attention deficit disorder. More importantly, the psychomotor stimulants are a class of drugs widely self-administered for non-medical reasons.
Psychomotor stimulants have been used throughout recorded history and in almost all parts of the world. There are records of Chinese physicians using the ephedra plant Ephedra vulgaris to produce Ma Huang over 5000 years ago. The active ingredient, ephedrine, was isolated in the 1880s but it was not characterized until the 1920s. There is evidence that Indians of South America chewed leaves of the Coca plant Erythroxylon coca as many as 2000 years ago. The active ingredient, cocaine, was first isolated in the 1800s. Cocaine, in its various forms including powder, freebase and crack, is currently one of the most popular street drugs in western society. In East Africa and the Middle East, leaves of the Khat shrub Catha edulis have been chewed for their stimulant effects for at least 700 years and this practice continues to be widespread among young men of this regions. The active ingredient in Khat, (-)-cathinone, was not isolated until the 1970s.
The use of cocaine for medical purposes was popularized by Sigmund Freud in the 1880s, who suggested that it was a miracle drug, with uses ranging from local anesthesia to the treatment of depression, indigestion, asthma, neurosis, syphilis and drug and alcohol addiction. Based in part on Freud's endorsement the use of cocaine became very popular. It was widely prescribed by physicians and even appeared in popular tonics, including Coca Cola (although coca leaves are still an ingredient in Coca Cola, the cocaine is removed before they are used in the drink). Presently, the only approved medical use of cocaine is as a local anesthetic.
The characterization of ephedrine in the 1920s led to an interest in developing and testing similar drugs. Ephedrine was being widely used to treat asthma and there was an interest in finding a synthetic substitute for this drug. Amphetamine, a drug similar in structure and activity to ephedrine, arose from this interest. Although amphetamine had been synthesized almost 40 years earlier, the interest in ephedrine led to the further characterization and use of this drug. Since then, many analogs of amphetamine have been developed and characterized, including the popular street drug, methamphetamine.
Amphetamines have been widely used for their stimulant effects. They were used in World War II, by the United States as well as others, to decrease fatigue and increase alertness of soliders. Truck drivers have used them for decades to increase wakefullness and altertness and allow them to drive for long distances without stopping for rest. Likewise, these stimulants have been popular with college students wishing to stay awake and study for exams.
The first condition for which amphetamine was used clinically was narcolepsy. Although it is not curative, it revolutionized therapy for this condition by making the patients relatively symptom free. Since then amphetamines have been used at various times to treat Parkinson's disease, depression, epilepsy, psychopathic states, attention deficit-hyperactivity disorder, and obesity. Because of their ability to decrease appetite, amphetamines were widely prescribed for many years for individuals wishing to lose weight. Because of their risk of abuse and dependence, use of stimulants has been considerably reduced over the years and newer more effective agents have been demonstrated to work in treating some of these conditions.
Psychomotor stimulants, most notably cocaine and amphetamine, produce a characteristic stimulation of behavior in both humans and experimental animals. At low to moderate doses these drugs induce wakefulness, increase activity, decrease appetite and stimulate the sympathetic nervous system. In humans, these doses also produce feelings of euphoria, well-being and self-confidence. The latter effects are reflected in experimental animals as powerful reinforcing actions. In appropriate experimental situations animals will work extremely hard, sometimes to the point of death, to obtain these drugs.
At higher doses the psychomotor stimulants produce stereotypic behaviors. Stereotypic behaviors are typically brief and highly patterned behavioral repertoires produced in a repetitive manner. Stereotypies in humans produced by high doses of stimulants include repetitive or continuous arranging of objects, bathing, house cleaning, mechanical work, grooming, and persistent repetition of words or sentences. At very high doses the psychomotor stimulants produce a psychosis characterized by vivid hallucinations and paranoid ideation, often indistinguishable from paranoid schizophrenia.
Psychomotor stimulants produce their characteristic behavioral effects by increasing synaptic activity of the monoamine neurotransmitters, dopamine, norepinephrine and serotonin. They are called indirect agonists because their primary effect is to increase the ability of the neurotransmitters to act, without having a direct effect on the postsynaptic receptors for these neurotransmitters. Although producing slightly different cellular and molecular effects, the final outcome for each drug in this class, an increase in monoamine activity, is quite similar.
Cocaine acts primarily by blocking the reuptake of monoamines. Reuptake is the first step in the process by which monoamines are destroyed in the brain. After they are released, these neurotransmitters are actively transported back into the cell from which they were released. By blocking reuptake cocaine increases the length of time that the monoamines can activate their receptors.
Amphetamine has more varied cellular effects than cocaine, increasing the activity of monoamines in several important ways: 1) Amphetamine stimulates the release of dopamine and norepinephrine from catecholamine nerve terminals, increasing the amount of these neurotransmitters in the synapse. 2) Like cocaine, amphetamine also inhibits reuptake of the catecholamines, increasing their ability to activate receptors. 3) In addition, amphetamine inhibits monoamine oxidase, the enzyme responsible for the destruction of monoamine neurotransmitters, further increasing the availability of these neurotransmitters. 4) Finally, there is some evidence that amphetamine may directly activate catecholamine receptors, further contributing to monoaminergic activity.
Psychopharmacological research has revealed the specific brain areas and neurotransmitters responsible for the behavioral effects of psychomotor stimulants. The most prominent monoamine neurotransmitter involved in the effects of these drugs is dopamine, which is responsible for the powerful reinforcing effects, the increase in activity, and the stereotypic and psychotogenic effects. Increased dopamine activity in a forebrain region known as the nucleus accumbens mediates the reinforcing effects and the motor stimulant effects of the psychomotor stimulants. Dopamine in this brain region also appears to mediate the psychotogenic effects produced by high doses of these drugs. Increased dopamine activity in an adjacent forebrain region, the striatum (or caudate-putamen), is responsible for the stereotypic effects of the stimulants.
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Keith A. Trujillo, Ph.D.
Andrea B. Chinn
Comments to author: keith@mailhost1.csusm.edu
All contents copyright (C) 1996, Keith A. Trujillo, Ph.D. All rights reserved.
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