The use of stimulant compounds has a long history. Chinese native physicians have been using the drug Ma-huang for more than 5000 years. In 1887, Nagai found the active agent in Ma-huang to be ephedrine.
Amphetamine proper was first synthesized in 1887 by Edeleau as part of a systematic program to manufacture aliphatic amines. Early investigations of the properties of amphetamine focused on the peripheral effects and found that amphetamine was a sympathomimetic agent with bronchodilator properties.
Oddly, the central nervous system actions were not reported until approximately 1933, and this was closely followed by the first reports of amphetamine abuse. Amphetamines produce feelings of euphoria and relief from fatigue, may improve performance on some simple tasks, increase activity levels, and produce anorexia.
The abuse liability of the amphetamines is thought to be primarily related to their euphorigenic effects which leads to high-dose use and the final stage—compulsive abuse. The following sections discuss the basic and clinical research regarding the licit and illicit use of amphetamines and related stimulants.
AMPHETAMINE NEUROPHARMACOLOGY: EFFECTS ON DOPAMINE RELEASE
Several chapters in The Fourth Generation of Progress detail catecholamine neurobiology and there are recent reviews of amphetamine neuropharmacology by Kuczenski and Segal (127). Here we present a summary of the acute neuropharmacology and will provide more extensive coverage of the chronic amphetamine effects elsewhere.
Amphetamine has several interactive effects on catecholamine release. We will primarily focus on dopamine (DA) as an example. Amphetamine acts in at least three ways: 1) reversal of the DA uptake carrier, 2) interference with uptake into the DA vesicle, and 3) inhibition (at higher concentrations) of monoamine oxidase.
The best known mechanism is binding of extracellular amphetamine to the uptake carrier and its transport into the terminal. It is subsequently dissociated into the cytoplasm, while the carrier binds cytosol DA with its transport out of the terminal (66, 169). More recently, a weak base model (208. 209) proposed that amphetamines, as weak bases, redistribute catecholamines from synaptic vesicles to the cytosol by collapsing the vesicle proton gradient that provides free energy for catechol accumulation.
Even non-stimulant weak bases work in this model (208). The excess cytosol DA is thought to promote reverse transport of DA via the membrane transporter (i.e., release). Amphetamine-induced release of DA is accompanied by a decrease in DOPAC, an effect thought to be due to a reduction of monoamine oxidase activity by amphetamine. Direct assessment in vivo suggests that MAO inhibition occurs at relatively high amphetamine concentrations (84, 149). (continued... to STIMULANT TOXICITY...)
Amphetamine proper was first synthesized in 1887 by Edeleau as part of a systematic program to manufacture aliphatic amines. Early investigations of the properties of amphetamine focused on the peripheral effects and found that amphetamine was a sympathomimetic agent with bronchodilator properties.
Oddly, the central nervous system actions were not reported until approximately 1933, and this was closely followed by the first reports of amphetamine abuse. Amphetamines produce feelings of euphoria and relief from fatigue, may improve performance on some simple tasks, increase activity levels, and produce anorexia.
The abuse liability of the amphetamines is thought to be primarily related to their euphorigenic effects which leads to high-dose use and the final stage—compulsive abuse. The following sections discuss the basic and clinical research regarding the licit and illicit use of amphetamines and related stimulants.
AMPHETAMINE NEUROPHARMACOLOGY: EFFECTS ON DOPAMINE RELEASE
Several chapters in The Fourth Generation of Progress detail catecholamine neurobiology and there are recent reviews of amphetamine neuropharmacology by Kuczenski and Segal (127). Here we present a summary of the acute neuropharmacology and will provide more extensive coverage of the chronic amphetamine effects elsewhere.
Amphetamine has several interactive effects on catecholamine release. We will primarily focus on dopamine (DA) as an example. Amphetamine acts in at least three ways: 1) reversal of the DA uptake carrier, 2) interference with uptake into the DA vesicle, and 3) inhibition (at higher concentrations) of monoamine oxidase.
The best known mechanism is binding of extracellular amphetamine to the uptake carrier and its transport into the terminal. It is subsequently dissociated into the cytoplasm, while the carrier binds cytosol DA with its transport out of the terminal (66, 169). More recently, a weak base model (208. 209) proposed that amphetamines, as weak bases, redistribute catecholamines from synaptic vesicles to the cytosol by collapsing the vesicle proton gradient that provides free energy for catechol accumulation.
Even non-stimulant weak bases work in this model (208). The excess cytosol DA is thought to promote reverse transport of DA via the membrane transporter (i.e., release). Amphetamine-induced release of DA is accompanied by a decrease in DOPAC, an effect thought to be due to a reduction of monoamine oxidase activity by amphetamine. Direct assessment in vivo suggests that MAO inhibition occurs at relatively high amphetamine concentrations (84, 149). (continued... to STIMULANT TOXICITY...)
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