Mechanism of Action of Drugs of Abuse.
Final rept. 1 Jul 73-31 Oct 75,
VANDERBILT UNIV NASHVILLE TENN SCHOOL OF MEDICINE
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Studies on the mechanism of action of amphetamines have provided evidence that the central stimulatory action of amphetamine is mediated through newly synthesized catecholamines, predominantly dopamine, whereas the action of p-chloroamphetamine depends on the store of catecholamines. The author has shown that S-amphetamine is predominantly hydroxylated in the periphery to S-p-droxyamphetamine which is then transported to the brain, taken up by noradrenergic neurons and converted by beta-hydroxylase to alpa-S, Beta-R p-hydroxynorephedrine PHN. Evidence is accumulating that PHN could be involved in the development of specific noradrenergic tolerance to S-amphetamine. Introduction of a Cl into para-position of the aromatic ring of amphetamine causes a shift of uptake blocking properties of amphetamine from catecholaminergic to serotoninergic neurons and produces long lasting neurotoxic effects on central serotoninergic neurons. Behavioral studies in rats have provided an animal model for 3 distinct phases of the action of amphetamine Facilitation, tolerance and post-amphetamine depression.