Mechanisms of neurotransmitter release by amphetamines: A review

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Abstract

Amphetamine and substituted amphetamines, including methamphetamine, methylphenidate (Ritalin), methylenedioxymethamphetamine (ecstasy), and the herbs khat and ephedra, encompass the only widely administered class of drugs that predominantly release neurotransmitter, in this case principally catecholamines, by a non-exocytic mechanism. These drugs play important medicinal and social roles in many cultures, exert profound effects on mental function and behavior, and can produce neurodegeneration and addiction. Numerous questions remain regarding the unusual molecular mechanisms by which these compounds induce catecholamine release. We review current issues on the two apparent primary mechanisms — the redistribution of catecholamines from synaptic vesicles to the cytosol, and induction of reverse transport of transmitter through plasma membrane uptake carriers — and on additional drug effects that affect extracellular catecholamine levels, including uptake inhibition, effects on exocytosis, neurotransmitter synthesis, and metabolism.

Section snippets

Introduction: what is an amphetamine?

Amphetamine (AMPH) (1; see Fig. 1 for enumerated chemical structures) and its many derivatives are so varied in structure and effects that they could be considered the orchids of the psychoactive drugs. This review addresses the multiple mechanisms of action that underlie these compounds’ most prominent and paradigmatic biological effect—to elevate extracellular levels of catecholamines and serotonin via a mechanism that is independent of the classical means of transmitter release by secretory

Natural AMPH sources

As is the case for nicotine, cocaine, opiates, marijuana, and alcohol, amphetamines have been administered as plant products for thousands of years. The principal species so used are members of the genus Ephedra and the tree Catha edulis, known in Arabic and Swahili as khat (qat) and over much of East Africa as myrrha (miraa).

Ephedra sinica, often known simply as ephedra and in China as Ma huang (“looking for trouble”), has been recovered from Middle Eastern Neolithic gravesites and Vedic

History of roles for plasma membrane transporters and secretory vesicles

The earliest scientific efforts into understanding AMPH action raised issues still debated today. This history is inextricably bound with the study of the adrenal medulla and its role as a secretor of catecholamines. The term catechol is derived from the plant product catechu (a.k.a. gambir), a cake of aqueous extract of leaves and twigs from the black catechu tree, Catechu nigrum, native to Burma and India, or from Uncaria gambier, a vine native to India and Malaysia. Catechu contains up to

Early studies on vesicular uptake

Given the very controversial role for synaptic vesicles in AMPH action, it is interesting that effects of these drugs on isolated vesicles have long been noted. The first secretory vesicles studied were, not surprisingly, the so-called chromaffin vesicles of the adrenal gland. The term chromaffin was introduced in 1902 by Alfred Kohn (1867–1959) (Kohn, 1902) of the Prague German Medical Faculty, who later survived imprisonment in the Nazi's Theresienstadt (Terezin) concentration camp (

Early studies of cellular monoamine uptake

While the sine qua non property of AMPH at monoamine transporters is the promotion of monoamine release via reverse transport, there are yet profound mysteries in understanding how this works. It is additionally clear that AMPH is an uptake blocker as well as a releaser, and differentiating between elevating extracellular monoamines by reverse transport or uptake blockade can be difficult. Of course, the many AMPH derivatives and different transporters maintain different combinatorial

Other mechanisms that affect extracellular catecholamine levels

There are many other properties of AMPH that contribute to drug effects, but we have attempted to limit this review to those that affect extracellular catecholamines. Here we review additional mechanisms that may be important in regulating extracellular catecholamines, in particular for AMPH and METH. For some mechanisms, such as MAO inhibition, the effects are clearly germane, while for others a genuine role is yet to be elucidated.

Epilogue

Despite the importance of self-administered drugs of reward and addiction, a thorough understanding of the mechanisms of action of some, including ethanol and AMPH, continues to elude us. Perhaps our deepest impression from perusing over a century of literature on AMPH is that while new technologies allow some long-standing hypotheses to be revised, refined, or discarded, variations on the earliest questions on mechanisms of action continue to re-arise. We hope that the historical approach we

Acknowledgments

We thank Dr. Harald Sitte for comments. This review is dedicated to the memory of Dr. Julius Axelrod (May 30, 1912–December 29, 2004), a pioneer of this field who passed away during the preparation of this manuscript.

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