Mechanisms of neurotransmitter release by amphetamines: a review

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.