The mechanism of action of amphetamine (high dose)

High-dose amphetamine can modify the action of dopamine and noradrenaline in the brain. At high doses, amphetamine increases the concentration of dopamine in the synaptic cleft in 4 ways: (1) it can bind to the pre-synaptic membrane of dopaminergic neurones and induce the release of dopamine from the nerve terminal; (2) amphetamine can interact with dopamine containing synaptic vesicles, releasing free dopamine into the nerve terminal;(3) amphetamine can bind to monoamine oxidase in dopaminergic neurones and prevent the degradation of dopamine, leaving free dopamine in the nerve terminal; and (4) amphetamine can bind to the dopamine re-uptake transporter, causing it to act in reverse and transport free dopamine out of the nerve terminal. High-dose amphetamine has a similar effect on noradrenergic neurones; it can induce the release of noradrenaline into the synaptic cleft and inhibit the noradrenaline re-uptake transporter.

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References

Chronic amphetamine use and abuse. The American Academy of Neuropsychopharmacology. http://www.acnp.org/g4/GN401000166/CH162.htm. Accessed on 30 January 2003.

Drugs of abuse. In Essential psychopharmacology – neuroscientific basis and practical applications. Stahl S. Cambridge University Press: Cambridge. 1996:332–366.