A large body of evidence supports the hypothesis that mesolimbic dopamine (DA) mediates,
in animal models, the reinforcing effects of central nervous system stimulants such
as cocaine and amphetamine. The role DA plays in mediating amphetamine-type subjective
effects of stimulants in humans remains to be established. Both amphetamine and cocaine
increase norepinephrine (NE) via stimulation of release and inhibition of reuptake,
respectively. If increases in NE mediate amphetamine-type subjective effects of stimulants
in humans, then one would predict that stimulant medications that produce amphetamine-type
subjective effects in humans should share the ability to increase NE. To test this
hypothesis, we determined, using in vitro methods, the neurochemical mechanism of
action of amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), (+)-methamphetamine,
ephedrine, phentermine, and aminorex. As expected, their rank order of potency for
DA release was similar to their rank order of potency in published self-administration
studies. Interestingly, the results demonstrated that the most potent effect of these
stimulants is to release NE. Importantly, the oral dose of these stimulants, which
produce amphetamine-type subjective effects in humans, correlated with the their potency
in releasing NE, not DA, and did not decrease plasma prolactin, an effect mediated
by DA release. These results suggest that NE may contribute to the amphetamine-type
subjective effects of stimulants in humans.