Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin

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 med iating 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 i ncreases in NE mediate amphetamine-type subjective effects of stimulants in humans, then one would predict that stimulant medications that produce amp hetamine-type subjective effects in humans should share the ability to incr ease NE. To test this hypothesis, we determined, using in vitro methods, th e neurochemical mechanism of action of amphetamine, 3,4-methylenedioxymetha mphetamine (MDMA), (+)-methamphetamine, ephedrine, phentermine, and aminore x. As expected, their rank order of potency for DA release was similar to t heir rank order of potency in published self-administration studies. Intere stingly, the results demonstrated that the most potent effect of these stim ulants is to release NE. Importantly, the oral dose of these stimulants, wh ich produce amphetamine-type subjective effects in humans, correlated with the their potency in releasing NE, not DA, and did not decrease plasma prol actin, an effect mediated by DA release. These results suggest that NE may contribute to the amphetamine-type subjective effects of stimulants in huma ns. Published 2001 Wiley-Liss, Inc.