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

TLDR

Mesolimbic dopamine is known to mediate reinforcing effects of stimulants in animals, but its role in human subjective effects remains unclear, while both amphetamine and cocaine also elevate norepinephrine through release and reuptake inhibition. The authors hypothesized that if norepinephrine increases mediate amphetamine‑type subjective effects in humans, then stimulants producing such effects should also increase norepinephrine. In vitro assays were employed to evaluate the neurochemical actions of amphetamine, MDMA, methamphetamine, ephedrine, phentermine, and aminorex. The stimulants’ dopamine‑release potency matched self‑administration data, yet their strongest effect was norepinephrine release, with oral doses correlating with norepinephrine potency rather than dopamine and not reducing prolactin, suggesting norepinephrine contributes to amphetamine‑type subjective effects.

Abstract

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.