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

Stimulants like amphetamine, MDMA, and methamphetamine are known to produce reinforcing effects in animals through the brain chemical dopamine. However, their subjective effects in humans—such as euphoria or alertness—may rely more on norepinephrine. Using lab tests, the authors measured how several stimulants affect the release of norepinephrine and dopamine. They found that all tested drugs were most potent at releasing norepinephrine. Crucially, the oral doses that produce amphetamine-like subjective effects in people correlated with the drugs' ability to release norepinephrine, not dopamine, and did not lower prolactin levels (a marker of dopamine release). These findings suggest norepinephrine may play a key role in the subjective experience of stimulants in humans.

Study at a glance

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.