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

Richard B Rothman, Michael H. Baumann, Christina M Dersch, Dana V. Romero, Kenner C Rice, F. Ivy Carroll, John S. Partilla

Synapse 2000 DOI: 10.1002/1098-2396(20010101)39:1<32::aid-syn5>3.0.co;2-3 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Topics MDMA Serotonin
Keywords Neurochemical Dopamine Methamphetamine Stimulant Pharmacology Norepinephrine Dextroamphetamine Fenfluramine
Citations 933
Key findings The potency of stimulants to release norepinephrine, not dopamine, correlated with the oral doses that produce amphetamine-type subjective effects in humans.

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.

In the evidence

This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.

  • State of the evidence: MDMA Supports

    Among stimulants tested, norepinephrine release potency, not dopamine release potency, correlated with oral doses producing amphetamine-type subjective effects in humans.

    Synthesized

  • State of the evidence: Serotonin Opposes

    Stimulant potency for releasing norepinephrine, not dopamine or serotonin, correlated with oral doses producing amphetamine-type subjective effects.

    Synthesized

Comparable studies

Other experimental studies on serotonin, most cited first.

Study Year Design Participants
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers 1998 Experimental study
Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain 1988 Experimental study
The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... 1992 Laboratory study
5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain 1997 Experimental study
Crystal structure of an LSD-bound human serotonin receptor 2017 Experimental study with structural biology and molecular dynamics simulations

Citations in the library

Cited by 117

and 112 more in the library

Cites 2

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MDMA Serotonin