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

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), (ϩ)-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. Synapse 39:32-41, 2001.

The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

“…Such a difference in the uptake mechanism in the presence of similar MAO inhibition is expected to produce higher extracellular NE compared with DA levels, as demonstrated by seminal papers [72]. This is critical in brain areas such as the PFC in which the numbers of DA and NE terminals are comparable.…”

“…In fact a variety of neurotransmitters are released under METH administration - namely, serotonin [66] glutamate [67-69] and acetylcholine [70, 71]. Among these, catecholamine neurons are considered as the main target since METH is a powerful DA and NE releaser [72, 73]. As a consequence, repetitive administration of METH leads to DA-and NE-dependent behavioural sensitization, which can be reproduced in different species.…”

“…In spite of that, the effects of METH can be assumed the same when considering intracellular NE and DA since the selective and powerful inhibition of MAO-A is presumed to alter similarly the oxidative deamination of both DA and NE within pre-synaptic terminals. On the other hand, the Ki for NET is 10 fold lower than the Ki for DAT, which leads to 10 fold higher effects of METH on NE compared with DA uptake blockade [72]. …”

“…This is critical in brain areas such as the PFC in which the numbers of DA and NE terminals are comparable. In this case, NE may have a leading role in sustaining the behavioural effects produced by METH administration [72]. This also occurs partly in the ventral striatum and specific limbic regions, which are rich in both DA and NE axon terminals [67, 93-96].…”

“…In this context, it needs to be remarked that NE is massively released following METH administration, being METH-induced NE release in selected brain areas higher than DA release [72]. This makes it likely that NE plays a direct and important role in METH-induced behavioral changes.…”