Many Drugs of Abuse May Be Acutely Transformed to Dopamine, Norepinephrine and Epinephrine In Vivo

Summary

Many drugs of abuse, including stimulants, opioids, psychedelics, and alcohol, may be directly converted in the body into catecholamines—dopamine, norepinephrine, and epinephrine—rather than merely modulating these neurotransmitter systems through receptor binding. This hypothesized transformation could explain both the intoxicating effects and the physiological side effects (elevated heart rate, blood pressure, rapid breathing, increased temperature, sweating, and dilated pupils) typically associated with these substances. If correct, this would revise understanding of catecholamine biosynthesis and the neural basis of substance abuse, dependence, and stress-induced relapse. The hypothesis can be tested by administering stable isotope-labeled drugs to rodents or humans and detecting labeled catecholamines in brain, blood, or urine using liquid chromatography-mass spectrometry.

Study at a glance

Abstract

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples.