Molecular basis of atypicality of bupropion inferred from its receptor engagement in nervous system tissues

Abstract

Despite decades of clinical use and research, the mechanism of action (MOA) of antidepressant medications remains poorly understood. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly prescribed antidepressants—atypical antidepressants such as bupropion have also proven effective, while exhibiting a divergent clinical phenotype. The difference in phenotypic profiles presumably lies in the differences among the MOAs of SSRIs/SNRIs and bupropion. We integrated the ensemble of bupropion’s affinities for all its receptors with the expression levels of those targets in nervous system tissues. This “combined target tissue” profile of bupropion was compared to those of duloxetine, fluoxetine, and venlafaxine to isolate the unique target tissue effects of bupropion. Our results suggest that the three monoamines—serotonin, norepinephrine, and dopamine—all contribute to the common antidepressant effects of SSRIs, SNRIs, and bupropion. At the same time, bupropion is unique in its action on 5-HT3AR in the dorsal root ganglion and nicotinic acetylcholine receptors in the pineal gland. These unique tissue-specific activities may explain unique therapeutic effects of bupropion, such as pain management and smoking cessation, and, given melatonin’s association with nicotinic acetylcholine receptors and depression, highlight the underappreciated role of the melatonergic system in bupropion’s MOA.Electronic supplementary materialThe online version of this article (10.1007/s00213-018-4958-9) contains supplementary material, which is available to authorized users.

Bupropion-Associated Neurotoxicity in Adolescent With Autism Spectrum Disorder on Stable Dose of Amantadine

“…Bupropion is a dopamine/norepinephrine reuptake inhibitor. Although the precise mechanism of action of bupropion is unknown, it is theorized to inhibit norepinephrine and dopamine reuptake and, thus, has been shown to increase neurotransmission of dopamine and norepinephrine in the central nervous system 8 . Amantadine is a dopamine agonist (anti-Parkinson agent), a weak noncompetitive N -methyl- d -aspartate receptor antagonist, and has indirect anticholinergic activity.…”

Comorbidity of Pain and Depression in a Lumbar Disc Herniation Model: Biochemical Alterations and the Effects of Fluoxetine

“…Previous studies concluded that FLX was effective to normalize BDNF (16, 17), enhance neurogenesis (18, 19), and inhibit GLU transmission (20, 21). Besides these, the effects of FLX on DA, NE, and 5-HT neurotransmission (22, 23) as well as neuroinflammatory factors (7, 8) were widely verified. Therefore, in this study, we also investigated the relationship between 5-HT levels, TNF-α mRNA expression, and the comorbidity of pain and depression and the effect of FLX on these measures.…”

Estudo comparativo entre bupropiona e vareniclina para o tratamento do tabagismo

“…Inicialmente indicada para tratamento do transtorno depressivo. (ALKONDON;ALBUQUERQUE, 2005;KIM et al, 2018;LERMAN et al, 2006;LERMAN et al, 2003).…”