Restoration of Serotonin Neuronal Firing Following Long-Term Administration of Bupropion but Not Paroxetine in Olfactory Bulbectomized Rats

Mansari, Mostafa El; Manta, Stella; Oosterhof, Chris; Iskandrani, Kareem S El; Chenu, Franck; Shim, Stacey; Blier, Pierre

doi:10.1093/ijnp/pyu050

Cited by 14 publications

(10 citation statements)

References 51 publications

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“…The antidepressant bupropion, which is thought to act as an NE and DA reuptake inhibitor (NDRI), has been shown to normalize suppressed dorsal raphe firing and increase tonic activation of 5-HT1A receptors in the hippocampus, unlike the SSRI paroxetine (El Mansari et al 2014 ). Those findings are consistent with bupropion not having strong (or any) 5-HT reuptake modulating properties.…”

Section: Norepinephrine-dopamine Reuptake Inhibitors (Ndris)mentioning

confidence: 99%

In vivo electrophysiological recordings of the effects of antidepressant drugs

Fitzgerald

Watson

2019

Exp Brain Res

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Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or “neural readout”) of the therapeutic effects of all classes of antidepressants.

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Section: Norepinephrine-dopamine Reuptake Inhibitors (Ndris)mentioning

confidence: 99%

In vivo electrophysiological recordings of the effects of antidepressant drugs

Fitzgerald

Watson

2019

Exp Brain Res

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“…Basic neurobiological research as well as clinical studies on SSRIs have established that disturbances in the ascending 5-HT neuron systems and their collateral networks to the forebrain, as well as their many 5-HT receptor subtypes, contribute to the etiology of depression and are targets for its treatment [ 14 , 23 , 26 , 27 , 28 , 29 , 30 , 31 ]. The therapeutic action of serotonin antidepressant drugs is of proven effectiveness, but the mechanisms underlying their effect are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment

et al. 2018

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Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A–FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A–FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A–5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1–15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1–GalR2–5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

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“…Importantly, BP’s action on the 5-HT system differs from the other three drugs in that it does not inhibit 5-HT reuptake (Ghanbari et al 2011 ; Piacentini et al 2003 ; Pandhare et al 2017 ; Mansari et al 2015 ), and its most prominent 5-HT protein target is expressed outside of the brain, in the dorsal root ganglion. Although these results suggest that all three monoaminergic systems contribute to all four drugs’ antidepressant effects, BP’s action on the 5-HT system may be more associated with a sensory side effect than its main MOA.…”

Section: Discussionmentioning

confidence: 99%

“…Not only is its inhibition of either the DA transporter or the NE transporter modest at best (Meyer et al 2002 ; Learned-Coughlin et al 2003 ; Tatsumi et al 1997 ), but there is also no correlation between its clinical efficacy and DA transporter occupancy (Argyelán et al 2005 ). It has also been shown to influence 5-HT neurotransmission, the primary target of more typical antidepressants, without inhibiting its reuptake (Ghanbari et al 2011 ; Piacentini et al 2003 ; Pandhare et al 2017 ; Mansari et al 2015 ). Due to its unique phenotypic effects, BP has been repurposed to facilitate smoking cessation, and although its efficacy in this area was initially believed to be due to its role as an NDRI (Stahl et al 2004 ; Johnston et al 2002 ), increasing evidence suggests that it is due instead to its non-competitive inhibition of several nicotinic acetylcholine receptors (nAChRs; also frequently abbreviated as “nACHRs”) (Crooks et al 2014 ; Slemmer et al 2000 ; Arias 2009 ; García-Colunga et al 2011 ; Vásquez-Gómez et al 2014 ; Miller et al 2002 ).…”

Section: Introductionmentioning

confidence: 99%

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

Kim

Felsövályi²,

Young

et al. 2018

Psychopharmacology

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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.

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Restoration of Serotonin Neuronal Firing Following Long-Term Administration of Bupropion but Not Paroxetine in Olfactory Bulbectomized Rats

Cited by 14 publications

References 51 publications

In vivo electrophysiological recordings of the effects of antidepressant drugs

In vivo electrophysiological recordings of the effects of antidepressant drugs

Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment

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

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