Sadighparvar S, Tale F, Shahabi P, Naderi S, Ghaderi Pakdel F. The Response of Ventral Tegmental Area Dopaminergic Neurons to Bupropion: Excitation or Inhibition?. BCN 2019; 10 (4) :281-304
URL:
http://bcn.iums.ac.ir/article-1-1044-en.html
1- Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran.; Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
2- Department of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
3- Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
4- Reproductive Health Research Center, Urmia University of Medical Sciences, Urmia, Iran.
5- Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran.; Reproductive Health Research Center, Urmia University of Medical Sciences, Urmia, Iran.
Abstract:
Introduction: Antidepressants can modulate brain monoamines by acting on pre-synaptic and postsynaptic receptors. Autoreceptors can reduce the monoamines effect on the somatodendritic or pre-synaptic regions despite its postsynaptic counter effects. The direct effect of some antidepressants is related to its temporal and spatial bioavailability in the vicinity of these receptors (still a matter of controversies). This research evaluated the direct effect of acute bupropion on the Ventral Tegmental Area (VTA) dopaminergic neuronal firing rate.
Methods: Male Wistar rats were divided into intracerebroventricular and microiontophoretic groups with 14 subgroups (n=5 in each subgroup). Amounts of 1, 0.5, 0.1, 0.01, 0.001, and 0.0001 mol of bupropion (5 μL/3 min) were microinfused to the first group and then the ejected amounts of bupropion at -500, -300, -150, -50 nA of electrical currents (1 mol, pH=4.5, 5 min) were applied to the second group. The control and sham subgroups were studied in each group, too. The units with stable firing rates were extracted, and the effect of bupropion was evaluated statistically with a P value less than 0.05 as the level of significance.
Results: The highest amount of bupropion in the intracerebroventricular application could excite 42% of the neurons and inhibit 56% of them, but the highest amount of microiontophoretic application of bupropion could inhibit 97.5% of the neurons. The neuronal response to bupropion was dose-dependent in all treated groups.
Conclusion: The dual effects of intracerebroventricular bupropion on the VTA dopaminergic neurons but solo inhibitory effect of its microiontophoretic application reflect the intra-VTA and extra-VTA heterogenic cellular and molecular control over the dopaminergic outflow that can be mediated by different receptors. The dopamine autoreceptors on the VTA dopaminergic neurons have complex modulatory effects on the dopaminergic response.
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Highlights
• Two routine methods of Intracerebroventricular and microiontophoresis applications are used to study the cellular effects of bupropion on the Ventral Tegmental Area (VTA) dopaminergic neurons.
• The dopaminergic VTA neuronal firings rates are extracted and assigned to evaluate the direct or indirect effects of bupropion.
• Bupropion can modulate the synaptic activity and post-synaptic neuronal spiking by the pre- or post-synaptic effects.
• Although the bupropion as an antidepressant, has excitatory effects on the dopaminergic neurons, its direct effect is inhibitory.
• The dissociation of direct and indirect effects of bupropion on the VTA dopaminergic neurons can explain some side effects of bupropion besides its anti-depressive property.
Plain Language Summary
Antidepressants comprise the major part of prescribed drugs worldwide. Bupropion was introduced as an antidepressant, but it was mainly used as smoke cessation. The mechanism of action of bupropion is not well known, and the wide range of its effects showed the complexity of its activities. This study examined the effects of indirect and direct application of bupropion on the cellular levels by intraventricular or iontophoretic methods, respectively. The findings of this study showed that the general indirect effect of bupropion on the dopaminergic VTA neurons is dual; excitatory, and inhibitory, but its direct effect is inhibitory. The dose-related presence of bupropion can show the different effects on the dopaminergic VTA neurons. These findings could explain some opposite effects and also side effects of bupropion.
Type of Study:
Original |
Subject:
Behavioral Neuroscience Received: 2017/10/10 | Accepted: 2018/04/21 | Published: 2019/07/1