Reversal of dopamine‐mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons

Aversa, Daniela; Martini, Alessandro; Guatteo, Ezia; Pisani, Antonio; Mercuri, Nicola Biagio; Berretta, Nicola

doi:10.1111/bph.14422

Cited by 14 publications

(18 citation statements)

References 63 publications

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“…Recently, our research team has reported that a similar form of firing recovery may be obtained in response to DA, through an opposing depolarizing current generated by activation of the dopamine transporter (DAT). 21 According to literature, the possibility that the same mechanism may also underlie our present results is very unlikely. Indeed, for it to occur, DOPAquinone should activate and be uptaken by DAT, while products of DA oxidation-like quinones have been shown to inhibit rather than stimulate DAT.…”

Section: ■ Results and Discussionmentioning

confidence: 59%

“…This perfusion time was selected to make sure that a clear steady-state level had been reached. 21 However, when DOPA-quinone 3 (300 μM) was added to the medium, still in the continuous presence of quinpirole, a partial recovery from firing inhibition was observed, attaining 81.85 ± 19.08% of control after 15 min, a value that was significantly different from that in quipirole alone (P < 0.01; F(2,12) = 15.99, n = 5; Figure 1). The possible desensitization of D2Rs by DOPA-quinone was ruled-out by looking at its effect on the GIRK-mediated response by GABA B receptor stimulation.…”

Section: ■ Results and Discussionmentioning

confidence: 90%

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L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons

Bizzarri

Botta

Aversa

et al. 2019

ACS Med. Chem. Lett.

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The oxidative degeneration of dopamine-releasing (DAergic) neurons in the substantia nigra pars compacta (SNc) has attracted much interest in preclinical research, due to its involvement in Parkinson's disease manifestations. Evidence exists on the participation of quinone derivatives in mitochondrial dysfunction, alpha synuclein protein aggregation, and protein degradation. With the aim to investigate the role of L-DOPA-quinone in DAergic neuron functions, we synthesized L-DOPA-quinone by use of 2-iodoxybenzoic acid and measured its activity in recovery from dopamine-mediated firing inhibition of SNc neurons. Noteworthy, L-DOPAquinone counteracts firing inhibition in SNc DAergic neurons caused by GIRK opening. A possible mechanism to explain the effect of L-DOPA-quinone on GIRK channel has been proposed by computational models. Overall, the study showed the possibility that L-DOPA-quinone stabilizes GIRK in a preopen conformation through formation of a covalent adduct with cysteine-65 on the GIRK2 subunit of the protein.

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Section: ■ Results and Discussionmentioning

confidence: 59%

Section: ■ Results and Discussionmentioning

confidence: 90%

L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons

Bizzarri

Botta

Aversa

et al. 2019

ACS Med. Chem. Lett.

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“…Dopaminergic neurons signal through their canonical neurotransmitter, dopamine, at multiple release sites, notably through somatodendritic release via a calcium-dependent manner 64,85 . Furthermore, dopaminergic signalling occurs at multiple timescales 9,86 , selfsignaling 59,80,82,[87][88][89][90] , and mechanisms outside of receptor-dependent modulation of activity 59,62,91 . While dopaminergic neurons receive diverse inputs into their respective 7 regions, little is known about the self-organized intrinsic dopaminergic networks of the VTA and SNC.…”

Section: Resultsmentioning

confidence: 99%

“…Functional networks emerge from local interactions between neurons 46,47,49 . In dopaminergic networks, dopamine neurons have the machinery to directly interact through both synaptic and non-synaptic signaling 65,91,130 . However these studies do not account for dopaminergic network properties and dynamics, and how they differ by brain region.…”

Section: Discussionmentioning

confidence: 99%

“…Dopamine transporter regulates the degree to which dopamine diffusion can occur through the reuptake of dopamine and ending dopamine signaling 77,125 . Furthermore, influx of dopamine or methamphetamine through the transporter produces depolarizing currents that alter the firing properties of these neurons 59,62,91 , which both transporter activity and firing rate are critical to dopaminergic synchronization 8,87 . Disruption of dopamine transporter function would therefore likely cascade across the network, disrupting network topology.…”

Section: Discussionmentioning

confidence: 99%

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Dopamine transporter is a master regulator of dopaminergic neural network connectivity

Miller

Guenther

Maurer

et al. 2021

Preprint

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Dopaminergic neurons of the substantia nigra (SNC) and ventral tegmental area (VTA) exhibit spontaneous firing activity. The dopaminergic neurons in these regions have been shown to exhibit differential sensitivity to neuronal loss and psychostimulants targeting dopamine transporter. However, it remains unclear whether these regional differences scale beyond individual neuronal activity to regional neuronal networks. Here we utilized live-cell calcium imaging to show that network connectivity greatly differs between SNC and VTA regions with higher incidence of hub-like neurons in the VTA. Specifically, the frequency of hub-like neurons was significantly lower in SNC dopamine neurons than in the adjacent VTA, consistent with the interpretation of a lower network resilience to SNC neuronal loss. We tested this hypothesis when activity of an individual dopaminergic neuron is suppressed, through whole-cell patch clamp electrophysiology, in either SNC, or VTA networks. Neuronal loss in the SNC decreased network clustering, whereas the larger number of hub-neurons in the VTA overcompensated by increasing network clustering in the VTA. We further show that network properties are regulatable via a dopamine transporter but not a D2 receptor dependent mechanism. Our results demonstrate novel regulatory mechanisms of functional network topology in dopaminergic brain regions.

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Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline

et al. 2022

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Early life stress (ELS) is known to modify trajectories of brain dopaminergic development, but the mechanisms underlying have not been determined. ELS perturbs immune system and microglia reactivity, and inflammation and microglia influence dopaminergic transmission and development. Whether microglia mediate the effects of ELS on dopamine (DA) system development is still unknown. We explored the effects of repeated early social stress on development of the dopaminergic system in male and female mice through histological, electrophysiological, and transcriptomic analyses. Furthermore, we tested whether these effects could be mediated by ELS-induced altered microglia/immune activity through a pharmacological approach. We found that social stress in early life altered DA neurons morphology, reduced dopamine transporter (DAT) and tyrosine hydroxylase expression, and lowered DAT-mediated currents in the ventral tegmental area but not substantia nigra of male mice only. Notably, stress-induced DA alterations were prevented by minocycline, an inhibitor of microglia activation. Transcriptome analysis in the developing male ventral tegmental area revealed that ELS caused downregulation of dopaminergic transmission and alteration in hormonal and peptide signaling pathways. Results from this study offer new insight into the mechanisms of stress response and altered brain dopaminergic maturation after ELS, providing evidence of neuroimmune interaction, sex differences, and regional specificity.

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Reversal of dopamine‐mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons

Abstract: Our results indicate that the DAT plays a major role in DIR, mediating it under conditions of sustained dopamine exposure, and point to DAT as an important target for pharmacological therapies leading to prolonged enhancement of the dopaminergic signal.

Cited by 14 publications

References 63 publications

L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons

L-DOPA-quinone Mediated Recovery from GIRK Channel Firing Inhibition in Dopaminergic Neurons

Dopamine transporter is a master regulator of dopaminergic neural network connectivity

Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline

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