Membrane potential shapes regulation of dopamine transporter trafficking at the plasma membrane

Richardson, Ben D.; Saha, Kaustuv; Krout, Danielle; Cabrera, Elizabeth; Felts, Bruce; Henry, L. Keith; Swant, Jarod; Zou, Mu‐Fa; Newman, Amy Hauck; Khoshbouei, Habibeh

doi:10.1038/ncomms10423

Cited by 56 publications

(71 citation statements)

References 70 publications

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“…An alternate possibility is that changes in DA neuron firing rate induced by HCRTr1 blockade in the absence of cocaine engenders adaptations in cocaine sensitivity at the terminal, as others have shown that changes in DA neuron excitability can affect DAT function (Richardson et al 2016). HCRTr1 blockade reduces DA neuron excitability, and thus it is possible that this effect could lead to changes in terminal calcium signaling that result in terminal DAT modifications that have been proposed to modulate DAT sensitivity to cocaine.…”

Section: Discussionmentioning

confidence: 99%

“…Potential mechanisms for altered DAT sensitivity to cocaine include differential DAT phosphorylation state (Moritz et al 2013), shifts in inward/outward facing DAT (Liang et al 2009), and changes in oligomer/monomer ratios (Chen and Reith 2007). DAT modification that is driven by changes in DA neuron excitability occurs within seconds of changes in DA neuron excitability (Richardson et al 2016), and thus we expect that this process could occur within the 30 min window that HCRTr1 blockade-induced reductions in terminal cocaine sensitivity have been observed. Ongoing experiments seek to test this possible explanation for altered terminal cocaine sensitivity following HCRTr1 blockade.…”

Section: Discussionmentioning

confidence: 99%

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Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling

et al. 2017

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Rationale Cocaine addiction is a chronic psychiatric disorder characterized by pathological motivation to obtain cocaine and behavioral and neurochemical hypersensitivity to cocaine-associated cues. These features of cocaine addiction are thought to be driven by aberrant phasic dopamine signaling. We previously demonstrated that blockade of the hypocretin receptor 1 (HCRTr1) attenuates cocaine self-administration and reduces cocaine-induced enhancement of dopamine signaling. Despite this evidence, the effects of HCRTr1 blockade on endogenous phasic dopamine release are unknown. Objective In the current studies we assessed whether blockade of HCRTr1 alters spontaneous and cue-evoked dopamine release in the nucleus accumbens core of freely moving rats. Methods We first validated the behavioral and neurochemical effects of the novel, highly selective, HCRTr1 antagonist RTIOX-276 using cocaine self-administration and fast-scan cyclic voltammetry (FSCV) in anesthetized rats. We then used FSCV in freely moving rats to examine whether RTIOX-276 impacts spontaneous and cue-evoked dopamine release. Finally, we used ex vivo slice FSCV to determine whether the effects of RTIOX-276 on dopamine signaling involve dopamine terminal adaptations. Results Doses of RTIOX-276 that attenuate the motivation for cocaine reduce spontaneous dopamine transient amplitude and cue-evoked dopamine release. Further, these doses attenuated cocaine-induced dopamine uptake inhibition at the level of DA terminals. Conclusion Our results provide support for the standing hypothesis that HCRTr1 blockade suppresses endogenous phasic dopamine signals, likely via actions at dopamine cell bodies. These results also elucidate a second process through which HCRTr1 blockade attenuates the effects of cocaine by reducing cocaine sensitivity at dopamine terminals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling

et al. 2017

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“…Adult male GT-tg bigenic mice, RFP::TH mice (Lin et al, 2016; Richardson et al, 2016; Saha et al, 2014; Sambo et al, 2017), and C57BL/6J wild-type (Jackson Labs, Bar Harbor, ME) mice (8–10 weeks of age) were maintained in the University of Florida animal facilities. All experiments were approved by the Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

HIV‐1Tat regulation of dopamine transmission and microglial reactivity is brain region specific

Miller

Shaerzadeh

Phan

et al. 2018

Glia

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The transactivator of transcription protein, HIV-1 Tat, is linked to neuroAIDS, where degeneration of dopamine neurons occurs. Using a mouse model expressing GFAP-driven Tat protein under doxycycline (Dox) regulation, we investigated microglial-neuronal interactions in the rostral substantia nigra pars compacta (SNc). Immunohistochemistry for microglia and tyrosine hydroxylase (TH) showed that the ratio of microglia to dopamine neurons is smaller in the SNc than in the ventral tegmental area (VTA) and that this difference is maintained following 7-day Dox exposure in wild type animals. Administration of Dox to wild types had no effect on microglial densities. In addressing the sensitivity of neurons to potentially adverse effects of HIV-1 Tat, we found that HIV-1 Tat exposure in vivo selectively decreased TH immunoreactivity in the SNc but not in the VTA, while levels of TH mRNA in the SNc remained unchanged. HIV-1 Tat induction in vivo did not alter the total number of neurons in these brain regions. Application of Tat (5 ng) into dopamine neurons with whole-cell patch pipette decreased spontaneous firing activity. Tat induction also produced a decline in microglial cell numbers, but no microglial activation. Thus, disappearance of dopaminergic phenotype is due to a loss of TH immunoreactivity rather than to neuronal death, which would have triggered microglial activation. We conclude that adverse effects of HIV-1 Tat produce a hypodopamine state by decreasing TH immunoreactivity and firing activity of dopamine neurons. Reduced microglial numbers after Tat exposure in vivo suggest impaired microglial functions and altered bidirectional interactions between dopamine neurons and microglia.

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“…In addition to PKC, αCaMKII (Calmodulin-dependent Protein Kinase IIα) also plays a role in regulating amphetamine-induced dopamine efflux as its inhibition attenuates DAT-mediated dopamine efflux (Steinkellner et al, 2012). Because DAT transport is a sodium dependent transporter, sodium concentrations and membrane potential have also been shown to regulate uptake and efflux with more positive membrane potential—affected by sodium and calcium gradients—reducing uptake and favoring efflux (Khoshbouei et al, 2003; Khoshbouei et al, 2004; Gnegy et al, 2004; Richardson et al, 2016). Along the same lines, site-directed mutagenesis and functional studies have shown that N-terminal T62 is crucial for determining the favored DAT conformation, and that N-terminal phosphorylation is critical for amphetamine-induced efflux (Khoshbouei et al, 2004; Guptaroy et al, 2009; Guptaroy et al, 2011; Fraser et al, 2014), This indicates that these are sites of modification necessary for changing and stabilizing DAT conformation.…”

Section: Dat Regulation Of Dopamine Metabolism and Signalingmentioning

confidence: 99%

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease

Mackie

Lebowitz

Saadatpour

et al. 2018

Brain, Behavior, and Immunity

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The second-most common neurodegenerative disease, Parkinson's Disease (PD) has three hallmarks: dysfunctional dopamine transmission due, at least in part, to dopamine neuron degeneration; intracellular inclusions of α-synuclein aggregates; and neuroinflammation. The origin and interplay of these features remains a puzzle, as does the underlying mechanism of PD pathogenesis and progression. When viewed in the context of neuroimmunology, dopamine also plays a role in regulating peripheral immune cells. Intriguingly, plasma dopamine levels are altered in PD, suggesting collateral dysregulation of peripheral dopamine transmission. The dopamine transporter (DAT), the main regulator of dopaminergic tone in the CNS, is known to exist in lymphocytes and monocytes/macrophages, but little is known about peripheral DAT biology or how DAT regulates the dopaminergic tone, much less how peripheral DAT alters immune function. Our review is guided by the hypothesis that dysfunctional peripheral dopamine signaling might be linked to the dysfunctional immune responses in PD and thereby suggests a potential bidirectional communication between central and peripheral dopamine systems. This review seeks to foster new perspectives concerning PD pathogenesis and progression.

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Membrane potential shapes regulation of dopamine transporter trafficking at the plasma membrane

Cited by 56 publications

References 70 publications

Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling

Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling

HIV‐1Tat regulation of dopamine transmission and microglial reactivity is brain region specific

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease

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