An unsuspected role for organic cation transporter 3 in the actions of amphetamine

Mayer, Felix P.; Schmid, Diethart; Owens, William A.; Gould, Georgianna G.; Apuschkin, Mia; Kudlacek, Oliver; Salzer, Isabella; Boehm, Stefan; Chiba, Peter; Williams, Piper; Wu, Hsiao Huei; Gether, Ulrik; Koek, Wouter; Daws, Lynette C.; Sitte, Harald H.

doi:10.1038/s41386-018-0053-5

Cited by 50 publications

(56 citation statements)

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“…; Mayer et al . ). Amphetamine‐induced DA release was significantly smaller in the SNc compared to previous FSCV measurements of amphetamine‐induced release in the striatal slices (Jones et al .…”

Section: Discussionmentioning

confidence: 97%

Action potential and calcium dependence of tonic somatodendritic dopamine release in the Substantia Nigra pars compacta

Yee

Forbes

Cheung

et al. 2018

Journal of Neurochemistry

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Despite the importance of somatodendritic dopamine (DA) release in the Substantia Nigra pars compacta (SNc), its mechanism remains poorly understood. Using a novel approach combining fast-scan controlled-adsorption voltammetry (FSCAV) and single-unit electrophysiology, we have investigated the mechanism of somatodendritic release by directly correlating basal (non-stimulated) extracellular DA concentration ([DA] ), with pharmacologically-induced changes of firing of nigral dopaminergic neurons in rat brain slices. FSCAV measurements indicated that basal [DA] in the SNc was 40.7 ± 2.0 nM (at 34 ± 0.5°C), which was enhanced by amphetamine, cocaine, and L-DOPA, and reduced by VMAT2 inhibitor, Ro4-1284. Complete inhibition of firing by TTX decreased basal [DA] , but this reduction was smaller than the effect of D receptor agonist, quinpirole. Despite similar effects on neuronal firing, the larger decrease in [DA] evoked by quinpirole was attributed to cell membrane hyperpolarization and greater reduction in cytosolic free Ca ([Ca ] ). Decreasing extracellular Ca also reduced basal [DA] , despite increasing firing frequency. Furthermore, inhibiting L-type Ca channels decreased basal [DA] , although specific Ca 1.3 channel inhibition did not affect firing rate. Inhibition of sarcoplasmic/endoplasmic reticulum Ca -ATPase (SERCA) also decreased [DA] , demonstrating the importance of intracellular Ca stores for somatodendritic release. Finally, in vivo FSCAV measurements showed that basal [DA] in the SNc was 79.8 ± 10.9 nM in urethane-anesthetized rats, which was enhanced by amphetamine. Overall, our findings indicate that although tonic somatodendritic DA release is largely independent of action potentials, basal [DA] is strongly regulated by voltage-dependent Ca influx and release of intracellular Ca .

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Section: Discussionmentioning

confidence: 97%

Action potential and calcium dependence of tonic somatodendritic dopamine release in the Substantia Nigra pars compacta

Yee

Forbes

Cheung

et al. 2018

Journal of Neurochemistry

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“…In peripheral cells, uptake of Met is mediated by the organic cation transporters OCT1 and OCT3 [ 37 , 38 , 39 ]. OCT3 is also found to be expressed in neurons [ 40 , 41 , 42 ]. Little is known about the expression pattern of Met transporters in the brains.…”

Section: Discussionmentioning

confidence: 99%

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Chen

Liu

et al. 2020

Brain Sciences

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Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons.

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“…Immunohistochemical studies with an OCT3-specific antibody have revealed that the transporter is expressed throughout the rat brain, with at least low levels of expression detected in nearly all brain regions (Gasser et al, 2009). The transporter is expressed in neurons (Cui et al, 2009;Graf et al, 2013;Hill and Gasser, 2013;Shang et al, 2003;Vialou et al, 2004), including dopamine neurons (Mayer et al, 2018), and glial cells, including astrocytes (Cui et al, 2009;Takeda et al, 2002) and microglia (He et al, 2017). It is also expressed in oligodendrocytes (Gasser et al, 2009), ependymal cells (Gasser et al, 2006;Gasser et al, 2009), and vascular endothelial cells in the brain (Li et al, 2013).…”

Section: Cellular and Subcellular Localization Of Oct3mentioning

confidence: 99%

“…Similarly, this review focused on our studies examining OCT3-mediated dopamine transport as it relates to the neurochemical and behavioral effects of cocaine. There is a growing body of work examining roles for OCT3mediated dopamine transport in the actions of other psychostimulant drugs, including amphetamine (Mayer et al, 2018;Vialou et al, 2008) and methamphetamine (Cui et al, 2009;Kitaichi et al, 2003;Nakayama et al, 2007). Clearly, many questions remain to be answered about the roles played by OCT3 and the other uptake 2 transporters in regulating monoamine signaling throughout the brain (Gasser and Daws, 2017).…”

Section: Corticosterone and The Regulation Of Cocaine-seeking Behaviomentioning

confidence: 99%

Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior

Gasser

2019

Neurochemistry International

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Transporter-mediated uptake determines the peak concentration, duration, and physical spread of released monoamines. Most studies of monoamine clearance focus on the presynaptic uptake transporters SERT, NET and DAT. However, recent studies have demonstrated the expression of the uptake transporter OCT3 (organic cation transporter 3), throughout the rodent brain. In contrast to NET, DAT and SERT, OCT3 has higher capacity and lower affinity for substrates, is sodium-independent, and is multi-specific, with the capacity to transport norepinephrine, dopamine, serotonin and histamine. OCT3 is insensitive to inhibition by cocaine and antidepressant drugs but is inhibited directly by the glucocorticoid hormone corticosterone. Thus, OCT3 represents a novel, stress hormone-sensitive, monoamine transport mechanism. Incorporating this transporter into current models of monoaminergic neurotransmission requires information on: A) the cellular and subcellular localization of the transporter; B) the effects of OCT3 inhibitors on monoamine clearance; and C) the consequences of decreased OCT3-mediated transport on physiology and/or behavior. This review summarizes studies describing the anatomical distribution of OCT3, its cellular and subcellular localization, its contribution to the regulation of dopaminergic signaling, and its roles in the regulation of behavior. Together, these and other studies suggest that both Uptake and Uptake transporters play key roles in regulating monoaminergic neurotransmission and the effects of monoamines on behavior.

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An unsuspected role for organic cation transporter 3 in the actions of amphetamine

Cited by 50 publications

References 50 publications

Action potential and calcium dependence of tonic somatodendritic dopamine release in the Substantia Nigra pars compacta

Action potential and calcium dependence of tonic somatodendritic dopamine release in the Substantia Nigra pars compacta

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior

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