Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

Hayashizaki, Seiji; Hirai, Shinobu; Ito, Yumi; Honda, Yoshiaki; Arime, Yosefu; Sora, Ichiro; Okado, Haruo; Kodama, Tohru

doi:10.1371/journal.pone.0075975

Cited by 14 publications

(13 citation statements)

References 34 publications

(49 reference statements)

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“…To examine the possible behavioral consequences of these events, we stimulated D1/D5 receptors with SKF38393 before AMPH treatment to inhibit Rho activation and were able to block the effects of AMPHinduced hyperlocomotion as well as DAT surface expression. Consistent with this model, D5 knockout mice display enhanced locomotor activity in response to methamphetamine (25). However, our data also suggest that there is a component of psychostimulantinduced hyperlocomotion that is not Rho-mediated because the activation of D1/D5 receptors does not bring the AMPHinduced hyperlocomotion down to control levels, but rather to the level produced by cocaine.…”

Section: Discussionsupporting

confidence: 82%

Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine

Wheeler

Underhill

Stolz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Acute amphetamine (AMPH) exposure elevates extracellular dopamine through a variety of mechanisms that include inhibition of dopamine reuptake, depletion of vesicular stores, and facilitation of dopamine efflux across the plasma membrane. Recent work has shown that the DAT substrate AMPH, unlike cocaine and other nontransported blockers, can also stimulate endocytosis of the plasma membrane dopamine transporter (DAT). Here, we show that when AMPH enters the cytoplasm it rapidly stimulates DAT internalization through a dynamin-dependent, clathrin-independent process. This effect, which can be observed in transfected cells, cultured dopamine neurons, and midbrain slices, is mediated by activation of the small GTPase RhoA. Inhibition of RhoA activity with C3 exotoxin or a dominant-negative RhoA blocks AMPHinduced DAT internalization. These actions depend on AMPH entry into the cell and are blocked by the DAT inhibitor cocaine. AMPH also stimulates cAMP accumulation and PKA-dependent inactivation of RhoA, thus providing a mechanism whereby PKA-and RhoA-dependent signaling pathways can interact to regulate the timing and robustness of AMPH's effects on DAT internalization. Consistent with this model, the activation of D1/D5 receptors that couple to PKA in dopamine neurons antagonizes RhoA activation, DAT internalization, and hyperlocomotion observed in mice after AMPH treatment. These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action.oth cocaine and amphetamine (AMPH) are psychostimulants that induce euphoria and hyperactivity by increasing extracellular dopamine. Despite the apparent commonalities in the effects and mechanism of action of the two drugs, amphetamine exposure has behavioral, neuroadaptive, and neurotoxic consequences not associated with cocaine use (1-5). These dissimilarities likely stem from several differences in the mechanism of action of the two drugs. Amphetamines, unlike cocaine and other nontransported inhibitors of the dopamine transporter (DAT), are transporter substrates that compete with dopamine for transport, enter dopamine neurons, enhance efflux of dopamine, and also stimulate internalization of the DAT from the cell surface (6, 7). To better understand how amphetamines mediate their effects within the cell, we undertook a series of studies to establish the cellular pathways and signaling mechanisms that underlie the endocytosis of the DAT triggered by amphetamines.AMPH-mediated DAT internalization has been shown to be dynamin-dependent (6). Dynamin-dependence is a key feature of clathrin-mediated endocytosis, and, indeed, previous reports of clathrin-dependent constitutive cycling (8) and PKC-mediated internalization (9) of DAT make it reasonable to consider that the same machinery would be involved in AMPH-mediated internalization. A secondary pathway of dynamin-mediated internalization of membrane-localized proteins involves small GTPases o...

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Section: Discussionsupporting

confidence: 82%

Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine

Wheeler

Underhill

Stolz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Methamphetamine induced mice showed a body weight reduction as shown in table 1 the finding is supported by previous studies 16,17,22 . T h ym o q u i n o n e (T Q) s h o we d s i gn if ic a nt neuroprotective effects in hippocampal neurons in neurodegenerative effects of Alzheimer disease (AD), which is highly consistent with this study as Nigella sativa produced similar effects in the present study against methamphetamine induced injury 22 . Another previous study has reported neuroprotective effects of TQ significantly against hippocampus injury in experimental animals by increasing anti-oxidant enzyme activity 24 .…”

Section: Discussionsupporting

confidence: 87%

Neuroprotective Role of Nigella Sativa on Methamphetamine induced Hippocampal Injury in Male Albino Mice

2019

J Liaquat Uni Med Health Sci

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on sixty adult male mice of average 25-40gms. All the animals were housed properly, fed on lab chow and tap water ad libitum. The mice were divided into group A (control), B, C and D were experimental groups. Group A was given normal saline orally at the volume of 1 ml/kg. Group B animals were given METH at volume of 10 mL/kg containing 10.0 mg/kg METH. Group C animals were given Kalonji extract at the volume of 3mg/ml of extract, and Group D animals were given METH plus Kalonji extract at the same volume and dose as mentioned earlier. The animals were sacrificed by cervical dislocation after one week of last injection. Brain of each animal was removed, immersed in 10% formaldehyde solution for microscopic studies. RESULTS: The weight of different groups at baseline was equal in all groups which is reduced at the end of study period. METH treated mice showing hyper cellularity of different layers, in contrast of N.S + METH treated mice showing marked decrease in cellularity of hippocampus. CONCLUSION: The findings of above study shows neuroprotective effect of Nigella sativa against methamphetamine induced cell injury in hippocampus of mice model.

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“…In contrast, D5 KO mice respond normally to acute and chronic cocaine and present normal conditioned place preference in response to cocaine 19 . Interestingly, D5 KO are more sensitive to a methamphetamine, an effect that is mediated by the DA transporter 20 . Startle response and pre-pulse inhibition are normal in these mice.…”

mentioning

confidence: 97%

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Castello

Cortés

Malave

et al. 2020

Sci Rep

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The dopamine D5 receptor (D5R) is a Gα s-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, it affects up to 4% of people aged 65 years or more 1. Hallmarks of the disorder are motor symptoms such as tremor, rigidity, bradykinesia and gait disturbances 2 , which are a result of the selective degeneration of dopaminergic neurons within the substantia nigra pars compacta and thus not by but of dopamine depletion 3. Up to today, L-DOPA treatment remains the gold standard treatment for PD. In the majority of patients, the efficacy of L-DOPA is reduced and debilitating involuntary movements, termed L-DOPA-induced dyskinesia (LID), develop during chronic L-DOPA treatment over several years 4. Various pharmacological tools are currently investigated with the aim to mitigate these complications. The striatum is comprised mainly by two types of GABAergic projection neurons (SPNs) that are categorized based on their predominant expression of either D1-or D2 receptors, together making up over 95% of all striatal neurons 5. The spiny neurons that project directly to the basal ganglia output nuclei are termed 'direct pathway' or dSPNs and express D1 receptor (D1R), that signals via the G proteins Gα s /Gα olf to PKA and enhances cAMP production. The other class of projection neurons is termed 'indirect pathway' or iSPNs, and they express the inhibitory, Gα i/o-coupled D2 receptor (D2R) 6 , leading to less cAMP being produced. The balance between the two pathways is crucial for voluntary movement control and is disturbed in PD. In addition, cholinergic interneurons (CINs), which represent 1-3% of striatal neurons but are extensively arborized, gat...

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Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

Cited by 14 publications

References 34 publications

Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine

Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine

Neuroprotective Role of Nigella Sativa on Methamphetamine induced Hippocampal Injury in Male Albino Mice

The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

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