Effect of MDMA-Induced Axotomy on the Dorsal Raphe Forebrain Tract in Rats: An In Vivo Manganese-Enhanced Magnetic Resonance Imaging Study

Chiu, Chung-Hsin; Siow, Tiing Yee; Weng, Yu Chun; Hsu, Yi Hua; Huang, Yuahn Sieh; Chang, Kang-Wei; Cheng, Cheng Yi; Hsing, Kuo

doi:10.1371/journal.pone.0138431

Cited by 10 publications

(7 citation statements)

References 46 publications

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“…To study the role of the striatum in RLS pathogenesis, we first used MEMRI imaging to determine the striatal neural activity in the systematic Btbd9 KO mice. MEMRI has been extensively used to track Ca 2+ -dependent synaptic activity (Lu et al, 2007; Hsu et al, 2008; Chiu et al, 2015; Dudek et al, 2015; Perrine et al, 2015). As a calcium analog, Mn 2+ enters active synapses through voltage-gated calcium channels (Fukuda and Kawa, 1977; Narita et al, 1990) and is sequestered and transynaptically transported antero- and retrogradely across active neural circuits (Sloot and Gramsbergen, 1994; Pautler et al, 1998; Takeda et al, 1998a, b; Saleem et al, 2002; Murayama et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

The Role of BTBD9 in Striatum and Restless Legs Syndrome

Lyu

Xiao

DeAndrade

et al. 2019

eNeuro

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Restless legs syndrome (RLS) is a sensory-motor neurological disorder characterized by uncomfortable sensations in the extremities, generally at night, which is often relieved by movements. Genome-wide association studies (GWAS) have identified mutations in BTBD9 conferring a higher risk of RLS. Knockout of the BTBD9 homolog in mice (Btbd9) and fly results in motor restlessness and sleep disruption. Clinical studies have found RLS patients have structural and functional abnormalities in the striatum; however, whether and how striatal pathology contributes to the pathogenesis of RLS is not known. Here, we used fMRI to map regions of altered synaptic activity in basal ganglia of systematic Btbd9 knock-out (KO) mice. We further dissected striatal circuits using patch-clamp electrophysiological recordings in brain slices. Two different mouse models were generated to test the effect of specific knockout of Btbd9 in either striatal medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) using the electrophysiological recording, motor and sensory behavioral tests. We found that Btbd9 KO mice showed enhanced neural activity in the striatum, increased postsynaptic currents in the MSNs, and decreased excitability of the striatal ChIs. Knocking out Btbd9 specifically in the striatal MSNs, but not the ChIs, led to rest-phase specific motor restlessness, sleep disturbance, and increased thermal sensation in mice, which are consistent with results obtained from the Btbd9 KO mice. Our data establish the role of Btbd9 in regulating the activity of striatal neurons. Increased activity of the striatal MSNs, possibly through modulation by the striatal ChIs, contributes to the pathogenesis of RLS.

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Section: Resultsmentioning

confidence: 99%

The Role of BTBD9 in Striatum and Restless Legs Syndrome

Lyu

Xiao

DeAndrade

et al. 2019

eNeuro

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“…One reason for this objective was to assess whether MEMRI detects changes in synaptic activity not linked to the transient or acute pharmacological actions of cocaine (e.g., increased extracellular levels of monoamines). MEMRI has also been utilized to investigate functional neural circuitry changes in response to other drugs, such as methamphetamine (Hsu et al, 2008), morphine (Sun et al, 2006), and methylenedioxymethamphetamine (MDMA) (Chiu et al, 2015). It should be noted that the above-cited studies were carried out in male rats only.…”

Section: Discussionmentioning

confidence: 99%

“…Animal imaging studies can help overcome this limitation using contrast agent enhanced imaging that offers a closer indication of neuronal and synaptic activity (Duong et al, 2000; Inoue et al, 2011; London et al, 1989; Silva et al, 2004). Manganese enhanced MRI (MEMRI) has been used to track calcium-dependent synaptic activity under several experimental paradigms, including experimental conditions involving acute and chronic drug exposure (Chiu et al, 2015; Dudek et al, 2015; Hsu et al, 2008; Lu et al, 2007; Perrine et al, 2015). The manganese ion (Mn 2+ ) is a calcium analog that enters active synapses through voltage-gated calcium channels (Fukuda and Kawa, 1977; Narita et al, 1990) and is sequestered and transynaptically transported antero- and retrogradely across active neural circuits (Murayama et al, 2006; Pautler et al, 1998; Saleem et al, 2002; Sloot and Gramsbergen, 1994; Takeda et al, 1998a; Takeda et al, 1998b).…”

Section: Introductionmentioning

confidence: 99%

Cocaine differentially affects synaptic activity in memory and midbrain areas of female and male rats: an in vivo MEMRI study

Pérez

Hall

Zubcevic

et al. 2017

Brain Imaging and Behavior

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Manganese enhanced magnetic resonance imaging (MEMRI) has been previously used to determine the effect of acute cocaine on calcium-dependent synaptic activity in male rats. However, there have been no MEMRI studies examining sex differences in the functional neural circuits affected by repeated cocaine. In the present study, we used MEMRI to investigate the effects of repeated cocaine on brain activation in female and male rats. Adult female and male rats were scanned at 4.7 Tesla three days after final treatment with saline, a single cocaine injection (15 mg kg, i.p. × 1 day) or repeated cocaine injections (15 mg kg, i.p. × 10 days). A day before imaging rats were provided with an i.p. injection of manganese chloride (70 mg kg). Cocaine produced effects on MEMRI activity that were dependent on sex. In females, we observed that a single cocaine injection reduced MEMRI activity in hippocampal CA3, ventral tegmental area (VTA), and median Raphé, whereas repeated cocaine increased MEMRI activity in dentate gyrus and interpeduncular nucleus. In males, repeated cocaine reduced MEMRI activity in VTA. Overall, it appeared that female rats showed a general trend towards increase MEMRI activity with single cocaine and reduced activity with repeated exposure, while male rats showed a trend towards opposite effects. Our results provide evidence for sex differences in the in vivo neural response to cocaine, which involves primarily hippocampal, amygdala and midbrain areas.

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“…The 4-[ 18 F]ADAM PET and autoradiography for imaging SERTs have been validated in 5,7-dihydroxy tryptamine-lesioned and p-chloroamphetamine-induced, 5-hydroxy tryptamine (5-HT) depletion and paroxetine SSRI-treated rat models [12, 13] to evaluate the degrees of MDMA neurotoxicity and therapeutic response. We previously reported the neuroprotective effect of dextromethorphan against MDMA-induced neurotoxicity [14].…”

Section: Introductionmentioning

confidence: 99%

In vivo long-lasting alterations of central serotonin transporter activity and associated dopamine synthesis after acute repeated administration of methamphetamine

et al. 2019

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Background Methamphetamine (METH)-associated alterations in the striatal dopamine (DA) system or dopamine transport (DAT) have been identified in clinical and preclinical studies with positron emission tomography (PET) imaging but have not been well correlated with in vivo serotonin transporter (SERT) availability due to the lack of appropriate imaging agents to assess SERTs. N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio) benzylamine (4-[18F]-ADAM) has been developed by our group and validated for its high affinity and selectivity for SERTs, allowing the in vivo examination of SERT density, location, and binding function. The aims of this study were to investigate the potential of SERT imaging using 4-[18F]-ADAM PET to estimate the long-lasting effects of METH-induced serotonergic neurotoxicity, and further determine whether a correlative relationship exists between SERT availability/activity and tyrosine hydroxylase (TH) activity in various brain regions due to the long-lasting consequences of METH treatment. Results Male rats received four administrations of METH (5 or 10 mg/kg, s.c.) or saline (1 ml/kg, s.c.) at 1-h intervals. At 30 days post-administration, in vivo SERT availability and activity were measured by 4-[18F]ADAM PET imaging. In contrast to the controls, the uptake of 4-[18F]ADAM in METH-treated mice was significantly reduced in a dose-dependent manner in the midbrain, followed by the hypothalamus, thalamus, striatum, hippocampus, and frontal cortex. The regional effects of METH on TH activity were assessed by quantitative immunohistochemistry and presented as integrated optical density (IOD). A significant decrease in TH immunostaining and IOD ratios was seen in the caudate, putamen, nucleus accumbens, substantia nigra pars compacta, and substantia nigra pars reticulata in the METH-treated rats compared to controls. Conclusion The present results suggested that the long-lasting response to METH decreased the uptake of 4-[18F]-ADAM and varied regionally along with TH immunoreactivity. In addition, 4-[18F]ADAM PET could be used to detect serotonergic neuron loss and to evaluate the severity of serotonergic neurotoxicity of METH.

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Effect of MDMA-Induced Axotomy on the Dorsal Raphe Forebrain Tract in Rats: An In Vivo Manganese-Enhanced Magnetic Resonance Imaging Study

Cited by 10 publications

References 46 publications

The Role of BTBD9 in Striatum and Restless Legs Syndrome

The Role of BTBD9 in Striatum and Restless Legs Syndrome

Cocaine differentially affects synaptic activity in memory and midbrain areas of female and male rats: an in vivo MEMRI study

In vivo long-lasting alterations of central serotonin transporter activity and associated dopamine synthesis after acute repeated administration of methamphetamine

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