NNC-711, a novel potent and selective γ-aminobutyric acid uptake inhibitor: pharmacological characterization

Suzdak, Peter D.; Frederiksen, Kristen; Andersen, Knud Erik; Sørensen, Per O.; Knutsen, Lars J. S.; Nielsen, Erik Tetens

doi:10.1016/0014-2999(92)90804-d

Cited by 156 publications

(111 citation statements)

References 34 publications

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“…Similar behavioral patterns were also observed in WT mice treated with either tiagabine or NO711, both GAT1 inhibitors (Nielsen et al, 1991;Suzdak et al, 1992;Suzdak, 1994). Epileptic patients treated with Tiagabine display similar side effects, including dizziness, asthenia, somnolence (sedation), nonspecific nervousness, tremor, and ataxia (Adkins and Noble, 1998).…”

Section: Discussionmentioning

confidence: 68%

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

Chiu

Brickley²,

Jensen³

et al. 2005

J. Neurosci.

213

170

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GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, Ϫ10%; male, Ϫ20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25-32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABA A receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABA A -, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.

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Section: Discussionmentioning

confidence: 68%

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

Chiu

Brickley²,

Jensen³

et al. 2005

J. Neurosci.

213

170

View full text Add to dashboard Cite

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“…After being washed (three times) with icecold Krebs-Ringer buffer, the cells were collected in 1N NaOH, and radioactivity was counted with a liquid scintillation counter . Nonspecific uptake was determined in parallel wells that received both the tritiated tracer and 10 M mazindol for DA uptake or 10 M NO-711 for GABA uptake (Suzdak et al, 1992). In addition, for GABA uptake, comparable results were obtained with the inclusion of ␤-alanine (1 mM), which preferentially affects glial GABA uptake (Mabjeesh et al, 1992).…”

Section: Methodsmentioning

confidence: 99%

Distinct Role for Microglia in Rotenone-Induced Degeneration of Dopaminergic Neurons

et al. 2002

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Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in the pathogenesis of Parkinson's disease. In experimental animals the exposure to a common herbicide, rotenone, induces features of parkinsonism; mechanistically, rotenone-induced destruction of dopaminergic neurons has been attributed to its inhibition of the activity of neuronal mitochondrial complex I. However, the role of microglia, the resident brain immune cells in rotenoneinduced neurodegeneration, has not been reported. Using primary neuron-enriched and neuron/glia cultures from the rat mesencephalon, we discovered an extraordinary feature for rotenone-induced degeneration of cultured dopaminergic neurons. Although little neurotoxicity was detected in neuronenriched cultures after treatment for 8 d with up to 20 nM rotenone, significant and selective dopaminergic neurodegeneration was observed in neuron/glia cultures 2 d after treatment with 20 nM rotenone or 8 d after treatment with 1 nM rotenone. The greatly enhanced neurodegenerative ability of rotenone was attributed to the presence of glia, especially microglia, because the addition of microglia to neuron-enriched cultures markedly increased their susceptibility to rotenone. Mechanistically, rotenone stimulated the release of superoxide from microglia that was attenuated by inhibitors of NADPH oxidase. Furthermore, inhibition of NADPH oxidase or scavenging of superoxide significantly reduced the rotenone-induced neurotoxicity. This is the first report demonstrating that microglia play a pivotal role in rotenone-induced degeneration of dopaminergic neurons. The results of this study should advance our understanding of the mechanism of action for pesticides in the pathogenesis of Parkinson's disease.

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“…To determine whether the impairment of TBS-induced LTP is due to acute absence of GABA uptake through GAT1 or indirect chronic effect of GAT1 gene deletion, we examined the effect of acute blockade of GAT1 function with the specific GAT1 inhibitor NO711 (Suzdak et al, 1992) in hippocampal slices from WT mice. The presence of NO711 (20 M) had no effect on the basal excitatory synaptic transmission, as shown by the input-output function and PPF of fEPSPs (supplemental Fig.…”

Section: Disruption Of Gat1 Activity Selectively Impaired Tbs-inducedmentioning

confidence: 99%

GABA Transporter-1 Activity Modulates Hippocampal Theta Oscillation and Theta Burst Stimulation-Induced Long-Term Potentiation

Gong

Li²,

Cai³

et al. 2009

J. Neurosci.

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The network oscillation and synaptic plasticity are known to be regulated by GABAergic inhibition, but how they are affected by changes in the GABA transporter activity remains unclear. Here we show that in the CA1 region of mouse hippocampus, pharmacological blockade or genetic deletion of GABA transporter-1 (GAT1) specifically impaired long-term potentiation (LTP) induced by theta burst stimulation, but had no effect on LTP induced by high-frequency stimulation or long-term depression induced by low-frequency stimulation. The extent of LTP impairment depended on the precise burst frequency, with significant impairment at 3-7 Hz that correlated with the time course of elevated GABAergic inhibition caused by GAT1 disruption. Furthermore, in vivo electrophysiological recordings showed that GAT1 gene deletion reduced the frequency of hippocampal theta oscillation. Moreover, behavioral studies showed that GAT1 knock-out mice also exhibited impaired hippocampus-dependent learning and memory. Together, these results have highlighted the important link between GABAergic inhibition and hippocampal theta oscillation, both of which are critical for synaptic plasticity and learning behaviors.

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NNC-711, a novel potent and selective γ-aminobutyric acid uptake inhibitor: pharmacological characterization

Cited by 156 publications

References 34 publications

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

Distinct Role for Microglia in Rotenone-Induced Degeneration of Dopaminergic Neurons

GABA Transporter-1 Activity Modulates Hippocampal Theta Oscillation and Theta Burst Stimulation-Induced Long-Term Potentiation

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