Inhibition of uptake, steady‐state currents, and transient charge movements generated by the neuronal GABA transporter by various anticonvulsant drugs

Eckstein-Ludwig, Ursula; Fei, Jian; Schwarz, Wolfgang

doi:10.1038/sj.bjp.0702794

Cited by 71 publications

(39 citation statements)

References 32 publications

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“…Our results are in contrast to those obtained by EcksteinLudwig et al (24) who report the inhibition of mouse GAT1-mediated GABA uptake by valproate, although it was also reported that valproate did not alter the steady-state or presteady-state currents of mouse GAT1. The authors propose a valproate-induced dissociation of GABA uptake and GABAinduced currents.…”

Section: Valproate Enhances the Presteady-state Charge Movements At Rcontrasting

confidence: 57%

“…These agents exhibit anticonvulsant activity in animal models, and one (tiagabine) that preferentially targets the most abundant GABA transporter isoform in the brain (GAT1) has been in clinical use since 1997 (16 -22). Several other clinically used antiepileptic drugs are reported to act, at least in part, via potentiating GABA-mediated inhibition in the brain (11,23); however, little is known regarding the potential effect of these drugs on the GABA transporters (24).…”

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confidence: 99%

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The Anticonvulsant Valproate Increases the Turnover Rate of γ-Aminobutyric Acid Transporters

Whitlow

Sacher

Loo

et al. 2003

Journal of Biological Chemistry

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Valproate is an important anticonvulsant currently in clinical use for the treatment of seizures. We used electrophysiological and tracer uptake methods to examine the effect of valproate on a ␥-aminobutyric acid (GABA) transporter (mouse GAT3) expressed in Xenopus laevis oocytes. In the absence of GABA, valproate (up to 50 mM) had no noticeable effect on the steady-state electrogenic properties of mGAT3. In the presence of GABA, however, valproate enhanced the GABA-evoked steady-state inward current in a dose-dependent manner with a halfmaximal concentration of 4.6 ؎ 0.5 mM. Maximal enhancement of the GABA-evoked current was 275 ؎ 10%. Qualitatively similar observations were obtained for human GAT1 and mouse GAT4. The valproate enhancement did not alter the Na ؉ or Cl ؊ dependence of the steady-state GABA-evoked currents. Uptake experiments under voltage clamp suggested that the valproate enhancement of the GABA-evoked current was matched by an enhancement in GABA uptake. Thus, despite the increase in GABA-evoked current, ion/GABA co-transport remained tightly coupled. Uptake experiments indicated that valproate is not transported by mouse GAT3 in the absence or presence of GABA. Valproate also enhanced the rate of the partial steps involved in transporter presteady-state charge movements. We propose that valproate increases the turnover rate of GABA transporters by an allosteric mechanism. The data suggest that at its therapeutic concentration, valproate may enhance the activity of neuronal and glial GABA transporters by up to 10%. ␥-Aminobutyric acid (GABA)1 is the most abundant inhibitory neurotransmitter in the central nervous system. Transport of GABA into cells is accomplished by Na ϩ -dependent and Cl Ϫ -facilitated GABA transporters (GATs) found in the plasma membrane of neurons and glia (1-10). Thus, the GABA transporters regulate synaptic and extra-synaptic concentrations of GABA and, in this capacity, are partly responsible for the regulation of inhibitory neurotransmission in the nervous system. Because of the inhibitory role of GABA, potentiation of GABAergic neurotransmission via inhibition or reversal of the GABA transporters is believed to have therapeutic value in treating epileptic seizures and stroke (11-13). Indeed, inhibitors of the GABA transporters are known to increase GABA levels in the brain (14 -16). These agents exhibit anticonvulsant activity in animal models, and one (tiagabine) that preferentially targets the most abundant GABA transporter isoform in the brain (GAT1) has been in clinical use since 1997 (16 -22). Several other clinically used antiepileptic drugs are reported to act, at least in part, via potentiating GABA-mediated inhibition in the brain (11, 23); however, little is known regarding the potential effect of these drugs on the GABA transporters (24).Valproate (2-propylpentanoate) has been in clinical use since 1967 and is effective against many types of epileptic seizures (both partial and generalized seizures). Although the exact mechanism of valproate action is not ...

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Section: Valproate Enhances the Presteady-state Charge Movements At Rcontrasting

confidence: 57%

mentioning

confidence: 99%

The Anticonvulsant Valproate Increases the Turnover Rate of γ-Aminobutyric Acid Transporters

Whitlow

Sacher

Loo

et al. 2003

Journal of Biological Chemistry

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“…Gabapentin has little affinity at ionotropic GABA A receptors or metabotropic GABA B receptors (Suman-Chauhan et al, 1993), but significantly increases GABA synthesis (Löscher et al, 1991) and release (Götz et al, 1993), most likely by reversal of the GABA transporter (Honmou et al, 1995). In addition, high concentrations of gabapentin also inhibit GABA uptake by blocking GABA binding to GABA transporters (Eckstein-Ludwig et al, 1999). Consistent with these findings observed in vitro, the present in vivo brain microdialysis study demonstrated that gabapentin (100-200 mg/kg) produced a modest (∼50%), delayed (∼2 h) increase in extracellular GABA levels, which lasted for at least 4 h. In contrast to this present finding, another in vivo microdialysis study reported that 100 mg/kg gabapentin alters neither basal levels of extracellular GABA, nor K + -, glutamate-or nipecotic acid-induced increases in extracellular GABA in the substantia nigra (SN) (Timmerman et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Effects of gabapentin on cocaine self-administration, cocaine-triggered relapse and cocaine-enhanced nucleus accumbens dopamine in rats

Peng

et al. 2008

Drug and Alcohol Dependence

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Gabapentin is a γ-aminobutyric acid (GABA) analogue, with GABAmimetic pharmacological properties. Gabapentin is used for the treatment of seizures, anxiety and neuropathic pain. It has been proposed that gabapentin may be useful in the treatment of cocaine dependence. However, clinical trials with gabapentin have shown conflicting results, while preclinical studies are sparse. In the present study, we investigated the effects of gabapentin on intravenous cocaine self-administration and cocaine-triggered reinstatement of drug-seeking behavior, as well as on cocaine-enhanced dopamine (DA) in the nucleus accumbens (NAc). We found that gabapentin (25-200 mg/kg, i.p., 30 min or 2 h prior to cocaine) failed to inhibit intravenous cocaine (0.5 mg/kg/infusion) selfadministration under a fixed-ratio reinforcement schedule or cocaine-triggered reinstatement of cocaine-seeking behavior. In vivo microdialysis showed that the same doses of gabapentin produced a modest increase (∼50%, p < 0.05) in extracellular NAc GABA levels, but failed to alter either basal or cocaine-enhanced NAc DA. These data suggest that gabapentin is a weak GABA-mimic drug. At the doses tested, it has no effect in the addiction-related animal behavioral models here tested. This

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“…It seems that gabapentin does not inhibit GABA uptake directly through inhibiting GABA transporter (73) unless the concentration of gabapentin is high (74). On the contrary, gabapentin may enhance promoted release of GABA, which is thought to be due to reverse operation of the GABA transporter (75), through increasing GABA uptake by a redistribution of GABA transporter protein from intracellular locations to the plasma membrane (73).…”

Section: -1-3 Gaba Levelmentioning

confidence: 99%

Mechanisms of the Antinociceptive Action of Gabapentin

2006

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Abstract. Gabapentin, a γ-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA B receptors consisting of GABA B1a and GABA B2 subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K + channels, activating hyperpolarization-activated cation channels, and modulating Ca 2+ current by selectively binding to the specific binding site of [3 H]gabapentin, the α 2 δ subunit of voltage-dependent Ca 2+ channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the α 2 δ subunit of spinal N-type Ca 2+ channels is very likely the analgesic action target of gabapentin.

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Inhibition of uptake, steady‐state currents, and transient charge movements generated by the neuronal GABA transporter by various anticonvulsant drugs

Cited by 71 publications

References 32 publications

The Anticonvulsant Valproate Increases the Turnover Rate of γ-Aminobutyric Acid Transporters

The Anticonvulsant Valproate Increases the Turnover Rate of γ-Aminobutyric Acid Transporters

Effects of gabapentin on cocaine self-administration, cocaine-triggered relapse and cocaine-enhanced nucleus accumbens dopamine in rats

Mechanisms of the Antinociceptive Action of Gabapentin

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