Gabapentin inhibits presynaptic Ca2+ influx and synaptic transmission in rat hippocampus and neocortex

Hooft, Johannes A. van; Dougherty, John J.; Endeman, Duco; Nichols, Robert A.; Wadman, Wytse J.

doi:10.1016/s0014-2999(02)02044-7

Cited by 78 publications

(51 citation statements)

References 29 publications

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“…100 -102 Other studies have shown inhibition of the release of glutamate and other neurotransmitters. [103][104][105] The variability in the effects on Ca 2ϩ current may relate to differences in expression of the ␣2-␦ subunit in different cell types or in response to different conditions. For example, in chronic neuropathic pain states, ␣2-␦ subunits may be upregulated, conferring gabapentin and pregabalin sensitivity.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…Gabapentin increases (1) the concentration and probably the synthesis of GABA in the brain (Taylor et al, 1998), (2) GABA release from rat striatal brain slices in vitro (Gotz et al, 1993), and (3) the nonvesicular release of GABA in rat optic nerves (Kocsis and Honmou, 1994) and rat hippocampal slices (Honmou et al, 1995). Gabapentin also decreases monoaminergic synaptic transmission in rat hippocampus and neocortex by selectively inhibiting Ca 2ϩ influx through voltage-operated Ca 2ϩ channels (VOCCs) (Fink et al, 2000;Dooley et al, 2002;van Hooft et al, 2002). In addition, gabapentin is an agonist for the endogenously expressed GABA B gb1a-gb2 heteromers coupled to inhibition of VOCCs in intermediate pituitary melanotrope cell lines and in hippocampal neurons Ng et al, 2001;van Hooft et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Gabapentin also decreases monoaminergic synaptic transmission in rat hippocampus and neocortex by selectively inhibiting Ca 2ϩ influx through voltage-operated Ca 2ϩ channels (VOCCs) (Fink et al, 2000;Dooley et al, 2002;van Hooft et al, 2002). In addition, gabapentin is an agonist for the endogenously expressed GABA B gb1a-gb2 heteromers coupled to inhibition of VOCCs in intermediate pituitary melanotrope cell lines and in hippocampal neurons Ng et al, 2001;van Hooft et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Roberto¹,

Gilpin²,

O’Dell³

et al. 2008

J. Neurosci.

115

128

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Gabapentin is a structural analog of GABA that has anticonvulsant properties. Despite the therapeutic efficacy of gabapentin, its molecular and cellular mechanisms of action are unclear. The GABAergic system in the central nucleus of the amygdala (CeA) plays an important role in regulating voluntary ethanol intake. Here, we investigated the effect of gabapentin on GABAergic transmission in CeA slices, on ethanol intake, and on an anxiety measure using animal models of ethanol dependence. Gabapentin increased the amplitudes of evoked GABA receptor-mediated IPSCs (GABA-IPSCs) in CeA neurons from nondependent rats, but decreased their amplitudes in CeA of ethanol-dependent rats. Gabapentin effects were blocked in the presence of a specific GABA B receptor antagonist. The sensitivity of the GABA-IPSCs to a GABA B receptor antagonist and an agonist was decreased after chronic ethanol, suggesting that ethanol-induced neuroadaptations of GABA B receptors associated with ethanol dependence may account for the differential effects of gabapentin after chronic ethanol. Systemic gabapentin reduced ethanol intake in dependent, but not in nondependent, rats and reversed the anxiogeniclike effects of ethanol abstinence using an acute dependence model. Gabapentin infused directly into the CeA also blocked dependenceinduced elevation in operant ethanol responding. Collectively, these findings show that gabapentin reverses behavioral measures of ethanol dependence and, in turn, dependence reverses the effects of gabapentin on CeA neurons, and suggest that gabapentin represents a potential medication for treatment of alcoholism.

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“…6,7 In a recent fine study of gabapentin effect in rat hippocampus and neocortex, the results suggested that gabapentin selectively inhibits Ca 2 þ influx by inhibiting voltage-operated Ca 2 þ channels in a subset of excitatory and inhibitory presynaptic terminals, thereby attenuating synaptic transmission. 8 Although the molecular targets of gabapentin remain unknown, the inhibition of Ca 2 þ efflux from muscle cells in the corpora, with a consequent inhibition of smooth muscle relaxation, might explain the effectiveness of gabapentin in the management of refractory priapism. An interesting issue is the ability of these men to have normal erections, although treated with gabapentin.…”

Section: Discussionmentioning

confidence: 99%

Gabapentin in the management of the recurrent, refractory, idiopathic priapism

et al. 2004

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Recurrent idiopathic priapism is a difficult problem to treat and a true emergency for the physicians, and often even invasive therapeutic interventions fail. We recently managed three men with refractory idiopathic priapism with oral gabapentin. They responded to treatment within 48 h. Two men continue not to experience prolonged erections while treated with lower doses of gabapentin for 16 and 24 months, respectively. The third, after a successful treatment for 6 months, stopped gabapentin and priapism recurred. He responded to treatment again and continues to be free of episodes for 9 months. Gabapentin may be a safe alternative for the management of refractory idiopathic priapism.

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Gabapentin inhibits presynaptic Ca2+ influx and synaptic transmission in rat hippocampus and neocortex

Cited by 78 publications

References 29 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Cellular and Behavioral Interactions of Gabapentin with Alcohol Dependence

Gabapentin in the management of the recurrent, refractory, idiopathic priapism

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