Roles of .GAMMA.-Aminobutyric AcidB (GABAB) and .GAMMA.-Hydroxybutyric Acid Receptors in Hippocampal Long-Term Potentiation and Pathogenesis of Absence Seizures.

Aizawa, Masahiro; Ito, Yoshihisa; Fukuda, Hideomi

doi:10.1248/bpb.20.1066

Cited by 22 publications

(23 citation statements)

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“…Vagal inputs to the different cortical areas may be mediated via thalamic nuclei and also via the parabrachial nucleus (19), the periaqueductal grey matter (20), and locus coeruleus (2 I ) together with direct projections from the nucleus of the solitary tract (22). Putative neurotransmitters in neurons along these pathways may include norepinephrine or y-aminobutyric acid (GABA), of which both have anticonvulsive applications and have been shown to modulate synaptic transmission in the cortex (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Slow Hyperpolarization in Cortical Neurons: A Possible Mechanism Behind Vagus Nerve Simulation Therapy for Refractory Epilepsy?

Zagon

Kemeny

2000

Epilepsia

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Summary:Purpose: Recent studies have shown that chronic, intermittent stimulation of the left vagus nerve (VNS) decreases the frequency, duration, andlor intensity of seizures in some patients with medically refractory focal seizures. Although VNS is being used in an increasing number of patients, the neuronal mechanism behind VNS therapy of refractory epileptic seizures is yet unclear. ~e t h~) d s ;In vivo intracellular recordings were used to study responses elicited by the VNS in pyramidal neurons of the parietal association cortex in anesthetized rats.Results: Low-intensity trains of VNS, which activated predominantly myelinated fibers (100 PA, 30 Hz, 0.5 millisecond, 20 seconds), elicited a slow hyperpolarization (onset latency 17.4 f 2.0 seconds, amplitude -4.7 -ir 0.6 mV, duration 35 i 3.2 seconds; n = 19). Increasing the intensity of VNS to recruit nonmyelinated vagal fibers (200 PA) led to an increase in the magnitude of the response in some neurons while failed to evoke a response in others. On increasing the stimulus intensity to 500 PA, only one in nine neurons exhibited a visible response. All recorded and visualised neurons were pyramidal cells in cortical layer V.Conclusions: Stimulus intensities that activate predominantly myelinated fibers (less than 200 PA) were most effective to induce slow vagal hyperpolarization. It is suggested that slow hyperpolarization may be one of the mechanisms that underlie the seizure-reducing effect of VNS, by means of reducing the excitability in neurons that would be involved in propagation of seizure activity. As the balance of activity i n myelinated and nonmyelinated primary vagal afferents influenced the effect of VNS stimulation, it is likely that the effect of VNS is modulated as changes occur in the underlying vagal tone.

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Section: Discussionmentioning

confidence: 99%

Slow Hyperpolarization in Cortical Neurons: A Possible Mechanism Behind Vagus Nerve Simulation Therapy for Refractory Epilepsy?

Zagon

Kemeny

2000

Epilepsia

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“…It was initially reported that the compound blocked various GHB-induced effects such as cataplexy, hypolocomotion, and ASs 106,107, but more recent studies have reported a lack of effects 108–110 or even an aggravation of GHB-induced activities 100,111. In addition, high doses of NCS-382 were able to drastically reduce SWDs induced by PTZ 112 and spontaneous ASs in GAERS 107 and lethargic mice 113, suggesting that its effects are not specific to the GHB model. Finally, putative agonists for the GHBR (e.g., trans-hydroxycrotonic acid (THCA), which displaces GHB from its high affinity binding sites, but does not bind to GABA B Rs 93), did not induce ASs in naïve animals or exacerbate seizures in GAERS 100,114.…”

Section: Putative Ghbr-mediated Effects: Ass Cellular Excitability mentioning

confidence: 99%

“…As far as potential GHBR-mediated effects of GHB are concerned, an in vivo study in anesthetized mice showed that NCS-382 blocked the increase in long-term potentiation in the hippocampus elicited by systemic GBL (50 mg/kg) 113. Unfortunately, the effect of GABA B R antagonists, that blocked a similar increase in long-term potentiation induced by baclofen, was not tested against the GBL action 113.…”

Section: Putative Ghbr-mediated Effects: Ass Cellular Excitability mentioning

confidence: 99%

“…Unfortunately, the effect of GABA B R antagonists, that blocked a similar increase in long-term potentiation induced by baclofen, was not tested against the GBL action 113. Another in vivo study in anesthetized rats reported that systemic GHB (5–10 mg/kg) first decreased and then increased the firing rate of unidentified cortical layer III–VI neurons, with the latter effect being blocked by NCS-382 115.…”

Section: Putative Ghbr-mediated Effects: Ass Cellular Excitability mentioning

confidence: 99%

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A Critical Evaluation of the Gamma‐Hydroxybutyrate (GHB) Model of Absence Seizures

2014

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Typical absence seizures (ASs) are nonconvulsive epileptic events which are commonly observed in pediatric and juvenile epilepsies and may be present in adults suffering from other idiopathic generalized epilepsies. Our understanding of the pathophysiological mechanisms of ASs has been greatly advanced by the availability of genetic and pharmacological models, in particular the γ-hydroxybutyrate (GHB) model which, in recent years, has been extensively used in studies in transgenic mice. GHB is an endogenous brain molecule that upon administration to various species, including humans, induces not only ASs but also a state of sedation/hypnosis. Analysis of the available data clearly indicates that only in the rat does there exist a set of GHB-elicited behavioral and EEG events that can be confidently classified as ASs. Other GHB activities, particularly in mice, appear to be mostly of a sedative/hypnotic nature: thus, their relevance to ASs requires further investigation. At the molecular level, GHB acts as a weak GABA-B agonist, while the existence of a GHB receptor remains elusive. The pre- and postsynaptic actions underlying GHB-elicited ASs have been thoroughly elucidated in thalamus, but little is known about the cellular/network effects of GHB in neocortex, the other brain region involved in the generation of ASs.

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“…Exogenously applied GHB controls hippocampal glutamate levels in a concentration-dependent manner. It is reported that the systemic administration of low doses of GBL, as a precursor of GHB, augments long-term potentiation/depolarization, causing transient plasticity in the CA1 intrahippocampal region and, mediated by GHBR activation, increases hippocampal glutamate transmission [99,100,101]. GHB in millimolar concentrations exerts the same effect [100,102] mediated by the N-methyl- D -aspartate receptor (NMDAR)-gated ion channel [103].…”

Section: Neurobiological Pathway Of Ghb Dependencementioning

confidence: 99%

The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review

Kamal

Noorden²,

Franzek³

et al. 2016

Neuropsychobiology

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Objective: γ-Hydroxybutyrate (GHB) has gained popularity as a drug of abuse. In the Netherlands the number of patients in treatment for GHB dependence has increased sharply. Clinical presentation of GHB withdrawal can be life threatening. We aim, through this overview, to explore the neurobiological pathways causing GHB dependency and withdrawal, and their implications for treatment choices. Methods: In this work we review the literature discussing the findings from animal models to clinical studies focused on the neurobiological pathways of endogenous but mainly exogenous GHB. Results: Chronic abuse of GHB exerts multifarious neurotransmitter and neuromodulator effects on γ-aminobutyric acid (GABA), glutamate, dopamine, serotonin, norepinephrine and cholinergic systems. Moreover, important effects on neurosteroidogenesis and oxytocin release are wielded. GHB acts mainly via a bidirectional effect on GABA_B receptors (GABA_BR; subunits GABA_B1 and GABA_B2), depending on the subunit of the GIRK (G-protein-dependent ion inwardly rectifying potassium) channel involved, and an indirect effect of the cortical and limbic inputs outside the nucleus accumbens. GHB also activates a specific GHB receptor and β₁-subunits of α₄-GABA_AR. Reversing this complex interaction of neurobiological mechanisms by the abrupt cessation of GHB use results in a withdrawal syndrome with a diversity of symptoms of different intensity, depending on the pattern of GHB abuse. Conclusion: The GHB withdrawal symptoms cannot be related to a single mechanism or neurological pathway, which implies that different medication combinations are needed for treatment. A single drug class, such as benzodiazepines, gabapentin or antipsychotics, is unlikely to be sufficient to avoid life-threatening complications. Detoxification by means of titration and tapering of pharmaceutical GHB can be considered as a promising treatment that could make polypharmacy redundant.

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Roles of .GAMMA.-Aminobutyric AcidB (GABAB) and .GAMMA.-Hydroxybutyric Acid Receptors in Hippocampal Long-Term Potentiation and Pathogenesis of Absence Seizures.

Cited by 22 publications

References 0 publications

Slow Hyperpolarization in Cortical Neurons: A Possible Mechanism Behind Vagus Nerve Simulation Therapy for Refractory Epilepsy?

Slow Hyperpolarization in Cortical Neurons: A Possible Mechanism Behind Vagus Nerve Simulation Therapy for Refractory Epilepsy?

A Critical Evaluation of the Gamma‐Hydroxybutyrate (GHB) Model of Absence Seizures

The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review

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