• The Korean Journal of Physiology and Pharmacology
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• v.1 no.6
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• pp.647-655
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• 1997

The purpose of present study is to investigate the influence of a spinal gamma-aminobutyric acid B($GABA_B$) receptor on a central regulation of blood pressure(BP) and heart rate(HR), and to define its mechanism in the spinal cord. In urethane-anesthetized, d-tubocurarine-paralyzed and artificially ventilated male Sprague-Dawley rats, intrathecal administration of drugs were carried out using injection cannula(33-gauge stainless steel) through the guide cannula(PE 10) which was inserted intrathecally at lower thoracic level through the puncture of a atlantooccipital membrane. Intrathecal injection of an $GABA_B$ receptor agonist, baclofen(30, 60, 100 nmol) decreased both BP and HR dose-dependently. Pretreatment with 8-bromo-cAMP(50 nmol), a cAMP analog, or glipizide(50 nmol), a ATP-sensitive $K^+$ channel blocker, attenuated the depressor and bradycardic effects of baclofen(100 nmol), but not with 8-bromo-cGMP(50 nmol), a cGMP analog. These results suggest that the $GABA_B$ receptor in the spinal cord plays an inhibitory role in central cardiovascular regulation and that this depressor and bradycardic actions are mediated by the decrease of cAMP via the inhibition of adenylate cyclase and the opening of $K^+$ channel.

• Journal of Ginseng Research
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• v.35 no.2
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• pp.219-225
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• 2011

Korean red ginseng (KRG) is a valuable and important traditional medicine in East Asian countries and is currently used extensively for botanical products in the world. KRG has both stimulatory and inhibitory effects on the central nervous system (CNS) suggesting its complicated action mechanisms. The substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis (Vc) are involved in orofacial nociceptive processing. Some studies reported that KRG has antinociceptive effects, but there are few reports of the functional studies of KRG on the SG neurons of the Vc. In this study, a whole cell patch clamp study was performed to examine the action mechanism of a KRG extract on the SG neurons of the Vc from juvenile mice. KRG induced short-lived and repeatable inward currents on all the SG neurons tested in the high chloride pipette solution. The KRG-induced inward currents were concentration dependent and were maintained in the presence of tetrodotoxin, a voltage gated $Na^+$ channel blocker. The KRG-induced inward currents were suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione, a non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist and/or picrotoxin, a gamma-aminobutyric acid $(GABA)_A$ receptor antagonist. However, the inward currents were not suppressed by d,l-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist. These results show that KRG has excitatory effects on the SG neurons of the Vc via the activation of non-NMDA glutamate receptor as well as an inhibitory effect by activation of the $GABA_A$ receptor, indicating the KRG has both stimulatory and inhibitory effects on the CNS. In addition, KRG may be a potential target for modulating orofacial pain processing.

• Journal of Ginseng Research
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• v.44 no.1
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• pp.86-95
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• 2020

Background: Ginsenoside Rb1 (Rb1), one of the most abundant protopanaxadiol-type ginsenosides, exerts excellent neuroprotective effects even though it has low intracephalic exposure. Purpose: The present study aimed to elucidate the apparent contradiction between the pharmacokinetics and pharmacodynamics of Rb1 by studying the mechanisms underlying neuroprotective effects of Rb1 based on regulation of microflora. Methods: A pseudo germ-free (PGF) rat model was established, and neuroprotective effects of Rb1 were compared between conventional and PGF rats. The relative abundances of common probiotics were quantified to reveal the authentic probiotics that dominate in the neuroprotection of Rb1. The expressions of the gamma-aminobutyric acid (GABA) receptors, including GABAA receptors (α2, β2, and γ2) and GABAB receptors (1b and 2), in the normal, ischemia/reperfusion (I/R), and I/R+Rb1 rat hippocampus and striatum were assessed to reveal the neuroprotective mechanism of Rb1. Results: The results showed that microbiota plays a key role in neuroprotection of Rb1. The relative abundance of Lactobacillus helveticus (Lac.H) increased 15.26 fold after pretreatment with Rb1. I/R surgery induced effects on infarct size, neurological deficit score, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were prevented by colonizing the rat gastrointestinal tract with Lac.H (1 × 10⁹ CFU) by gavage 15 d before I/R surgery. Both Rb1 and Lac.H upregulated expression of GABA receptors in I/R rats. Coadministration of a GABA_A receptor antagonist significantly attenuated neuroprotective effects of Rb1 and Lac.H. Conclusion: In sum, Rb1 exerts neuroprotective effects by regulating Lac.H and GABA receptors rather than through direct distribution to the target sites.

• Biomolecules & Therapeutics
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• v.23 no.5
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• pp.479-485
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• 2015

This study was performed to investigate the sedative-hypnotic activity of ${\gamma}$-aminobutyric acid (GABA)-enriched fermented marine organisms (FMO), including sea tangle (FST) and oyster (FO) by Lactobacillus brevis BJ20 (L. brevis BJ20). FST and FO were tested for their binding activity of the $GABA_A$-benzodiazepine and 5-$HT_{2C}$ receptors, which are well-known molecular targets for sleep aids. We also measured the sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of FST and FO. In $GABA_A$ and 5-$HT_{2C}$ receptor binding assays, FST displayed an effective concentration-dependent binding affinity to $GABA_A$ receptor, similar to the binding affinity to 5-$HT_{2C}$ receptor. FO exhibited higher affinity to 5-$HT_{2C}$ receptor, compared with the $GABA_A$ receptor. The oral administration of FST and FO produced a dose-dependent decrease in sleep latency and increase in sleep duration in pentobarbital-induced hypnosis. The data demonstrate that FST and FO possess sedativehypnotic activity possibly by modulating $GABA_A$ and 5-$HT_{2C}$ receptors. We propose that FST and FO might be effective agents for treatment of insomnia.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.5
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• pp.255-262
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• 2005

Striatum is involved in the control of movement and habitual memory. It receives glutamatergic input from wide area of the cerebral cortex as well as an extensive serotonergic (5-hydroxytryptamine, 5-HT) input from the raphe nuclei. In our study, the effects of 5-HT on synaptic transmission were studied in the rat corticostriatal brain slice using in vitro whole-cell recording technique. 5-HT inhibited the amplitude as well as frequency of spontaneous excitatory postsynaptic currents (sEPSC) significantly, and neither ${\gamma}-aminobutyric$ acid (GABA)A receptor antagonist bicuculline (BIC), nor $N-methyl-_{D}-aspartate$ (NMDA) receptor antagonist, $_{DL}-2-amino-5-phosphonovaleric$ acid (AP-V) could block the effect of 5-HT. In the presence non-NMDA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenxo[f] quinoxaline-7-sulfonamide (NBQX), the inhibitory effect of 5-HT was blocked. We also figured out that 5-HT change the channel kinetics of the sEPSC. There was a significant increase in the rise time during the 5-HT application. Our results suggest that 5-HT has an effect on both pre- and postsynaptic site with decreasing neurotransmitter release probability of glutamate and decreasing the sensitivity to glutamate by increasing the rise time of non-NMDA receptor mediated synaptic transmission in the corticostriatal synapses.

• The Korean Journal of Pain
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• v.19 no.1
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• pp.22-32
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• 2006

Background: This study was conducted to investigate the roles of the spinal and peripheral ${\gamma}$-aminobutyric acid (GABA)- ergic systems for the mechanical hypersensitivity produced by chronic compression of the dorsal root ganglion (CCD). Methods: CCD was performed at the left 5th lumbar dorsal root ganglion. The paw withdrawal threshold (PWT) to von Frey stimuli was measured. The mechanical responsiveness of the lumbar dorsal horn neurons was examined. GABAergic drugs were delivered with intrathecal (i.t.) or intraplantar (i.pl.) injection or by topical application onto the spinal cord. Results: CCD produced mechanical hypersensitivity, which was evidenced by the decrease of the PWT, and it lasting for 10 weeks. For the rats showing mechanical hypersensitivity, the mechanical responsiveness of the lumbar dorsal horn neurons was enhanced. A similar increase was observed with the normal lumbar dorsal horn neurons when the GABA-A receptor antagonist bicuculline was topically applied. An i.t. injection of GABA-A or GABA-B receptor agonist, muscimol or baclofen, alleviated the CCD-induced hypersensitivity. Topical application of same drugs attenuated the CCD-induced enhanced mechanical responsiveness of the lumbar dorsal horn neurons. CCD-induced hypersensitivity was also improved by low-dose muscimol applied (i.pl.) into the affected hind paw, whereas no effects could be observed with high-dose muscimol or baclofen. Conclusions: The results suggest that the neuropathic pain associated with compression of the dorsal root ganglion is caused by hyperexcitability of the dorsal horn neurons due to a loss of spinal GABAergic inhibition. Peripheral application of low-dose GABA-A receptor agonist can be useful to treat this pain.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.6
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• pp.517-524
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• 2014

Phasic and tonic ${\gamma}$-aminobutyric acidA ($GABA_A$) receptor-mediated inhibition critically regulate neuronal information processing. As these two inhibitory modalities have distinctive features in their receptor composition, subcellular localization of receptors, and the timing of receptor activation, it has been thought that they might exert distinct roles, if not completely separable, in the regulation of neuronal function. Inhibition should be maintained and regulated depending on changes in network activity, since maintenance of excitation-inhibition balance is essential for proper functioning of the nervous system. In the present study, we investigated how phasic and tonic inhibition are maintained and regulated by different signaling cascades. Inhibitory postsynaptic currents were measured as either electrically evoked events or spontaneous events to investigate regulation of phasic inhibition in layer 2/3 pyramidal neurons of the rat visual cortex. Tonic inhibition was assessed as changes in holding currents by the application of the $GABA_A$ receptor blocker bicuculline. Basal tone of phasic inhibition was maintained by intracellular $Ca^{2+}$ and $Ca^{2+}$/calmodulin-dependent protein kinase II (CaMKII). However, maintenance of tonic inhibition relied on protein kinase A activity. Depolarization of membrane potential (5 min of 0 mV holding) potentiated phasic inhibition via $Ca^{2+}$ and CaMKII but tonic inhibition was not affected. Thus, phasic and tonic inhibition seem to be independently maintained and regulated by different signaling cascades in the same cell. These results suggest that neuromodulatory signals might differentially regulate phasic and tonic inhibition in response to changes in brain states.

• Biomolecules & Therapeutics
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• v.26 no.3
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• pp.268-273
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• 2018

Sleep is the most basic and essential physiological requirement for mental health, and sleep disorders pose potential risks of metabolic and neurodegenerative diseases. Tryptic hydrolysate of ${\alpha}_{S1}$-casein (${\alpha}_{S1}-CH$) has been shown to possess stress relieving and sleep promoting effects. However, the differential effects of ${\alpha}_{S1}-CH$ on electroencephalographic wave patterns and its effects on the protein levels of ${\gamma}$-aminobutyric acid A ($GABA_A$) receptor subtypes in hypothalamic neurons are not well understood. We found ${\alpha}_{S1}-CH$ (120, 240 mg/kg) increased sleep duration in mice and reduced sleep-wake cycle numbers in rats. While ${\alpha}_{S1}-CH$ (300 mg/kg) increased total sleeping time in rats, it significantly decreased wakefulness. In addition, electroencephalographic theta (${\theta}$) power densities were increased whereas alpha (${\alpha}$) power densities were decreased by ${\alpha}_{S1}-CH$ (300 mg/kg) during sleep-wake cycles. Furthermore, protein expressions of $GABA_A$ receptor ${\beta}_1$ subtypes were elevated in rat hypothalamus by ${\alpha}_{S1}-CH$. These results suggest ${\alpha}_{S1}-CH$, through $GABA_A$ receptor modulation, might be useful for treating sleep disorders.

• Clinical and Experimental Reproductive Medicine
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• v.48 no.1
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• pp.50-60
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• 2021

Objective: This study investigated the mRNA expression of gamma-aminobutyric acid (GABA) receptors in the sperm of oligoasthenoteratozoospermic (OAT) and teratozoospermic (TER) men compared to normozoospermic (NOR) men, as well as the relationships between GABA receptor expression and sperm parameters, fertilization rate, and embryo quality. Methods: The mRNA expression of GABA A-α1 and GABA B-R2 receptors in sperm was examined using reverse transcription-polymerase chain reaction in three groups of patients: NOR (n=32), OAT (n=22), and TER (n=45). The fertilization rate and embryo quality were assessed in 35 patients undergoing intracytoplasmic sperm injection (ICSI; 10 NOR, 10 OAT, and 15 TER men). Results: OAT men had significantly higher mRNA expression of GABA A-α1 and GABA B-R2 receptors in sperm than NOR men; however, the difference between TER and NOR men was not significant. High levels of these receptors were significantly correlated with low sperm concentration, motility, and morphology, as well as the rate of good-quality embryos (GQEs) at the cleavage stage after ICSI. Patients whose female partners had a >50% GQE rate at the cleavage stage had significantly lower levels of GABA A-α1 receptor expression than those whose partners had a ≤50% GQE rate. Conclusion: Our findings indicate that mRNA levels of GABA receptors in human sperm are correlated with poor sperm quality and associated with embryo development after ICSI treatment. The GABA A-α1 receptor in sperm has a stronger relationship with embryo quality at the cleavage stage than the GABA B-R2 receptor.

• Journal of Yeungnam Medical Science
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• v.9 no.2
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• pp.382-395
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• 1992

GABA is an inhibitory neurotransmitter in central nervous system and produce sedative, antianxiety and muscle reaxing effects via $GABA_A$ receptor or $GABA_B$ receptor. Recently it is known that GABA is widely distributed throughout peripheral organs and may playa physiological role in certain organ. The vas deferens is innervated by species-difference. These study, therefore, was performed to investigate the mode and the mechanism of action of GABA on the norepiniphrine-, ATP- and electric stimulation-induced contraction of vas deferens of rat. Sprague-Dawley rats were sacrificed by cervical dislocation. The smooth muscle strips were isolated from the prostastic portion and were mounted in the isolated muscle bath. PSS in the bath was aerated with 95/5%-$O_2/CO_2$ at $33^{\circ}C$. Muscle tensions were measured by isometric tension transducer and were recorded by biological recording system. 1. GABA, muscimol, a $GAB_A$ agonist, and baclofen, a $GABA_B$ agonist inhibited the electric field stimulation(EFS, 0.2Hz, 1mSec, 80 V, monophasic square wave)-induced contraction with a rank order of potency of GABA greater than baclofen greater than muscimol. 2. The inhibitory effect of GABA was antagonized by delta aminovaleric acid(DAVA), a $GABA_B$ antagonist, but not by bicuculline, a $GABA_A$ mtagonist. 3. The inhibitory effect of baclofen was antagonized by DAVA, but the effect of muscimol was not antagonized by bicuculline. 4. Exogenous norepinephrine(NE) and ATP contracted muscle strip concentration dependently, but the effect of acetylcholine was negligible : and GABA did not affect the NE-and ATP-induced contractions. 5. GABA, baclofen and muscimol did not affect basal tone, and GABA did not affect the NE-and ATP-induced contractionsm 6. EFS-induced contraction was including 2 distinctable components. The first phasic component was inhibited by beta gamma-methylene ATP(mATP), a desensitizing agent of APT receptor and the second tonic component was reduced by pretreatment of reserpine(3 mg/Kg, IP). 7. GABA inhibited the EFS-induced contraction of reserpinized strips, but not the mATP-treated strips. These results suggest that in the prostatic portion of the rat vas deferens, adrenergic and purinergic neurotransmissions are exist, and GABA inhibits the release of ATP via presynaptic $GABA_B$ receptor on the excitatory neurons.