• Biomolecules & Therapeutics
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• 제22권4호
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• pp.314-320
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• 2014

This study was investigated to know whether pachymic acid (PA), one of the predominant triterpenoids in Poria cocos (Hoelen) has the sedative-hypnotic effects, and underlying mechanisms are mediated via ${\gamma}$-aminobutyric acid (GABA)-ergic systems. Oral administration of PA markedly suppressed locomotion activity in mice. This compound also prolonged sleeping time, and reduced sleep latency showing synergic effects with muscimol (0.2 mg/kg) in shortening sleep onset and enhancing sleep time induced by pentobarbital, both at the hypnotic (40 mg/kg) and sub-hypnotic (28 mg/kg) doses. Additionally, PA elevated intracellular chloride levels in hypothalamic primary cultured neuronal cells of rats. Moreover, Western blotting quantitative results showed that PA increased the amount of protein level expression of $GAD_{65/67}$ over a broader range of doses. PA increased ${\alpha}$- and ${\beta}$-subunits protein levels, but decreased ${\gamma}$-subunit protein levels in $GABA_A$ receptors. The present experiment provides evidence for the hypnotic effects as PA enhanced pentobarbital-induced sleeping behaviors via $GABA_A$-ergic mechanisms in rodents. Taken together, it is proposed that PA may be useful for the treatment of sleep disturbed subjects with insomnia.

• The Korean Journal of Physiology and Pharmacology
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• 제7권3호
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• pp.169-174
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• 2003

${\gamma}$-Aminobutyric acid (GABA) has been reported to enhance exocrine secretion evoked not only by secretagogues but also by intrinsic neuronal excitation in the pancreas. The pancreas contains cholinergic neurons abundantly that exert a stimulatory role in exocrine secretion. This study was undertaken to examine effects of GABA on an action of cholinergic neurons in exocrine secretion of the pancreas. Intrinsic neurons were excited by electrical field stimulation (EFS; 15 V, 2 msec, 8 Hz, 45 min) in the isolated, perfused rat pancreas. Tetrodotoxin or atropine was used to block neuronal or cholinergic action. Acetylcholine was infused to mimic cholinergic excitation. GABA $(30{\mu}M)$ and muscimol $(10{\mu}M)$, given intra-arterially, did not change spontaneous secretion but enhanced cholecystokinin (CCK; 10 pM)-induced secretions of fluid and amylase. GABA (3, 10, $30{\mu}M$) further elevated EFS-evoked secretions of fluid and amylase dose-dependently. GABA (10, 30, $100{\mu}M$) also further increased acetylcholine $(5{\mu}M)$-induced secretions of fluid and amylase in a dose-dependent manner. Bicuculline $(10{\mu}M)$ effectively blocked the enhancing effects of GABA $(30{\mu}M)$ on the pancreatic secretions evoked by either EFS or CCK. Both atropine $(2{\mu}M)$ and tetrodotoxin $(1{\mu}M)$ markedly reduced the GABA $(10{\mu}M)$-enhanced EFS- or CCK-induced pancreatic secretions. The results indicate that GABA enhances intrinsic cholinergic neuronal action on exocrine secretion via the $GABA_A$ receptors in the rat pancreas.

• Natural Product Sciences
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• 제21권3호
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• pp.219-225
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• 2015

In the previous experiments, we reported that ethanol extract of Gastrodiae Rhizoma, the dried tuber of Gastrodia ElataBlume (Orchidaceae) increased pentobarbital-induced sleeping behaviors. These experiments were undertaken to know whether 4-hydroxybenzaldehyde (4-HBD), is one of the major compounds of Gastrodiae Rhizoma increases pentobarbital-induced sleeping behaviors and changes sleep architectures via activating GABA_A-ergic systems in rodents. 4-HBD decreased locomotor activity in mice. 4-HBD increased total sleep time, and decreased of sleep onset by pentobarbital (28 mg/kg and 40 mg/kg). 4-HBD showed synergistic effects with muscimol (a GABA_A receptor agonist), shortening sleep onset and enhancing sleep time on pentobarbital-induced sleeping behaviors. On the other hand, 4-HBD (200 mg/kg, p.o.) itself significantly inhibited the counts of sleepwake cycles, and prolonged total sleep time and non-rapid eye movement (NREM) in rats. Moreover, 4-HBD increased intracellular Cl⁻ levels in the primary cultured cerebellar cells. The protein levels of glutamic acid decarboxylase (GAD) and GABA_A receptors subunits were over-expressed by 4-HBD. Consequently, these results demonstrate that 4-HBD increased NREM sleep as well as sleeping behaviors via the activation of GABA_A-ergic systems in rodents.

• Biomolecules & Therapeutics
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• 제16권4호
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• pp.343-350
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• 2008

Oroxylin A is a flavonoid isolated from Scutellaria baicalensis, which is one of the most important medicinal herbs in traditional Korean medicine. In this study, we investigated the psychopharmacological activities of oroxylin A using the open field, rota-rod, balanced wire and plus-maze tests in Spontaneously Hypertensive Rats (SHR) and Wistar Kyoto Rats (WKY). Oroxylin A reduced hyperactivity in SHR (ADHD animal model) although it tended to increase locomotor activity in WKY. Methylphenidate did not reduce hyperactivity. Oroxylin A alleviated impulsive behaviors such as rearing, the percentage of moving time to the central area and the tendency to move into an unstable condition (open area in elevated plus-maze). Methylphenidate also reduced the percentage of staying time in the central area and the tendency to move into an unstable condition. Both oroxylin A and methylphenidate enhanced motor attention in SHR and WKY. Oroxylin A antagonized the muscimol ($GABA_A$ receptor agonist)-induced $Cl^-$current and its action was similar to that of bicuculline ($GABA_A$ receptor antagonist). The effects of oroxylin A may be caused by the antagonism at the $GABA_A$ receptor. Thus, oroxylin A may be a candidate of drug for treatment of ADHD.

• Archives of Pharmacal Research
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• 제29권5호
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• pp.400-404
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• 2006

This study examined the effect of Gamma-Amino butyric acid (GABA) and selective GABA receptor related drugs on the electrically stimulated relaxation in the lower esophageal sphincter muscle (LES) of a cat. Tetrodotoxin $(10^{-6}\;M)$ suppressed the electrically stimulated (0.5-5 Hz) relaxation of the LES. However, guanethidine $(10^{-6}\;M)$ and atropine $(10^{-6}\;M)$ had no effect indicating that the relaxations were neurally mediated via the nonadrenergic and noncholinergic (NANC) pathways. NG-nitro-L-arginine methyl ester ($10^{-4}M$, L-NAME) also inhibited the relaxant response but did not completely abolish the electrically stimulated relaxation with 60% inhibition, which suggests the involvement of nitric oxide as an inhibitory transmitter. This study examined the role of GABA, an inhibitory neurotransmitter, on neurally mediated LES relaxation. GABA ($10^{-3}-10^{-5}M$, non selective receptor agonist), muscimol ($10^{-3}-10^{-5}M$, GABA-A agonist), and baclofen ($10^{-3}-10^{-5}M$, GABA-B agonist) had no significant effect on the electrically stimulated relaxation. Moreover, bicuculline ($10^{-5}M$, GABA-A antagonist) and phaclofen ($10^{-5}M$, GABA-B antagonist) had no inhibitory effect on the electrically stimulated relaxation. This suggests that GABA and the GABA receptor are not involved in the electrically stimulated NANC relaxation in the cat LES.

• International Journal of Oral Biology
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• 제30권3호
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• pp.91-98
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• 2005

Gamma-aminobutyric acid (GABA) is known as an inhibitory neurotransmitter in the neurons of the central nervous system. However, its detailed action mechanisms in the rostral gustatory zone of the nucleus tractus solitarius (rNTS) have not been established. The present study was aimed to investigate the distribution, role and action mechanisms of GABA in rNTS. Membrane potentials were recorded by whole cell recordings in isolated brain slices of the rat medulla. Superfusion of GABA resulted in a concentration-dependent reduction in input resistance in the neurons in rNTS. The change in input resistance ws accompanied by response to a depolarizing pulse were diminished by GABA. Superfusion of the slices with either $GABA_A$ agonist, muscimol, $GABA_B$ agonist, baclofen or $GABA_C$ agonist, TACA, decreased input resistance and reduced the nerve activity in association with membrane hyperpolarization. It is suggested that inhibitory signals playa role in sensory processing by the rNTS, in that GABA actions occur through activation of $GABA_A,\;GABA_B\;and\;GABA_C$ receptor. These results suggest that GABA has an inhibitory effect on the rNTS through an activation of $GABA_A,\;GABA_B\;and\;GABA_C$ receptors and that the GABAergic inhibition probably plays an important role in sensory processing by the rNTS.

• Biomolecules & Therapeutics
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• 제3권4호
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• pp.322-326
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• 1995

General pharmacology of LB20304, a quinolone antibiotic, were examined in terms of general behaviour, cardiovascular, and central nervous system. LB20304 at oral dose of 2,000 mg/kg did not induce significant behavioural changes in mice. In contrast with ciprofloxacin, LB20304 at dose of 20 mg/kg, iv. did not show any observable effects on the blood pressure in rats. Displacement of [$^3$H]muscimol binding to the rat brain synaptic membranes was measured. LB20304 was shown to be about five times less potent than ciprofloxacin in specific GABA receptor binding. Drug interaction between LB20304 and 4-biphenyl acetic acid, an active metabolite of fenbufen, was assessed in mice by measuring convulsion and/or subsequent death. A single oral pretreatment with 4-BPA at 400 mg/kg increased the incidence of convulsion and death after oral administration of ciprofloxacin at the doses of 25, 50, and 100 from zero of five to three of five, two of five, and four of five, respectively, whereas LB20304 alone or combination with 4-BPA caused neither convulsions nor death at the doses of 12.5, 25, 50, and 100 mg/kg, respectively. Quinolones-induced epileptogenic activities were assessed by a direct intracerebral injection of test articles. The CD$_{50}$ values (nmole) are as follows; 169.47, 35.36, 105.29, and 88.67 for LB20304, ciprofloxacin, of loxacin, and lomefloxacin, respectively. From these data, LB 20304 at therapeutic doses seems to be much more safe than any other quinolones tested.d.

• The Korean Journal of Physiology and Pharmacology
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• 제14권2호
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• pp.59-69
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• 2010

Impairment in spinal inhibition caused by quantitative alteration of GABAergic elements following peripheral nerve injury has been postulated to mediate neuropathic pain. In the present study, we tested whether neuropathic pain could be induced or reversed by pharmacologically modulating spinal GABAergic activity, and whether quantitative alteration of spinal GABAergic elements after peripheral nerve injury was related to the impairment of GABAergic inhibition or neuropathic pain. To these aims, we first analyzed the pain behaviors following the spinal administration of GABA antagonists ($1{\mu}g$ bicuculline/rat and $5{\mu}g$ phaclofen/rat), agonists ($1{\mu}g$ muscimol/rat and $0.5{\mu}g$ baclofen/rat) or GABA transporter (GAT) inhibitors ($20{\mu}g$ NNC-711/rat and $1{\mu}g$ SNAP-5114/rat) into naive or neuropathic animals. Then, using Western blotting, PCR or immunohistochemistry, we compared the quantities of spinal GABA, its synthesizing enzymes (GAD65, 67) and its receptors (GABAA and GABAB) and transporters (GAT-1, and -3) between two groups of rats with different severity of neuropathic pain following partial injury of tail-innervating nerves; the allodynic and non-allodynic groups. Intrathecal administration of GABA antagonists markedly lowered tail-withdrawal threshold in naive animals, and GABA agonists or GAT inhibitors significantly attenuated neuropathic pain in nerve-injured animals. However, any quantitative changes in spinal GABAergic elements were not observed in both the allodynic and non-allodynic groups. These results suggest that although the impairment in spinal GABAergic inhibition may play a role in mediation of neuropathic pain, it is not accomplished by the quantitative change in spinal elements for GABAergic inhibition and therefore these elements are not related to the generation of neuropathic pain following peripheral nerve injury.

• International Journal of Oral Biology
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• 제40권3호
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• pp.117-125
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• 2015

The present study investigated the role of central $GABA_A$ and $GABA_B$ receptors in orofacial pain in rats. Experiments were conducted on Sprague-Dawley rats weighing between 230 and 280 g. Intracisternal catheterization was performed for intracisternal injection, under ketamine anesthesia. Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia and inferior alveolar nerve injury-induced mechanical allodynia were employed as orofacial pain models. Intracisternal administration of bicuculline, a $GABA_A$ receptor antagonist, produced mechanical allodynia in naive rats, but not thermal hyperalgesia. However, CGP35348, a $GABA_B$ receptor antagonist, did not show any pain behavior in naive rats. Intracisternal administration of muscimol, a $GABA_A$ receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. On the contrary, intracisternal administration of bicuculline also attenuated the mechanical allodynia in rats with inferior alveolar nerve injury. Intracisternal administration of baclofen, a $GABA_B$ receptor agonist, attenuated the thermal hyperalgesia and mechanical allodynia in rats with CFA treatment and inferior alveolar nerve injury, respectively. In contrast to $GABA_A$ receptor antagonist, intracisternal administration of CGP35348 did not affect either the thermal hyperalgesia or mechanical allodynia. Our current findings suggest that the $GABA_A$ receptor, but not the $GABA_B$ receptor, participates in pain processing under normal conditions. Intracisternal administration of $GABA_A$ receptor antagonist, but not $GABA_B$ receptor antagonist, produces paradoxical antinociception under pain conditions. These results suggest that central GABA has differential roles in the processing of orofacial pain, and the blockade of $GABA_A$ receptor provides new therapeutic targets for the treatment of chronic pain.