Exploring the transition from inter-ictal to ictal epileptiform discharges (IDs) and how GABA receptor-mediated action affects the onset of IDs will enrich our understanding of epileptogenesis and epilepsy treatment. We used Mg-free artificial cerebrospinal fluid (ACSF) to induce epileptiform discharges in juvenile mouse hippocampal slices and used a micro-electrode array to record the discharges. After the slices were exposed to Mg-free ACSF for 10 min-20 min, synchronous recurrent seizure-like events were recorded across the slices, and each event evolved from inter-ictal epileptiform discharges (IIDs) to pre-ictal epileptiform discharges (PIDs), and then to IDs. During the transition from IIDs to PIDs, the duration of discharges increased and the inter-discharge interval decreased. After adding 3 μmol/L of the GABA receptor agonist muscimol, PIDs and IDs disappeared, and IIDs remained. Further, the application of 10 μmol/L muscimol abolished all the epileptiform discharges. When the GABA receptor antagonist bicuculline was applied at 10 μmol/L, IIDs and PIDs disappeared, and IDs remained at decreased intervals. These results indicated that there are dynamic changes in the hippocampal network preceding the onset of IDs, and GABA receptor activity suppresses the transition from IIDs to IDs in juvenile mouse hippocampus.
Animals ; Animals, Newborn ; Bicuculline ; pharmacology ; Disease Models, Animal ; Epilepsy ; pathology ; GABA-A Receptor Agonists ; pharmacology ; GABA-A Receptor Antagonists ; therapeutic use ; Hippocampus ; drug effects ; metabolism ; physiopathology ; In Vitro Techniques ; Magnesium ; metabolism ; pharmacology ; Male ; Membrane Potentials ; drug effects ; Mice ; Mice, Inbred C57BL ; Muscimol ; pharmacology ; Nerve Net ; drug effects ; Receptors, GABA-A ; metabolism

OBJECTIVE: Suvorexant is a novel hypnotic drug that does not interact with the conventional γ-aminobutyric acid (GABA)-A receptor. We investigated the method by which suvorexant was introduced in insomnia patients who were taking benzodiazepine receptor agonists (BzRA). METHODS: This was a retrospective study. We extracted clinical data for patients who were prescribed suvorexant and were already using BzRA. The patients were assigned to two groups, the switching and add-on groups. We assessed the suvorexant discontinuation rate at one month after the prescription of the drug. RESULTS: One hundred and nineteen patients were assigned to the switching group, and 109 were assigned to the add-on group. The add-on group exhibited a significantly higher all-cause discontinuation rate than the switching group (odds ratio, 2.7; 95% confidence interval, 1.5 to 5.0; adjusted p < 0.001). Intolerability was a significantly stronger risk factor for suvorexant discontinuation in the add-on group (22.0% vs. 7.6%, p < 0.002), and the most common adverse effect was oversedation. CONCLUSION: Our results show that the add-on of suvorexant increases the frequency of oversedation compared with switching in insomnia patients that are taking BzRA. However, this was only a preliminary retrospective study, and further studies will be required to confirm our findings.
Benzodiazepines* ; Humans ; Methods ; Orexin Receptor Antagonists ; Prescriptions ; Receptors, GABA-A* ; Retrospective Studies* ; Risk Factors ; Sleep Initiation and Maintenance Disorders*

The present study was designed to investigate the inhibitory effects of intravenous general anesthetic propofol (0.1-3.0 mmol/L) on excitatory synaptic transmission in supraoptic nucleus (SON) neurons of rats, and to explore the underlying mechanisms by using intracellular recording technique and hypothalamic slice preparation. It was observed that stimulation of the dorsolateral region of SON could elicit the postsynaptic potentials (PSPs) in SON neurons. Of the 8 tested SON neurons, the PSPs of 7 (88%, 7/8) neurons were decreased by propofol in a concentration-dependent manner, in terms of the PSPs' amplitude (P < 0.01), area under curve, duration, half-width and 10%-90% decay time (P < 0.05). The PSPs were completely and reversibly abolished by 1.0 mmol/L propofol at 2 out of 7 tested cells. The depolarization responses induced by pressure ejection of exogenous glutamate were reversibly and concentration-dependently decreased by bath application of propofol. The PSPs and glutamate-induced responses recorded simultaneously were reversibly and concentration-dependently decreased by propofol, but 0.3 mmol/L propofol only abolished PSPs. The excitatory postsynaptic potentials (EPSPs) of 7 cells increased in the condition of picrotoxin (30 µmol/L, a GABA(A) receptor antagonist) pretreatment. On this basis, the inhibitory effects of propofol on EPSPs were decreased. These data indicate that the presynaptic and postsynaptic mechanisms may be both involved in the inhibitory effects of propofol on excitatory synaptic transmission in SON neurons. The inhibitory effects of propofol on excitatory synaptic transmission of SON neurons may be related to the activation of GABA(A) receptors, but at a high concentration, propofol may also act directly on glutamate receptors.
Anesthetics, Intravenous ; pharmacology ; Animals ; Excitatory Postsynaptic Potentials ; drug effects ; GABA-A Receptor Antagonists ; pharmacology ; Glutamic Acid ; pharmacology ; In Vitro Techniques ; Neurons ; drug effects ; Propofol ; pharmacology ; Rats ; Receptors, Glutamate ; metabolism ; Supraoptic Nucleus ; cytology

Animals ; Anticonvulsants ; pharmacology ; Drug Evaluation, Preclinical ; methods ; GABA-A Receptor Antagonists ; pharmacology ; Motor Activity ; drug effects ; Pentylenetetrazole ; pharmacology ; Valproic Acid ; pharmacology ; Zebrafish

BACKGROUNDAsthma is a chronic inflammatory disease characterized by reversible bronchial constriction, pulmonary inflammation and airway remodeling. Current standard therapies for asthma provide symptomatic control, but fail to target the underlying disease pathology. Furthermore, no therapeutic agent is effective in preventing airway remodeling. A substantial amount of evidence suggests that statins have anti-inflammatory properties and immunomodulatory activity. In this study, we investigated the effect of rosuvastatin on airway inflammation and its inhibitory mechanism in mucus hypersecretion in a murine model of chronic asthma.

METHODSBALB/c mice were sensitized and challenged by ovalbumin to induce asthma. The recruitment of inflammatory cells into bronchoalveolar lavage fluid (BALF) and the lung tissues were measured by Diff-Quik staining and hematoxylin and eosin (H&E) staining. ELISA was used for measuring the levels of IL-4, IL-5, IL-13 and TNF-α in BALF. Periodic acid-Schiff (PAS) staining was used for mucus secretion. Gamma-aminobutyric acid type A receptor (GABAAR) β2 expression was measured by means of immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.

RESULTSRosuvastatin reduced the number of total inflammatory cells, lymphocytes, macrophages, neutrophils, and eosinophils recruited into BALF, the levels of IL-4, IL-5, IL-13 and TNF-α in BALF, along with the histological mucus index (HMI) and GABAAR β2 expression. Changes occurred in a dose-dependent manner.

CONCLUSIONSBased on its ability to reduce the inflammatory response and mucus hypersecretion by regulating GABAAR activity in a murine model of chronic asthma, rosuvastatin may be a useful therapeutic agent for treatment of asthma.

Animals ; Asthma ; drug therapy ; metabolism ; Chronic Disease ; Disease Models, Animal ; Female ; Fluorobenzenes ; pharmacology ; therapeutic use ; GABA-A Receptor Antagonists ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Lung ; chemistry ; Mice ; Mice, Inbred BALB C ; Mucus ; secretion ; Pyrimidines ; pharmacology ; therapeutic use ; Receptors, GABA-A ; analysis ; Rosuvastatin Calcium ; Sulfonamides ; pharmacology ; therapeutic use

.This study is to investigate the analgesic effect produced by intrathecal injection (ith) of oxysophoridine (OSR) and the mechanism of GABAA receptor. Warm water tail-flick test was used to detect the analgesic effect of OSR (12.5, 6.25, and 3.13 mg.kg-1 ith) and to observe the influence of GABA (gamma aminobutyric acid) agonist or antagonist on the analgesic effect of OSR in mice. Immunohistochemistry method were used to detect the influence of OSR (12.5 mg.kg-1, ith) on the GABAARalpha1 protein expression in spinal cord. The results obtained covers that OSR (12.5 and 6.25 mg.kg-, ith) alleviates pain significantly with the warm water tail-flick test (P<0.05, P<0.01), the rate of pain threshold increases by 68.45%; GABA and muscimol (MUS) produces analgesic synergism together with the OSR, picrotoxin (PTX) and bicuculline (BIC) antagonize the analgesic effect of OSR; OSR (12.5 mg.kg-1, ith) significantly increase the positive number of GABAARalpha1 nerve cell in spinal cord (P<0.01) and significantly decrease the average grey levels (P<0.01). In conclusion, OSR intrathecal injection has significant analgesic effect. And GABAA receptor in spinal cord is involved in the analgesic mechanism.
Alkaloids ; administration & dosage ; pharmacology ; Analgesics ; administration & dosage ; pharmacology ; Animals ; Bicuculline ; pharmacology ; Female ; GABA-A Receptor Agonists ; pharmacology ; GABA-A Receptor Antagonists ; pharmacology ; Injections, Spinal ; Male ; Mice ; Muscimol ; pharmacology ; Pain Threshold ; drug effects ; Picrotoxin ; pharmacology ; Random Allocation ; Receptors, GABA-A ; metabolism ; Spinal Cord ; metabolism ; gamma-Aminobutyric Acid ; pharmacology

OBJECTIVETo investigate the effect of bicuculline, a selective GABAA receptor antagonist, on airway remodeling in the murine model of chronic allergen-induced asthma.

METHODSForty BALB/C mice were randomized into 4 groups, namely the control group, asthmatic model (induced by ovalbumin sensitization and challenge) group, budesonide inhalation group and bicuculline inhalation group. The mice were sacrificed 24 h after the last ovalbumin inhalation, and the lungs were lavaged with PBS and the total cells, eosinophils and lymphocytes counts were examined. Periodic acid-Schiff (PAS) staining was used for counting mucin-positive goblet cells in the lung tissue, and Masson Trichrome staining was used to evaluate collagen deposition. GABAARbeta2 and VEGF were quantified by immunohistochemistry.

RESULTSThe numbers of the total cells, eosinophils and lymphocytes counts in BALF were significantly greater in the bicuculline group than in the control and budesonide groups (P<0.01), but comparable to those in the asthmatic model group (P>0.05). The airway collagen deposition in the bicuculline group was comparable to that in the control and budesonide group (P>0.05), but was significantly less than that in the asthmatic model group (P<0.05). Significant differences were found in the airway histological mucus index between the bicuculline group and the other 3 groups (P<0.05). The airway GABAARbeta2-positive cell percentage in the bicuculline group was significantly greater that those in the control and budesonide (P<0.01 and 0.05), but similar with that in the asthmatic model group (P>0.05). The percentage of pulmonary perivascular VEGF-positive cells in the bicuculline group was significantly greater in the control and budesonide groups (P<0.01 and P<0.05), but comparable to that in the asthmatic model group (P>0.05).

CONCLUSIONGABAARbeta2 is expressed in both the airway epithelium and smooth muscles. Bicuculline inhalation can effectively suppress collagen deposition with a stronger inhibitory effect on mucus hypersecretion than budesonide.

Airway Remodeling ; drug effects ; Animals ; Asthma ; drug therapy ; pathology ; Bicuculline ; therapeutic use ; Disease Models, Animal ; GABA-A Receptor Antagonists ; therapeutic use ; Male ; Mice ; Mice, Inbred BALB C

In the present study, the correlated activities of adjacent ganglion cells of transient subtype in response to full-field white light stimulation were investigated in the chicken retina. Pharmacological studies and cross-correlation analysis demonstrated that application of the GABA(A) receptor antagonist bicuculline (BIC) significantly down-regulated the correlation strength while increasing the firing activities. Meanwhile, application of the GABA(A) receptor agonist muscimol (MUS) potentiated the correlated activities while decreasing the firing rates. However, application of the GABA(C) receptor antagonist (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) did not have a consistent influence on either the firing rates or the correlation strength. These results suggest that in the chicken retina, correlated activities among neighborhood transient ganglion cells can be increased while firing activities are reduced with the activation of GABA(A) receptors. The GABA(A)-receptor-mediated inhibitory pathway may be critical for improving the efficiency of visual information transmission.
Action Potentials ; Animals ; Bicuculline ; pharmacology ; GABA-A Receptor Antagonists ; pharmacology ; Mice ; Muscimol ; pharmacology ; Phosphinic Acids ; pharmacology ; Pyridines ; pharmacology ; Receptors, GABA-A ; metabolism ; Retina ; physiology ; Retinal Ganglion Cells ; physiology ; gamma-Aminobutyric Acid

The echolocating big brown bats (Eptesicus fuscus) emit trains of frequency-modulated (FM) biosonar signals with duration, amplitude, repetition rate, and sweep structure changing systematically during interception of their prey. In the present study, the sound stimuli of temporally patterned pulse trains at three different pulse repetition rates (PRRs) were used to mimic the sounds received during search, approach, and terminal stages of echolocation. Electrophysiological method was adopted in recordings from the inferior colliculus (IC) of midbrain. By means of iontophoretic application of bicuculline, the effect of GABAergic inhibition on the intensity sensitivity of IC neurons responding to three different PRRs of 10, 30 and 90 pulses per second (pps) was examined. The rate-intensity functions (RIFs) were acquired. The dynamic range (DR) of RIFs was considered as a criterion of intensity sensitivity. Comparing the average DR of RIFs at different PRRs, we found that the intensity sensitivity of some neurons improved, but that of other neurons decayed when repetition rate of stimulus trains increased from 10 to 30 and 90 pps. During application of bicuculline, the number of impulses responding to the different pulse trains increased under all stimulating conditions, while the DR differences of RIFs at different PRRs were abolished. The results indicate that GABAergic inhibition was involved in modulating the intensity sensitivity of IC neurons responding to pulse trains at different PRRs. Before and during bicuculline application, the percentage of changes in responses was maximal in lower stimulus intensity near to the minimum threshold (MT), and decreased gradually with the increment of stimulus intensity. This observation suggests that GABAergic inhibition contributes more effectively to the intensity sensitivity of the IC neurons responding to pulse trains at lower sound level.
Acoustic Stimulation ; Animals ; Bicuculline ; pharmacology ; Chiroptera ; Echolocation ; Electrophysiological Phenomena ; GABA-A Receptor Antagonists ; pharmacology ; Inferior Colliculi ; cytology ; Neurons ; cytology

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.
Animals ; Back Pain ; Baclofen ; Bicuculline ; GABA-A Receptor Agonists ; GABA-A Receptor Antagonists ; GABA-B Receptor Agonists ; gamma-Aminobutyric Acid ; Ganglia, Spinal ; Hyperalgesia ; Hypersensitivity* ; Muscimol ; Neuralgia ; Posterior Horn Cells ; Rats* ; Receptors, GABA ; Spinal Cord