This study was designed to investigate the effect of diazepam on the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus. Female rat (Sprague-Dawley) pretreated with oophorectomy and 4 days administration of estrogen. Weighing about 200 g, was sacrificed by cervical dislocation, and the uteruses were isolated. A longitudinal muscle strip was placed in temperature controlled (37℃) muscle chamber containing Locke's solution and myographied isometrically. Diazepam inhibited the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus in a concentration-dependent manner. GABA, muscimol, a GABA A receptor agonist, bicuculline, a competitive GABA A receptor antagonist, picrotoxin, a non competitive GABA A receptor antagonist, baclofen, a GABA B receptor agonist, and delta-aminovaleric acid, a GABA B receptor antagonist, did not affect on the spontaneous and oxytocin induced contraction of the isolated rat uterus. The inhibitory actions of diazepam on the spontaneous and oxytocin induced contraction were not affected by all the GABA receptor agonists and antagonists, but exceptionally potentiated by bicuculline. This potentiation-effect by bicuculline was not antagonized by muscumol. In normal calcium PSS, addition of calcium restored the spontaneous contraction preinhibited by diazepam and recovered the contractile of oxtrocin preinhibited by diazepam. A23187, a calcium inophore, enhanced the restoration of both the spontaneous and oxytocin induced contraction by addition of calcium. In calcium-free PSS, diazepam suppressed the restoration of spontaneous motility by addition of calcium but allowed the recovery of spontaneous motility to a considerable extent. Diazepam could not inhibit some development of contractility by oxytocin in calcium-free PSS, but inhibited the increase in contractility by subsequent addition of calcium. These results suggest that the inhibitory action of diazepam on the rat uterine motility does not depend on or related to GABA receptors and that diazepam inhibits the extracellular calcium influx to suppress the spontaneous and oxytocin induced contractilities.
Animals ; Baclofen ; Bicuculline ; Calcimycin ; Calcium ; Diazepam* ; Dislocations ; Estrogens ; Female ; GABA Agonists ; GABA-A Receptor Agonists ; GABA-A Receptor Antagonists ; GABA-B Receptor Agonists ; GABA-B Receptor Antagonists ; gamma-Aminobutyric Acid ; Humans ; Muscimol ; Ovariectomy ; Oxytocin* ; Picrotoxin ; Rats* ; Receptors, GABA ; Uterus*

Single unit responses of the ventral posterior medial (VPM) thalamic neurons to stimulation were monitored in anesthetized rats during activation of contralateral primary somatosensory (SI) cortex by GABA antagonist. The temporal changes of afferent sensory transmission were quantitatively analyzed by poststimulus time histogram (PSTH). Mainly, afferent sensory transmission to VPM thalamus was facilitated (15 neurons of total 23) by GABA antagonist (bicuculline) applied to contralateral cortex, while 7 neurons were suppressed. However, when ipsilateral cortex was inactivated by GABA agonist, musimol, there was significant suppression of afferent sensory transmission of VPM thalamus. This suppressed responsiveness by ipsilateral musimol was not affected by bicuculline applied to contralateral cortex. These results suggest that afferent transmission to VPM thalamus may be subjected to the interhemispheric modulation via ipsilateral cortex during inactivation of GABAergic neurons in contralateral SI cortex.
Animals ; Bicuculline ; GABA Agonists ; GABA Antagonists ; GABAergic Neurons ; gamma-Aminobutyric Acid ; Neurons ; Rats ; Somatosensory Cortex* ; Thalamus*

This study was designed to investigate the effect of GABA and related substances on the spontaneous contraction of rat small intestine. The rats (Sprague-Dawley), weighing 200-250g, were sacrificed by cervical dislocation, and the small intestine was isolated. Longitudinal muscle strips from duodenum, jejunum and ileum were suspended in Biancani's isolated muscle chambers and myographied isometrically. GABA and muscimol, a GABA A receptor agonist relaxed the duodenum and jejunum significantly, but baclofen-induced relaxation in those muscle strips negligible. The effectiveness of GABA and muscimol in various regions were the greatest on duodenum, and greater on jejunum than on ileum The effect of GABA and muscimol was antagonized by bicuculline, a competitive GABA A receptor antagonist and picrotoxin, a noncompetitive GABA A receptor antagonist. Duodenal relaxation induced by GABA and muscimol was unaffected by hexamethonium, but was prevented by tetrodotoxin. These results suggest that GABA inhibit the contractility of smooth muscle with distinct regional difference of efficacy, and the site of inhibitory action is the GABA A receptor existing at the presynaptic membrane of postganglionic excitatory nerves.
Animals ; Bicuculline ; Dislocations ; Duodenum ; GABA-A Receptor Agonists ; GABA-A Receptor Antagonists ; gamma-Aminobutyric Acid* ; Hexamethonium ; Ileum ; Intestine, Small* ; Jejunum ; Membranes ; Muscimol ; Muscle, Smooth ; Picrotoxin ; Rats* ; Receptors, GABA-A ; Relaxation ; Tetrodotoxin

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

The aim of this study was to examine the effects of various concentrations of glutamate(10(-8), 10(-6) and 10(-4) M) on the circling movement induced by apomorphine in the unilateral substantia nigra-lesioned rats. Subcutaneous apomorphine(0.1 mg/kg) elicited contralateral circling movement(641.7+/-163.9/hr), Glutamate(10(-6)-10(-4) M) significantly reduced the numbers of apomorphine-induced circling movement. This reducing effect of glutamate was antagonized and/or reversed by 10(-7) M GABA antagonist bicuculline. These results suggest that glutamate reduces circling movement induced by apomorphine and this reducing effect of glutamate may be mediated by increased GABA concentration in striatum and substantia nigra.
Animals ; Apomorphine ; Bicuculline ; Dopamine ; GABA Antagonists ; gamma-Aminobutyric Acid ; Glutamic Acid* ; Rats* ; Substantia Nigra

BACKGROUND: A phosphodiesterase 5 inhibitor, sildenafil, has been effective against nociception. Several lines of evidence have demonstrated the role of the GABAergic pathway in the modulation of nociception. The impact of the GABA receptors on sildenafil was studied using the formalin test at the spinal level. METHODS: Male SD rats were prepared for intrathecal catheterization. The formalin test was induced by subcutaneous injection of formalin solution. The change in the activity of sildenafil was examined after pretreatment with GABA receptor antagonists (GABAA receptor antagonist, bicuculline; GABAB receptor antagonist, saclofen). RESULTS: Intrathecal sildenafil dose-dependently attenuated the flinching observed during phase 1 and 2 in the formalin test. The antinociceptive effect of sildenafil was reversed by the GABAB receptor antagonist (saclofen) but not by the GABAA receptor antagonist (bicuculline) in both phases. CONCLUSIONS: Intrathecal sildenafil suppressed acute pain and the facilitated pain state. The antinociception of sildenafil is mediated via the GABAB receptor, but not the GABAA receptor, at the spinal level.
Acute Pain ; Animals ; Bicuculline ; Catheterization ; Catheters ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Formaldehyde* ; GABA Antagonists ; Humans ; Injections, Subcutaneous ; Male ; Nociception ; Pain Measurement* ; Rats* ; Receptors, GABA ; Sildenafil Citrate

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 microgram bicuculline/rat and 5 microgram phaclofen/rat), agonists (1 microgram muscimol/rat and 0.5 microgram baclofen/rat) or GABA transporter (GAT) inhibitors (20 microgram NNC-711/rat and 1 microgram 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.
Animals ; Blotting, Western ; GABA Agonists ; GABA Antagonists ; gamma-Aminobutyric Acid ; Immunohistochemistry ; Negotiating ; Neuralgia ; Peptides ; Peripheral Nerve Injuries ; Polymerase Chain Reaction ; Rats

BACKGROUND: Androsterone is one of the major metabolites from testosterone whose clinical importance remains unclear. This study evaluated the effects of androsterone on seizure susceptibility in mouse models of epilepsy. METHODS: The efficacy of androsterone (10~200 mg/kg, i.p.) against seizures induced by various GABA receptor antagonists and glutamate receptor agonists was evaluated. RESULTS: Androsterone protected mice against seizures induced by PTZ (pentylenetetrazol), PCX (picrotoxin), and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) in a dose-dependent manner. Androsterone did not protect against seizures induced by kainic acid, NMDA (N-methyl-D-aspartic acid), or 4-AP (4-aminopyridine) in mice. CONCLUSIONS: These results suggest that androsterone exhibits anticonvulsant activity that occurs largely via nongenomic mechanisms. Testosterone-derived androsterone might be an endogenous protective neuroactive steroid in the brain.
Androsterone ; Animals ; Carbolines ; Epilepsy ; GABA Antagonists ; gamma-Aminobutyric Acid ; Kainic Acid ; Mice ; N-Methylaspartate ; Receptors, Glutamate ; Seizures ; Testosterone

PURPOSE: The goal of this study was to investigate the effect of tetraethylammonium (TEA) on the excitability of visual cortex, and observe the induction of epileptiform activity. Also, it was aimed to define the characteristics of spontaneous activity and observe the effect of GABAA antagonist, NMDA antagonist and non-NMDA antagonist on the TEA-induced epileptiform activity. METHODS: The visual cortex slices in this study were obtained from 19 to 23 day-old Sprague-Dawley rats. Extracellular cellular recording was performed to observe the induction of epileptiform discharge perfused by artificial CSF containing 1, 5 and 10 mM TEA and the effect of 10 ?M 6-cyano-7-nitroquinoxaline-dione disodium(CNQX) and 50 microM D-(-)-2-amino-5-phosphonopentanoic acid(D-AP5) on the 10 mM TEA-induced epileptiform activity. RESULTS: Spontaneous epileptiform activities were observed in 5 and 10 mM TEA groups. The addition of 5 ?M BIC blocked the TEA-induced spontaneous ictal epileptiform activity but didn't block the TEA-induced spontaneous interictal epileptiform activity. The addition of 10 ?M CNQX shortened duration, decreased frequency and amplitude of the TEA-induced spontaneous epileptiform activity. The addition of 50 microM D-AP5 blocked the TEA-induced spontaneous ictal and interictal epileptiform activity. CONCLUSION: TEA induced the increased excitability in the visual cortex and spontaneous epileptiform activity. 5 ?M BIC blocked the TEA-induced spontaneous ictal epileptiform activity and GABAA antagonist BIC plays a role in limiting the epileptiform discharge. The TEA-induced spontaneous epileptiform activity induction was decreased by CNQX and blocked by D-AP5. NMDA and non-NMDA are required to modify the TEA-induced spontaneous epileptiform activity.
6-Cyano-7-nitroquinoxaline-2,3-dione ; Animals ; GABA Antagonists ; N-Methylaspartate ; Rats* ; Rats, Sprague-Dawley ; Tea ; Tetraethylammonium ; Visual Cortex*

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