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PubMed1998

Determination of gamma-aminobutyric acid in microdialysis samples by microbore column liquid chromatography and fluorescence detection.

A method for the determination of gamma-aminobutyric acid (GABA) at concentrations as low as 1.5 nM in microdialysis samples is described. A high-performance liquid chromatography (HPLC) autosampler was used for precolumn derivatizations of samples with phthalaldehyde-2-mercaptoethanol reagent, as well as for automated injections of acetonitrile to wash the microbore column between injections. This permitted the use of only one isocratic pump and reduced the run-to-run analysis time to below 20 min, without any risk for late-eluting peaks. Three different microbore columns were evaluated. The optimal column was a 150 x 1 mm I.D., C18 reversed-phase silica column with a particle size of 3 microm, operated at a flow-rate of 50 microl/min. The mobile phase was 0.1 M sodium acetate buffer, pH 5.4, containing 20% acetonitrile. Under these conditions, the column exhibits a low back-pressure of about 11.1 MPa and is usable for at least 1000 injections. Good correlation was found between fluorescence and electrochemical detector responses for o-phthaldialdehyde-GABA derivatives, although the latter detector type generally required more skill and maintenance for routine use. Microdialysis samples of 10-20 microl, recovered from various rat brain nuclei, were assayed using the described method.

Animals↗
PubMed1991

L-dopa stimulates the release of [3H]gamma-aminobutyric acid in the basal ganglia of 6-hydroxydopamine lesioned rats.

L-DOPA stimulated the K(+)-induced [3H]GABA (gamma-aminobutyric acid) release from slices of substantia nigra pars reticulata, entopeduncular nucleus, globus pallidus and caudate-putamen isolated from the ipsilateral side of 6-hydroxydopamine-lesioned rats, but the release from ipsilateral subthalamic slices was not affected. In substantia nigra, L-DOPA stimulation (EC50 = 1 microM) of [3H]GABA release was dose-dependently blocked (IC50 = 0.1 microM for the stimulation caused by 10 microM L-DOPA) by the D1 antagonist SCH 23390, but was not affected by (-)-sulpiride, a D2 antagonist. SCH 23390 also blocked the stimulation in the other nuclei. The DOPA decarboxylase inhibitor NSD-1015 (500 microM) did not prevent the stimulation induced by L-DOPA in all of the studied nuclei. The results suggest that L-DOPA is able to activate D1 receptors located on the terminals of striatal projections via the dopamine formed by a decarboxylation mediated by an NSD-1015-resistant enzyme. Activation of the presynaptic D1 receptors results in stimulation of GABA release.

Animals↗
PubMed1985

Characterization of the relationship between gamma-aminobutyric acid B agonists and transmitter-coupled cyclic nucleotide-generating systems in rat brain.

Baclofen and other gamma-aminobutyric acid B (GABAB) agonists potentiate the cyclic AMP response in rat brain slices that occurs during exposure to norepinephrine, isoproterenol, adenosine, vasoactive intestinal peptide, and histamine. By themselves the GABAB agonists have only a slight effect on basal cyclic AMP levels. Dose-response and time-course studies revealed that baclofen has little influence on neurotransmitter recognition site affinity, but rather enhances the synthesis or accumulation of second messenger that occurs in response to these agents. Baclofen appears to be neither an inhibitor of phosphodiesterases nor does it require adenosine to promote the response to other transmitters. The synergistic interaction between baclofen and catecholamines is a calcium-dependent process and is evident only in the rat brain cerebral cortex, hippocampus and corpus striatum, being undetectable in the pons-midbrain, cerebellum, and spinal cord. In contrast to the findings with neurotransmitter receptor stimulants, GABAB agonists inhibited the cyclic AMP response to forskolin. It remains unclear whether this action is related to the neurotransmitter potentiating effect of baclofen. These data suggest that GABAB agonists may modulate neurotransmitter receptor function by influencing a component of the cyclic nucleotide-generating system beyond the level of the hormone recognition site.

Adenosine↗
PubMed1999

The irreversible gamma-aminobutyric acid (GABA) transaminase inhibitor gamma-vinyl-GABA blocks cocaine self-administration in rats.

gamma-Vinyl gamma-aminobutyric acid (GABA) (GVG) is an irreversible inhibitor of GABA transaminase, the primary enzyme involved in GABA metabolism. Acute administration of GVG increases brain GABA levels and blocks cocaine-induced locomotor activity, cocaine-induced lowering of brain stimulation reward thresholds, and cocaine-induced conditioned place preference. To further evaluate the effects of GVG on cocaine-induced reward, we examined its effects on cocaine self-administration in male Wistar rats on fixed ratio 5 and progressive ratio schedules of reinforcement. Additionally, the effects of GVG on operant responding for a food reward were examined on the same two schedules to determine whether the effects of GVG were specific to cocaine reward or generalized to other types of reward. GVG dose dependently decreased responding for cocaine on both schedules of reinforcement, suggesting that GVG attenuated the reward value of the cocaine. Responding for food was also decreased by GVG, suggesting that the effects of increased GABA levels induced by GVG may have a general effect on central reward systems. Data from this and other studies indicate that GVG does not induce motor impairment, decrease spontaneous locomotor activity, or induce catalepsy. Taken together, these data suggest that increases in GABAergic activity induced by GVG have an attenuating effect on centrally mediated reward systems and that the GABA system may be a useful target in the development of new therapeutic strategies for cocaine addiction.

4-Aminobutyrate Transaminase↗
PubMed1992

Ontogeny of glutamate and gamma-aminobutyric acid release in the hippocampus of the guinea pig.

The ontogeny of the L-glutamate (GLU) and gamma-aminobutyric acid (GABA) neuronal systems in the guinea pig hippocampus was investigated with respect to tissue amino acid content, and spontaneous and K(+)-stimulated release of GLU and GABA. Transverse hippocampal slices were prepared from the guinea pig fetus at day 45 (brain growth spurt), 55 and 63 of gestation (term, about 68 days), from the 5-days-old neonate, and from the young adult. GLU and GABA release was determined as efflux from hippocampal slices into Krebs'-bicarbonate medium using a dynamic, submerged, superfusion apparatus. Hippocampal GLU content decreased during development, whereas GABA content was constant for all the ages investigated. The magnitude of spontaneous GLU efflux decreased during development; there was no measurable spontaneous GABA efflux. The K+ concentration-GLU efflux response curve was bell-shaped for the fetus at the three selected gestational ages, and was curvilinear for the neonate and adult. The apparent EC75 of K(+)-stimulated GLU efflux was higher for the neonate and adult compared with the fetus. In contrast, the K+ concentration-GABA efflux response curve was curvilinear, and the apparent EC75 of K+ was similar for all the ages investigated. K(+)-stimulated efflux of GLU and GABA was Ca++ dependent, but this was not the case for spontaneous GLU efflux. These data indicate that, in the guinea pig hippocampus, the GLU neuronal system is developing throughout gestation, whereas the GABA neuronal system appears to mature before the brain growth spurt.

Animals↗
PubMed2006

Role of the conserved glutamine 291 in the rat gamma-aminobutyric acid transporter rGAT-1.

We investigated the role of the Q291 glutamine residue in the functioning of the rat gamma-aminobutyric acid (GABA) transporter GAT-1. Q291 mutants cannot transport GABA or give rise to transient, leak and transport-coupled currents even though they are targeted to the plasma membrane. Coexpression experiments of wild-type and Q291 mutants suggest that GAT-1 is a functional monomer though it requires oligomeric assembly for membrane insertion. We determined the accessibility of Q291 by investigating the impact of impermeant sulfhydryl reagents on cysteine residues engineered in close proximity to Q291. The effect of these reagents indicates that Q291 faces the external aqueous milieu. The introduction of a steric hindrance close to Q291 by means of [2-(trimethylammonium)ethyl] methanethiosulfonate bromide modification of C74A/T290C altered the affinity of the mutant for cations. Taken together, these results suggest that this irreplaceable residue is involved in the interaction with sodium or in maintaining the cation accessibility to the transporter.

Amino Acid Sequence↗
PubMed2000

Possible contribution of central gamma-aminobutyric acid receptors to resting vascular tone in freely moving rats.

Previous studies have shown that central administration of GABA (gamma -aminobutyric acid), an inhibitory neurotransmitter, preferentially reduces hindquarters and carotid vascular resistances but not renal and coeliac vascular resistances in conscious rats. This study tested the hypothesis that these preferential actions of central GABA receptors are related to differences between vessels in resting autonomic vascular tone in freely moving rats. Rats were chronically implanted with intracisternal cannulas and/or electromagnetic probes to measure regional blood flows. In response to GABA administration, the changes in vascular resistance (arterial blood pressure/regional blood flow) of the hindquarters (n = 23) and carotid (n = 12) vascular beds were significantly and negatively correlated with basal vascular resistance. No such relationship was found for the renal (n = 21), coeliac (n = 13) and superior mesenteric (n = 23) vascular beds. This finding indicates that the responsiveness to GABA of brainstem pathways controlling the hindquarters and carotid vascular beds co-varies with resting resistance in hindquarters and carotid vessels. A similar analysis was performed, correlating the ongoing vascular resistance of each vessel with its response to ganglionic blockade by chlorisondamine. In this case, a significant negative correlation was also found for the hindquarters (n = 26) and carotid (n = 15) vascular beds, but not for the coeliac (n = 17) or superior mesenteric (n = 19) vessels. Together, these findings suggest that central GABA receptors accessible from the cisterna magna preferentially affect two vascular beds which, in the freely moving rat, show resting autonomic vascular tone.

Animals↗
PubMed2004

Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model.

Gamma-aminobutyric acid (GABA) is both a major inhibitory neurotransmitter in the CNS and a product of beta cells of the peripheral islets. Our previous studies, and those of others, have shown that T cells express functional GABAA receptors. However, their subunit composition and physiological relevance are unknown. In this study, we show that a subset of GABAA receptor subunits are expressed by CD4+ T cells, including the delta subunit that confers high affinity for GABA and sensitivity to alcohol. GABA at relatively low concentrations down-regulated effector T cell responses to beta cell Ags ex vivo, and administration of GABA retarded the adoptive transfer of type 1 diabetes (T1D) in NOD/scid mice. Furthermore, treatment with low dose of GABA (600 microg daily) dramatically inhibited the development of proinflammatory T cell responses and disease progression in T1D-prone NOD mice that already had established autoimmunity. Finally, GABA inhibited TCR-mediated T cell cycle progression in vitro, which may underlie GABA's therapeutic effects. The immunoinhibitory effects of GABA on T cells may contribute to the long prodomal period preceding the development of T1D, the immunological privilege of the CNS, and the regulatory effects of alcohol on immune responses. Potentially, pharmacological modulation of GABAA receptors on T cells may provide a new class of therapies for human T1D as well as other inflammatory diseases.

Adoptive Transfer↗
PubMed1996

Immunohistochemical investigation of gamma-aminobutyric acid ontogeny and transient expression in the central nervous system of Xenopus laevis tadpoles.

The ontogeny of the gamma-aminobutyric acid (GABA)-positive neurons in the brain of Xenopus laevis tadpoles was investigated by means of immunohistochemistry, using specific antibodies both against GABA and its biosynthetic enzyme, glutamate decarboxylase (GAD). The results obtained with the two antisera were comparable. The GABA system differentiates very early during development. At stages 35/36, numerous GABA-positive neurons were seen throughout the prosencephalon and formed two main bilateral clusters within the lateral walls of the forebrain that ran caudally toward the hindbrain. Other GABA-immunolabeled cell bodies, together with a conspicuous network of GABAergic fibers, were seen in the posterior hypothalamus. In the spinal cord, the lateral marginal zone was GABA-positive, as were Rohon-Beard neurons, interneurons, and Kolmer-Agdhur cells. A very rich GABA innervation was observed in the pars intermedia of the pituitary. At stage 50, plentiful immunopositive neurons and fibers were found in the telencephalic hemispheres, the diencephalon, and the mesencephalon (optic tectum and tegmentum). By stage 54, the number of GABA-immunoreactive neurons in the posterior hypothalamus had decreased, so that, at stage 58, there were very few GABA-labeled cell bodies in the dorsolateral walls of the infundibulum, despite a strong GABAergic innervation within the median eminence and the pars intermedia. From stage 58 to stage 66, the distribution pattern was very similar to that described in the adult X. laevis and in other amphibian species. These results point to transient GABA expression within the hypothalamus, possibly related to either 1) a naturally occurring cell death or 2) a phenotypic switch.

Animals↗
PubMed2006

Expression of gamma-aminobutyric acid and glutamic acid decarboxylases in rat descending colon and their relation to epithelial differentiation.

OBJECTIVE: To detect the expression of gamma-aminobutyric acid (GABA) and glutamic acid decarboxylases (GADs; including two isoforms GAD65 and GAD67) in the epithelial growth zones of the descending colon in rats, and to investigate their relation to epithelial differentiation and proliferation. METHODS: The expression of GABA and GADs in rat descending colon was investigated by immunofluorescent staining and confocal laser scanning techniques, and goblet cells were further investigated by wheat-germ agglutinin histochemistry. In addition, GAD65 and GAD67 mRNAs were also detected by reverse transcription-polymerase chain reaction. Furthermore, evaluation of cell kinetics in colonic epithelia was conducted by ABC immunostaining using a monoclonal antibody against proliferating cell nuclear antigen (PCNA). RESULTS: Immunoreactive GABA and GADs were distributed in the upper third of the crypts and at the luminal surface in the rat descending colon. Strong staining for GABA and GADs was localized mainly in the cytoplasm of epithelial cells near the neck of the crypts and along the luminal surface. In addition, GABA and GAD65 were also detected at the lamina propria in colonic mucosa. No staining for GABA or GADs was found in goblet cells. GAD65 and GAD67 mRNAs were identified in homogenates of rat descending colon. PCNA labeled nuclei were found in the lower two-thirds of the crypts. CONCLUSIONS: The expression of GABA and GADs in the maturation and function zones of rat descending colon suggests that GABA may be involved in the differentiation of colonic epithelial cells.

Animals↗
PubMed2002

Effects of gamma-aminobutyric acid on action of gastrin-releasing peptidergic neurons in exocrine secretion of isolated, perfused rat pancreas.

INTRODUCTION: gamma-Aminobutyric acid (GABA) has been reported to enhance exocrine secretion evoked by intrinsic neuronal excitation in the pancreas. AIM: To see the effect of GABA on the action of gastrin-releasing peptide (GRP)ergic neurons in exocrine secretion of the pancreas. METHODOLOGY: Pancreatic neurons were excited by electrical field stimulation (EFS) in the isolated, perfused rat pancreas. GRP in the pancreatic circulation was neutralized by an anti-GRP antiserum to block GRPergic neuronal action on pancreatic exocrine secretion. RESULTS: GABA (3, 10, 30 microM), given intra-arterially, elevated the EFS-evoked pancreatic secretions of fluid and amylase dose-dependently. An anti-GRP antiserum (10 microL/mL: titer of 1:66,000) reduced the GABA (10 microM)-enhanced EFS-evoked pancreatic secretions. Synthetic porcine GRP-27 (30, 100, 300 p ) increased the pancreatic secretions dose-dependently, and these were further elevated by GABA (10 microM). The anti-GRP antiserum also reduced the GABA-enhanced GRP (100 p )-induced pancreatic secretions. Bicuculline (10 microM) reduced the enhancing effect of GABA on pancreatic secretions evoked by EFS as well as GRP. CONCLUSION: GABA enhances pancreatic secretions evoked by EFS as well as GRP, which is reduced by the anti-GRP antiserum. The enhancing effects of GABA on the EFS- and GRP-induced pancreatic secretions are diminished by bicuculline. The results indicate that GABA enhances intrinsic GRPergic neuronal action on exocrine secretion via the GABA(A) receptors in the rat pancreas.

Amylases↗
PubMed1999

Adaptive responses of gamma-aminobutyric acid neurons in the ventral tegmental area to chronic ethanol.

We have recently identified a homogeneous population of gamma-aminobutyric acid (GABA)-containing neurons in the ventral tegmental area (VTA), an area implicated in the reinforcing properties of alcohol. We evaluated the effects of local and systemic ethanol on VTA GABA neuron spontaneous activity in ethanol naive and chronically treated freely behaving rats and in anesthetized rats. In freely behaving animals, acute i.p. administration of 0.2 to 2.0 g/kg ethanol reduced the firing rate of VTA GABA neurons. Chronic administration of 2.0 g/kg i.p. ethanol enhanced baseline activity of VTA GABA neurons and induced tolerance to ethanol inhibition of their firing rate. In a separate group of freely behaving animals, tolerance to 0.4 to 2.0 g/kg i.p. ethanol-induced inhibition of VTA GABA neuron firing rate was observed following 2 weeks of chronic exposure to ethanol vapors producing intermittent blood alcohol levels of 158 mg/100 ml. In acute studies in halothane-anesthetized animals, ethanol applied locally into the VTA decreased the spontaneous firing rate of VTA GABA neurons, whereas systemic ethanol produced an early inhibition followed by a late excitation at 30 to 60 min after the ethanol injection, suggesting that ethanol modulation of an extrinsic input may excite VTA GABA neurons. Tolerance to local ethanol inhibition of VTA GABA neuron firing rate was produced by 2 weeks of chronic exposure to intermittent ethanol vapors. These results demonstrate the marked sensitivity of these neurons to ethanol and suggest that chronic ethanol administration produces selective adaptive circuit responses within the VTA or in extrategmental structures that regulate VTA GABA neuron activity.

Adaptation, Physiological↗
PubMed1991

The influence of gamma-aminobutyric acid on hormone release by the mouse and rat endocrine pancreas.

The present study was aimed at localizing gamma-aminobutyric acid (GABA) and its enzyme of synthesis, glutamic acid decarboxylase (GAD), in the mouse pancreas by immunocytochemical methods. The influence of GABA on hormone release was also studied with normal mouse and rat islets and the isolated perfused rat pancreas. Particular attention was paid to glucagon release to test a recent hypothesis suggesting that GABA mediates the still unexplained glucose-induced inhibition of glucagon release. GABA and GAD were identified only in islet cells and never in the exocrine tissue. Exogenous GABA, baclofen (agonist of GABAB receptors), muscimol (agonist of GABAA receptors), or bicuculline (antagonist of GABAA receptors) did not affect insulin and somatostatin release by isolated mouse or rat islets. GABA was also without effect on glucose-induced electrical activity in mouse B-cells. Glucagon secretion by mouse islets was only slightly inhibited (approximately 20%) by GABA. Since muscimol had a similar effect, and baclofen was ineffective, the inhibition by GABA probably involves GABAA receptor activation. Bicuculline, however, did not antagonize the inhibitory effects of GABA and muscimol, probably because the antagonist alone also decreased glucagon secretion. In contrast to GABA, low (3 mM) and high (20 mM) concentrations of glucose strongly inhibited (approximately 50-65%) glucagon release; this inhibition was not prevented by bicuculline. Similar results were obtained with the perfused rat pancreas; muscimol slightly inhibited glucagon release under various conditions, and bicuculline did not reverse the strong inhibition produced by 16.7 mM glucose. In conclusion, GABA does not affect insulin and somatostatin secretion, but inhibits A-cells, probably by acting on GABAA receptors. It is unlikely, however, that this small inhibitory effect can account for the inhibition of glucagon release produced by glucose.

Animals↗
PubMed1988

Gamma-aminobutyric acid concentration in brain tissue at two stages of Alzheimer's disease.

The concentration of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), was measured in the cerebral cortex obtained at diagnostic craniotomy from 10 patients with Alzheimer's disease of 3 yrs mean duration and 6 patients with other causes of dementia, and from 31 subjects undergoing other neurosurgical procedures (for which removal of apparently normal tissue was necessary). GABA content of 5 areas of the cerebral cortex and the cerebellar cortex was measured postmortem in the brains of 23 Alzheimer and 19 control subjects and 5 patients with other causes of dementia. Fourteen of these specimens, including 7 from patients with Alzheimer's disease of 8 yrs mean duration, were obtained within 3 h of death. These were processed in a similar manner to the neurosurgical specimens and are regarded also as fresh tissue samples. The remaining 33 specimens are regarded as conventional postmortem samples as the mean interval of death to autopsy was 21 h. GABA concentration in conventional autopsy specimens from Alzheimer subjects was not reduced as compared with controls in either cingulate or cerebellar cortex. In the inferior parietal cortex, agonal status confounded this comparison. The concentration was reduced in superior parietal, frontal and temporal cortex but there is a possibility that agonal state also confounded these comparisons. There was no deficit in GABA concentration in fresh cortical tissue from Alzheimer patients except for the temporal lobe from autopsy specimens. The content of somatostatin-like immunoreactivity was, like GABA, found to be comparable to control in some groups of Alzheimer specimens. It is argued that the deficits in autopsy samples and lack of change in surgical specimens is likely to be due to the duration of illness at the time of sampling. Losses of choline acetyltransferase activity were observed in all groups of Alzheimer specimens in all areas of brain studied. The data are consistent with other results which suggest that cholinergic under-activity is most closely related to the clinical course of Alzheimer's disease.

Aged↗
PubMed1992

The gamma-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats.

The effect of systemic administration of the gamma-aminobutyric acid (GABA) uptake inhibitor, R(-)N-(4,4-di(3-methyl-thien-2-yl)-but-3-enyl) nipecotic acid, hydrochloride (tiagabine) (previously NO-328), on extracellular GABA levels in the globus pallidus, ventral pallidum and substantia nigra of awake Sprague-Dawley rats was investigated using in vivo microdialysis. Tiagabine was administered in doses of 11.5 or 21.0 mg/kg i.p. (ED50 and ED85 doses, respectively, for inhibiting pentylenetetrazole-induced tonic seizures). Tiagabine increased the extracellular concentrations of GABA in globus pallidus with peak values 310% of basal level (after 21 mg/kg) and 240% of basal level (after 11.5 mg/kg). A significant increase in extracellular GABA levels was also found in the ventral pallidum (280% increase after 11.5 mg/kg and 350% increase after 21 mg/kg) and in the substantia nigra where the ED85 dose of tiagabine (21 mg/kg) produced a peak value of 200% compared to the basal level. Thus, tiagabine acts as a GABA uptake inhibitor in vivo also.

Analysis of Variance↗
PubMed1982

The topographical distribution of alanine, aspartate, gamma-aminobutyric acid, glutamate, glutamine, and glycine in the pigeon optic tectum and the effect of retinal ablation.

The concentrations of alanine, aspartate, gamma-aminobutyric acid, glutamine, glutamate, and glycine were measured in the pigeon optic nerve and in the individual tectal layers. Characteristic topographical distribution patterns were observed for the different amino acids. After unilateral retinal ablation, the concentration of aspartate and glutamate was decreased in the nerve and contralateral tectum. The reduction was restricted to the superficial part of the tectum, which receives a direct retinal input. The maximal loss was measured in the first two layers, where aspartate was reduced by 51% and glutamate by 75% in comparison with the ipsilateral side 4 weeks after ablation. The results favor a special role for aspartate and glutamate in pigeon retino-tectal afferents.

Alanine↗
PubMed1989

Autoradiographic localization of [3H] gamma-aminobutyric acid in neuronal elements of the rat gastric antrum and intestine.

High-affinity uptake and localization of radiolabelled gamma-aminobutyric acid (GABA) has been examined using light microscopic autoradiography in laminar preparations and transverse paraffin sections of the rat stomach, and small and large intestine. In the presence of beta-alanine (10(-3) M), a substrate specific inhibitor of high-affinity GABA transport into glia, tritiated GABA was accumulated by a high-affinity uptake system into myenteric ganglia and a subpopulation of mucosal cells. In the small and large intestine high-affinity uptake of [3H]GABA was evident in myenteric ganglion cells, extra-ganglionic sites and in the deep muscular nerve plexus of the circular muscle layer. Such labelling could be prevented in tissue treated with the specific neuronal high-affinity uptake blocker, L-2,4-diaminobutyric acid dihydrochloride (L-DABA; 10(-3) M), and therefore represented the selective distribution of [3H]GABA uptake sites to intrinsic neuronal elements of the rat gastrointestinal tract.

Acetanilides↗
PubMed2004

Isoflurane facilitates hiccup-like reflex through gamma aminobutyric acid (GABA)A- and suppresses through GABAB-receptors in pentobarbital-anesthetized cats.

UNLABELLED: The mechanism by which volatile anesthetics exert inconsistent effects on hiccups is unknown. We elicited a hiccup-like reflex by mechanical stimulation of the dorsal epipharynx in mechanically ventilated cats. The magnitude of the hiccup-like reflex was measured as the peak negative esophageal pressure (nPes) generated against an occluded airway. First, we examined the effects of different end-expiratory concentrations of isoflurane on nPes. Second, we determined the effects of 1.0 minimum alveolar anesthetic concentration of isoflurane on nPes after a peripherally restricted gamma aminobutyric acid (GABA)(A)-receptor antagonist, bicuculline methiodide (BM), a GABA(B)-receptor antagonist, CGP 35348, a peripherally restricted GABA(B)-receptor antagonist, CGP 54626, or saline had been administered IV. Third, BM, CGP 35348, or artificial cerebrospinal fluid was administered intracisternally before 1.0 minimum alveolar anesthetic concentration of isoflurane exposure. During isoflurane anesthesia, nPes was inversely proportional to the end-expiratory isoflurane concentration. The rank order of nPes values obtained after IV drug pretreatment and isoflurane exposure was BM < saline < CGP54626 < CGP35348. After intracisternal drug pretreatment and isoflurane administration, the order of nPes was BM < artificial cerebrospinal fluid < CGP35348. Isoflurane modulates the hiccup-like reflex in opposite directions through both central and peripheral GABA(A) and GABA(B) receptors, with the net effect being a dose-dependent suppression. IMPLICATIONS: Isoflurane facilitated the hiccup-like reflex through activation of central and peripheral gamma aminobutyric acid (GABA)(A) receptors but suppressed it via activation of central and peripheral GABA(B) receptors. The net result was that the hiccup-like reflex was inhibited in proportion to the alveolar isoflurane concentration.

Anesthesia↗