Injection Of Gamma-aminobutyric Acid Research Articles

The hepatic GABAergic system promotes liver macrophage M2 polarization and mediates HBV replication in mice

Macrophages display functional phenotypic plasticity. Hepatitis B virus (HBV) infection induces polarizations of liver macrophages either to M1-like pro-inflammatory phenotype or to M2-like anti-inflammatory phenotype. Gamma-aminobutyric acid (GABA) signaling exists in various non-neuronal cells including hepatocytes and some immune cells. Here we report that macrophages express functional GABAergic signaling components and activation of type A GABA receptors (GABAARs) promotes M2-polarization thus advancing HBV replication. Notably, intraperitoneal injection of GABA or the GABAAR agonist muscimol increased HBV replication in HBV-carrier mice that were generated by hydrodynamical injection of adeno-associated virus/HBV1.2 plasmids (pAAV/HBV1.2). The GABA-augmented HBV replication in HBV-carrier mice was significantly reduced by the GABAAR inhibitor picrotoxin although picrotoxin had no significant effect on serum HBsAg levels in control HBV-carrier mice. Depletion of liver macrophages by liposomal clodronate treatment also significantly reduced the GABA-augmented HBV replication. Yet adoptive transfer of liver macrophages isolated from GABA-treated donor HBV-carrier mice into the liposomal clodronate-pretreated recipient HBV-carrier mice restored HBV replication. Moreover, GABA or muscimol treatment increased the expression of “M2” cytokines in macrophages, but had no direct effect on HBV replication in the HepG2.2.15 cells, HBV1.3-transfected Huh7, HepG2, or HepaRG cells, or HBV-infected Huh7-NTCP cells. Taken together, these results suggest that increasing GABA signaling in the liver promotes HBV replication in HBV-carrier mice by suppressing the immunity of liver macrophages, but not by increasing the susceptibility of hepatocytes to HBV infection. Our study shows that a previously unknown GABAergic system in liver macrophage has an essential role in HBV replication.

Induction of hypothalamic GABA synthetic enzymes mRNA (Gad 1 and Gad 2) expression by negative energy balance in broiler and layer chicks

Broiler and layer chicks have been selected for higher and lower food intake and body weight gain, respectively. It has recently been reported that glutamate decarboxylase (Gad1) mRNA, a gamma-aminobutyric acid (GABA) synthetic enzyme gene, is a reliable proxy for GABA release. Previous studies have revealed that GABAergic system has a stimulatory role on food intake in both mammals and birds. Over the recent years, evidence has identified the presence of GABAergic neurons as either the first- or second-order neurons within the various feeding nuclei of hypothalamus of laboratory rodents. They respond to the negative energy balance representing a critical role for GABA in the regulation of food intake. In the current study, the mRNA abundance of Gad 1 and Gad 2 was measured within the hypothalamus of both broiler and layer free fed, 12 h-fasted and 12 h-fasted / 3 h refed chicks. Furthermore, the effect of intracerebroventricular (ICV) injection of GABA was studied on food intake of chicks. The results indicated an increase in both Gad 1 and 2 expressions during fasting which tended to return to the baseline after refeeding. However, this increase was greater in broilers than in layers. The results also showed that ICV injection of GABA had no effect on food intake with the exception of an increase in free fed broilers. This study suggests a role for hypothalamic GABAergic system in birds that respond to negative energy balance, which seems to be more considerable in broilers than in layers.

EA at PC6 Promotes Gastric Motility: Role of Brainstem Vagovagal Neurocircuits.

Background We aimed to assess whether electroacupuncture (EA) at PC6 affects gastric motility via the vagovagal reflex and if so whether brainstem vagovagal neurocircuits and related transmitters are involved. Methods Gastric motility was measured in male Sprague-Dawley (SD) rats by placing a small manometric balloon in the gastric antrum. The rats were subjected to control, sham surgery, vagotomy, sympathectomy, and microinjection group, including artificial cerebrospinal fluid, gamma-aminobutyric acid (GABA), and glutamic acid (L-Glu). The effect of EA at PC6 on gastric motility was measured. Moreover, electrophysiological testing was used to measure the effect of EA at PC6 on the parasympathetic and sympathetic nerves. In addition, artificial cerebrospinal fluid, L-Glu, and GABA have been microinjected into the dorsal motor nucleus of the vagus (DMV) to measure the changes in gastric motility and parasympathetic nerve discharge induced by EA at PC6. Key Results EA facilitated the gastric motility in control group. In the vagotomy group, gastric motility was not affected by EA at PC6. However, in the sympathectomy group, gastric motility was similar to control group. Acupuncture at PC6 increased parasympathetic nerve discharge but not sympathetic nerve discharge. Furthermore, the microinjection of L-Glu into the DMV increased gastric motility, although EA at PC6 showed no remarkable change in this group. The injection of GABA reduced gastric motility and parasympathetic nerve discharge, but EA at PC6 significantly increased gastric motility and the parasympathetic nerve discharge in this group. Conclusions and Inferences EA at PC6—primarily by inhibiting GABA transmission to DMV—reduced the inhibition of efferent vagal motor fibers and thus promoted efferent vagus nerve activity and increased gastric motility.

Effect of gamma aminobutyric acid (GABA) or GABA with glutamic acid decarboxylase (GAD) on the progression of type 1 diabetes mellitus in children: Trial design and methodology

BackgroundEvidence suggests that GABA may reduce pancreatic inflammation, protect β-cells from autoimmune destruction, and potentiate the regeneration of new β-cells in the setting of type 1 diabetes mellitus (T1DM). The enzyme GAD, also expressed in human pancreatic β-cells, is an antigenic target of reactive T cells. We hypothesized that treatment of children with recent onset T1DM with GABA or combination GABA with GAD will preserve β-cell function and ameliorate autoimmune dysregulation. MethodsThis is a one-year, prospective, randomized, double-blind, placebo-controlled trial. Ninety-nine patients aged 4–18 years with newly diagnosed T1DM are randomized into three treatment groups: 1) oral GABA twice daily in addition to two injections of recombinant GAD enzyme, 2) oral GABA plus placebo GAD injections, or 3) placebo GABA and placebo GAD. Patients are evaluated at baseline and months 1, 5, 8 and 12. Mixed meal tolerance testing is performed at all but the 8-month visit. Laboratory studies will assess indices of beta and alpha cell function, glycemic control, immunophenotyping, and diabetes-related autoantibodies. ResultsThe primary outcome is the effect on pancreatic β-cell function as measured by meal-stimulated c-peptide secretion compared between the treatment groups before and after one year of treatment. Secondary outcomes include: 1) fasting and meal stimulated glucagon and proinsulin levels, 2) response in insulin usage by participants, 3) indices of immune cell function, and 4) effect on autoantibodies GAD65, ICA512, and ZnT8.Conclusions: This trial will determine the safety and efficacy of GABA and combination GABA/GAD therapy to delay T1DM progression in children.

Electrophysiological Detection of Cortical Neurons under Gamma-Aminobutyric Acid and Glutamate Modulation Based on Implantable Microelectrode Array Combined with Microinjection.

Understanding the relationships between different cortical neurons under excitatory or inhibitory modulation is important for researches of many neurological disorders. In order to monitor the neural activities in cortex under gamma-aminobutyric acid (GABA) and glutamate (Glu) modulation, an implantable microelectrode array (MEA) was combined with microinjection capillary. The neurons in motor cortex of rat were modulated by GABA and Glu injection, and multichannel neural electrophysiological signals were simultaneously recorded. Spike analysis showed that the interneurons recorded by the MEA were inhibited after GABA injection and excited after Glu injection, but one pyramidal neuron was found to be not sensitive to the drug. The local field potentials (LFP) were most affected in the frequency band of 5~10 Hz after Glu injection, which greatly increased the amplitudes of the spindle-like waveforms. The MEA combined with microinjection provided a low-cost and effective tool for neurological drug modulation and evaluation in brain tissue.

Systemic treatment with the inhibitory neurotransmitter gamma-aminobutyric acid aggravates experimental autoimmune encephalomyelitis by affecting proinflammatory immune responses

Transcriptomic and proteomic analyses of multiple sclerosis (MS) lesions indicate alterations in the gamma-aminobutyric acid (GABA) inhibitory system, suggesting its involvement in the disease process. To further elucidate the role of GABA in central nervous system (CNS) inflammation in vivo, the chronic myelin oligodendrocyte glycoprotein (MOG)35–55 experimental autoimmune encephalomyelitis (EAE) model was used. Daily GABA injections (200mg/kg) from day 3 onwards significantly augmented disease severity, which was associated with increased CNS mRNA expression levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6. GABA-treated mice showed enhanced MOG-dependent proliferation and were skewed towards a T helper 1 phenotype. Moreover, in vitro, the lipopolysaccharide (LPS)-induced increase in interleukin (IL)-6 production by macrophages was enhanced at low GABA concentrations (0.03–0.3mM). In sharp contrast to exogenous GABA administration, endogenous GABA increment by systemic treatment with the GABA-transaminase inhibitor vigabatrin (250mg/kg) had prophylactic as well as therapeutic potential in EAE. Together, these results indicate an immune amplifying role of GABA in neuroinflammatory diseases like MS.

Circular Swimming by the Medaka, Oryzias latipes, Induced by Microinjection of GABA-ergic Agonists and Antagonists into the Posterior Thalamus

The thalamic mechanism involved in locomotor control, particularly in steering control, was studied in a teleost, Oryzias latipes. Ipsilateral circular swimming was induced by injection of bicuculline, a selective gamma-aminobutyric acid (GABA)-A antagonist, into the unilateral posterior thalamus. δ-Amino-valeric acid, phaclofen and 2-hydroxysaclofen (weak GABA-B antagonists) had weak, but similar effects. In contrast to antagonists, injection of GABA, muscimol (GABA-A agonist), baclofen (GABA-B agonist), nipecotic acid (blocker of Na + -coupled GABA uptake carrier), and γ-hydroxybutyric acid (possible GABA-A and -B agonist) into the unilateral posterior thalamus induced contralateral circular swimming

Plasticity of GABAergic Mechanisms Within the Nucleus of the Solitary Tract in Hypertension

Adaptive changes have long been recognized to occur in the heart and vasculature in response to chronic hypertension. What might be less well-appreciated is the fact that chronically increased blood pressure is also associated with adaptive changes in neurons within the central nervous system (CNS). Changes in the properties of ligand-gated and voltage-gated channels have been described in a variety of neurons in a variety of central nuclei and in a variety of models of hypertension. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in virtually every region in the adult brain. Microinjections of GABA and GABA receptor subtype-selective agonists and antagonists have been performed within various cardiovascular-related regions of the CNS. In every cardiovascular-related region of the CNS tested, activation of GABA receptors alters cardiovascular function. This is likely attributable to the ubiquitous role of GABA within the CNS. GABAergic inhibition can be mediated by activation of receptors located in presynaptic and postsynaptic loci. Two major subtypes of the GABA receptor exist: the GABAA receptor is a pentameric, chloride ionophore that primarily mediates postsynaptic inhibition,1 whereas the GABAB receptor is a G-protein-coupled receptor that can induce reductions in calcium conductance to mediate presynaptic inhibition and increases in potassium conductance to mediate postsynaptic inhibition.2 GABAergic inhibition of central neurons can result in pressor or depressor responses depending on the central site being examined. Pressor responses are often assumed to be the result of GABAergic inhibition of neurons that reduce sympathetic discharge. Depending on the specific area being studied, GABA injections into the CNS can also alter vagal cardiac function and levels of vasoactive hormones such as vasopressin and angiotensin, in addition to changes in sympathetic outflow.3,4 In addition to microinjection studies, in vivo and in vitro electrophysiological analyses of functionally identified neurons in cardiovascular-related CNS …

Supernormal ERG Oscillatory Potentials in Transgenic Rabbit with Rhodopsin P347L Mutation and Retinal Degeneration

To determine the properties of the retina of a rhodopsin P347L transgenic (Tg) rabbit model of retinal degeneration by electroretinography (ERG). Full-field ERGs were recorded in 12- to 48-week-old wild-type (WT) and Tg rabbits. The a-wave was analyzed by the a-wave fitting model of Hood and Birch. The stimulus-response function of the b-wave was analyzed by the Michaelis-Menten equation. Oscillatory potentials (OPs) were extracted by digital filtering after subtracting the a-wave. OPs were also recorded before and after an intravitreal injection of l-2 amino-4-phosphonobutyric acid (APB), cis-2,3 piperidine dicarboxylic acid (PDA), gamma-amino butyric acid (GABA), or tetrodotoxin citrate (TTX). All the ERG components of Tg rabbits decreased progressively with age with the a-wave more affected than the b-wave, and the OPs were most preserved. Of interest, the summed OP amplitudes of the Tg rabbits were significantly larger than those of WT rabbits when they were 12 weeks of age. The changes in the amplitudes of the OPs after intravitreal injections of APB, PDA, or GABA in Tg rabbits did not differ significantly from those of WT rabbits. However, injection of TTX resulted in a significantly larger amplitude reduction of the OPs in Tg (65.3%) than in WT (28.6%) rabbits. The significantly larger OPs in Tg rabbits resulted from alterations in the inner retinal neurons. The greater effect of TTX on the OP amplitudes in Tg rabbits suggests that the supernormal OPs in Tg rabbits may be related to secondary changes in the spiking neurons of the inner retina after photoreceptor degeneration.

Immediate post-reminder injection of gamma-amino butyric acid (GABA) agonist midazolam attenuates reactivation of forgotten fear in the infant rat.

J. H. Kim, G. McNally, and R. Richardson (2006) reported that pretest injection of FG7142, a GABA inverse agonist, alleviated infantile amnesia in rats. From this, it was concluded that GABAergic neurotransmission is involved in the forgetting seen in the developing rat. The present study extends that finding by examining the role of GABA in the reactivation of a forgotten memory in the infant rat. Sixteen-day-old rats were conditioned to fear a white noise. When tested 3 days later, rats that had not received a reminder treatment exhibited substantial forgetting. Reactivation of memory (as assessed by high levels of freezing) was observed in rats that were given a reminder shock and injected with saline the day before test. However, rats given a reminder shock and injected with midazolam immediately afterward failed to exhibit the reactivation effect. A subsequent experiment replicated this finding and further showed that midazolam did not reduce the memory reactivation effect when injected 2 hr after the reminder episode. From this, it appears that alterations in GABAergic neurotransmission may be an underlying process mediating memory reactivation in the infant rat.

Does gabapentin act as an agonist at native GABA(B) receptors?

Gabapentin, a novel anticonvulsant and analgesic, is a gamma-aminobutyric acid (GABA) analogue but was shown initially to have little affinity at GABA(A) or GABA(B) receptors. It was recently reported to be a selective agonist at GABA(B) receptors containing GABA(B1a)-GABA(B2) heterodimers, although several subsequent studies disproved that conclusion. In the present study, we examined whether gabapentin is an agonist at native GABA(B) receptors using a rat model of postoperative pain in vivo and periaqueductal gray (PAG) slices in vitro; PAG contains GABA(B) receptors, and their activation results in antinociception. An intrathecal injection of gabapentin or baclofen, a GABA(B) receptor agonist, induced antiallodynia in this postoperative pain model. Intrathecal injection of GABA(B) receptor antagonists CGP 35348 and CGP 55845 antagonized baclofen- but not gabapentin-induced antiallodynia. In ventrolateral PAG neurons, baclofen activated G-protein-coupled inwardly rectifying K(+) (GIRK) channels in a manner blocked by CGP 35348 or CGP 55845. However, gabapentin displayed no effect on the membrane current. In neurons unaffected by gabapentin, baclofen activated GIRK channels through GABA(B) receptors. It is concluded that gabapentin is not an agonist at GABA(B) receptors that are functional in baclofen-induced antiallodynia in the postoperative pain model in vivo and in GIRK channel activation in ventrolateral PAG neurons in vitro.

The role of gamma-aminobutyric acid and glutamate for hypoxic ventilatory response in anesthetized rabbits.

Acute hypoxia produces an increase in ventilation. When the hypoxia is sustained, the initial increase in ventilation is followed by a decrease in ventilation. Hypoxia causes changes in brain neurotransmitters depending on its severity and durations. The purpose of this study was to investigate the role of gamma-aminobutyric acid (GABA) and glutamate for hypoxic ventilatory response in rabbits. The experiments were performed in peripheral chemoreceptors intact and denervated rabbits anesthetized with Na-pentobarbitate. For intracerebroventricular (ICV) injections of reagents in each animal, cannula was placed in left lateral cerebral ventricle by stereotaxic method. After ICV injection of GABA (0.48 mg/kg), air breathing in both groups caused a depression of respiratory activity. On the other hand, after ICV injection of GABA, breathing of hypoxic gas mixture (8% O(2)-92% N(2)) in both groups produced the hypoxic hyperventilation. After ICV injection of GABA, blockade of GABA(A) receptors with bicuculline (0.2 mg/kg) did not prevent the hypoxic hyperventilation. In contrast, after ICV GABA injection, blockade of glutamate NMDA receptors with MK-801 (0.09 mg/kg) completely abolished the hypoxic hyperventilation observed while the animals were breathing hypoxic gas mixture. Our findings suggest that ICV injection of GABA causes respiratory depression in normoxic conditions, and that it increases ventilation in hypoxic conditions with or without peripheral chemoreceptor impulses by increasing glutamate.

The inhibitory effects of (gamma)-aminobutyric acid (GABA) on growth hormone secretion in the goldfish are modulated by sex steroids.

Double-labelling studies at the electron microscopic level demonstrated that gamma-aminobutyric acid (GABA)-immunoreactive nerve endings are associated with growth-hormone-secreting cells in the proximal pars distalis of the goldfish pituitary gland, suggesting that GABA may be important for the control of growth hormone release in this species. An in vitro assay for GABA-transaminase activity demonstrated that the pituitary is a site for the metabolism of GABA to succinic acid. In vitro, GABA or the GABA antagonists bicuculline and saclofen did not affect the rate of growth hormone release from dispersed pituitary cells in static incubation. In contrast, intracerebroventricular injection of GABA reduced serum growth hormone levels within 30 min. During the seasonal gonadal cycle, intraperitoneal injection of GABA was without effect in sexually regressed goldfish, but caused a significant decrease in serum growth hormone levels in sexually recrudescent animals. Intraperitoneal implantation of solid silastic pellets containing oestradiol increased serum GH levels fivefold in sexually regressed and recrudescent goldfish; in both groups, GABA suppressed the oestradiol-stimulated increase in circulating growth hormone levels. The effect of oestradiol on basal serum growth hormone levels was specific since progesterone and testosterone were without effect. However, in recrudescent animals treated with progesterone and testosterone, the inhibitory effects of GABA on serum growth hormone levels were absent, indicating a differential role for these steroids in growth hormone release. Taken together, these results demonstrate that GABA has an inhibitory effect on growth hormone release in goldfish.

Effects of adenosine and gamma-aminobutyric acid A receptor antagonists on N-methyl-D-aspartate induced neurotoxicity in the rat hippocampus.

This study investigated the modulatory actions of adenosine and gamma-aminobutyric acid (GABA) on several aspects of N-methyl-D-aspartate (NMDA)-induced neurotoxicity, including neuronal loss, atrophy, necrosis, and calcium accumulation in the hippocampus. For this purpose, we combined unilateral intrahippocampal injections of NMDA (24 nmoles) with acute injections of the selective A1 adenosine receptor antagonist DPCPX (0.03 pmoles), the selective adenosine A2a receptor antagonist CSC (1.5 pmoles), a combination of these two antagonists, and injections of the selective GABA A receptor antagonist bicuculline (60 pmoles). Fifteen days after NMDA injection, neuronal loss with preservation of architecture was observed in stratum oriens, pyramidale, radiatum, lacunosum-moleculare, and stratum moleculare of Ammon's horn, and in radial and granular layers of the dentate gyrus. NMDA plus vehicle also produced a small degree of brain tissue necrosis (holes in the structure) in four of five brains. Acute injections of CSC, but not DPCPX or bicuculline, significantly increased the extent of neuronal loss produced by NMDA plus vehicle. CSC in combination with NMDA induced significantly more necrosis than NMDA plus vehicle. A significant degree of atrophy was observed in the hippocampus after treatment with NMDA plus vehicle, and bicuculline significantly increased the magnitude of this atrophy. NMDA-induced calcium deposits were detected within the radiatum and lacunosum-moleculare layers of the hippocampus and in the hilus of the dentate, but not in the stratum oriens, stratum pyramidale, or in the granular layer of the dentate gyrus. However, treatment with the different antagonists did not significantly modify the magnitude of the NMDA-induced calcium deposits. These results reveal a selective vulnerability of certain areas of the hippocampus to the accumulation of calcium deposits, and a selective interaction between adenosine receptors and NMDA-induced neurotoxicity in the hippocampus.

The effect of changes in hepatocyte membrane potential on immediate-early proto-oncogene expression following partial hepatectomy in rats.

The stimulus responsible for inducing hepatocytes to enter the cell cycle following partial hepatectomy (PHx) remains to be identified. One suggested candidate is the change in hepatocyte membrane potential (PD) that occurs immediately following PHx. To test this possibility, we monitored changes in hepatocyte PD and immediate-early proto-oncogene expression in rats pretreated with saline or gamma aminobutyric acid (GABA), an amino-acid neurotransmitter that hyperpolarizes isolated hepatocytes. Intraperitoneal injections of saline or GABA (500 microg/g body weight) were administered to adult, male Sprague-Dawley rats 1 hour prior to 70% PHx. Rats were sacrificed and the livers excised at various times until 180 minutes post-PHx for messenger RNA (mRNA) and protein analyses. In additional groups of saline- and GABA-treated rats, PD changes were recorded continuously from -260 to 180 minutes post-PHx. Serum GABA concentrations were determined by ion-exchange chromatography with orthopthaldehyde fluorescence detection. Hepatocyte PD's were recorded in situ by intracellular microelectrodes with an Axoprobe-1A amplifier. Steady-state levels of c-fos, c-jun, jun-B, and c-myc transcripts and proteins were documented by Northern blots of poly(A)-enriched RNA derived from resected livers and Western blots of total nuclear protein, respectively. Serum GABA concentrations remained unchanged in saline-treated controls but increased 10- to 20-fold above baseline values in GABA-treated rats. In saline-treated controls, hepatocyte depolarization occurred immediately and was maintained throughout the 180 minutes post-PHx period (PD pre-PHx, -36.8 +/- 5.1; 15 minutes post-PHx, -27.5 +/- 5.7; and 180 minutes post-PHx, -28.3 +/- 4.4 mV, mean +/- SD); whereas in GABA-treated rats, hepatocyte PD remained unchanged (-37.0 +/- 1.1; -36.4 +/- 3.1 and -39.2 +/- 2.7 mV, respectively). Despite abrogation of hepatocyte PD changes, proto-oncogene mRNA and protein levels in saline- and GABA-treated rats were either similar or, in the case of c-fos and c-jun, increased five- to sevenfold in GABA-treated rats. The results of this study indicate the following: 1) hepatocytes depolarize immediately post-PHx and remain depolarized throughout the priming phase of the cell cycle; 2) elevated serum GABA concentrations prevent PHx-induced hepatocyte depolarization; and 3) depolarization is not the stimulus responsible for priming hepatocytes into replicative competence.

Square-wave jerks and square-wave oscillations: treatment with valproic acid

Experimental studies in monkeys have demonstrated that injection of gamma-aminobutyric acid (GABA) agonists into the superior colliculus restricts saccadic eye movements, while injection of GABA antagonists leads to square-wave jerks (SWJ). To investigate the role of GABA in saccadic interruptions of fixation, we treated five patients who had SWJ and square-wave oscillations (SWO) with valproic acid (VPA) (2000 mg/d), which has been shown to increase brain GABA levels. VPA effectively reduced the SWJ/SWO in three patients, abolished them in one patient, but was ineffective in the fifth, who had a localized lesion in the cerebellar vermis. VPA effects may have been due to the restoration of the GABAergic tonic inhibitory action from the substantia nigra pars reticulata to the superior colliculus.

Effects of gamma-aminobutyric acid on regional vascular resistances of conscious spontaneously hypertensive rats.

1. The regional vascular effects of a central injection of gamma-aminobutyric acid (GABA) in conscious spontaneously hypertensive rats (SHR) were compared with normotensive control rats (NCR), including Wistar-Kyoto rats (male, 10-20 weeks of age). One week or more after insertion of a cannula into the cisterna magna, an electromagnetic flow probe was implanted around one of five arteries, and a catheter for measurement of blood pressure and heart rate was inserted into the terminal aorta or common carotid artery. Cardiovascular changes were observed in the conscious animal after recovery from the surgery. Peripheral resistance was calculated as pressure divided by flow. 2. Ten min following intracisternal injection of 10 mu mol of GABA, mean arterial pressure and heart rate were significantly lowered (P < 0.05; t-test): - 29 and -16% (70 d.f.) in SHR versus -23 (116 d.f.) and -19% (112 d.f.) in NCR. Hindquarters, carotid, superior mesenteric and renal, but not coeliac, vascular resistances were significantly lowered (P < 0.05; t-test, 21, 9, 18 d.f.) in SHR. However, when comparing the effect of GABA injection in SHR and NCR, there were no significant differences in coeliac, carotid and hindquarters vascular resistances, but there were significant decreases in superior mesenteric and renal vascular resistances in SHR. 3. These results indicate that: (i) a cisternal injection of GABA in SHR decreases both peripheral vascular resistance and heart rate, and thereby lowers blood pressure; (ii) the vascular resistance of the superior mesenteric and renal vascular beds was more decreased in SHR than in NCR. This suggests that the GABAergic control of regional vascular resistance differs in the SHR and the NCR.

Pharmacological induction and modulation of stridulation in two species of acridid grasshoppers

The influence of neurotransmitters and neuroactive substances on stridulatory behaviour was analysed in two species of acridid grasshoppers (Omocestus viridulus and Chorthippus mollis). Acetylcholine, octopamine, gamma-aminobutyric acid and glutamate were applied by pressure injection (0.5&shy;1.0 nl, 10(-3) mol l-1) into the protocerebrum. All except octopamine were also applied to the metathoracic ganglion by pressure injection or superfusion (1 ml). Injection of acetylcholine into the medial dorsal neuropile of the protocerebrum elicited continuous long-lasting species-specific stridulation in both acridid species. All other substances tested had no effect when injected into the brain. Injection of acetylcholine into the medial dorsal neuropile of the metathoracic ganglion enhanced the amplitude of the stridulatory leg movements elicited by electrical brain stimulation. It did not alter the repetition rate or coordination of the movements in O. viridulus; but it decreased the length of stridulatory cycles in C. mollis. Injection of gamma-aminobutyric acid into the medial dorsal metathoracic neuropile in both species suppressed the stridulatory leg movements ipsilateral to the injection site but did not alter those on the contralateral side. Superfusion of the metathoracic ganglion with gamma-aminobutyric acid suppressed the movements of both hindlegs. Pressure injection of glutamate into the metathoracic ganglion had no effect on the stridulatory leg movements, but superfusion enhanced the stridulatory movements.

Rat vasopressin cell responses to simulated hemorrhage: stimulus-dependent role for A1 noradrenergic neurons.

c-fos expression mapping and electrophysiological recording experiments were done to clarify the role of the A1 noradrenergic cell group in the vasopressin response to hypotensive hemorrhage. In pentobarbital-anesthetized rats, moderate and severe hypotensive hemorrhages were simulated by brief occlusion of the inferior vena cava sufficient to reduce mean arterial pressure to approximately 50 or 30 mmHg, respectively. Both stimuli significantly increased the number of A1 region catecholamine cells displaying Fos-like immunoreactivity, this effect being most prominent at the level of the area postrema. Both stimuli also increased the number of supraoptic nucleus vasopressin cells displaying Fos-like immunoreactivity. Accordingly, electrophysiological studies involving separate animals confirmed that both moderate and severe caval occlusion significantly increased the firing of functionally identified vasopressin cells recorded in the supraoptic nucleus. However, although interruption of A1 region neuronal function by injection of gamma-aminobutyric acid at the level of the area postrema eliminated the increase in vasopressin cell firing elicited by moderate caval occlusion, it did not block the response to severe caval occlusion. These findings suggest that, in the rat, the vasopressin response to an acute reduction in central blood volume, such as that produced by hemorrhage, depends on the A1 projection only if the stimulus is of moderate intensity. Severe stimuli appear to involve activation of both the A1 projection and an additional vasopressin-stimulatory pathway that bypasses the A1 region.

GABA stimulation of gonadotropin-II release in goldfish: involvement of GABAA receptors, dopamine, and sex steroids

The involvement of gamma-aminobutyric acid (GABA) in regulation of pituitary gonadotropin-II (GTH-II) release was studied in the goldfish. Intraperitoneal injection of GABA (300 micrograms/g) stimulated an increase in serum GTH-II levels at 30 min postinjection. The GABAA receptor agonist muscimol (0.1-10 micrograms/g) stimulated GTH-II in a dose-dependent manner. Baclofen, a GABAB receptor agonist, had a small but significant stimulatory effect at 1 and 10 micrograms/g; the amount of GTH-II released in response to baclofen was significantly less (P < 0.05) than that released by muscimol. Pretreatment of goldfish with bicuculline, a GABAA receptor antagonist, but not saclofen, a GABAB receptor antagonist, blocked the stimulatory effect of GABA on serum GTH-II. Elevation of brain and pituitary GABA levels with the GABA transaminase inhibitor, gamma-vinyl-GABA (GVG), decreased hypothalamic and pituitary dopamine (DA) turnover rates, indicating that GABA may stimulate GTH-II release in the goldfish by decreasing dopaminergic inhibition of GTH-II release. The release of GTH-II stimulated by muscimol and GVG was potentiated by pharmacological agents that decrease inhibitory dopaminergic tone, indicating that DA may also inhibit GABA-stimulated GTH-II release. Based on the linear 24-h accumulation of GABA in brain and pituitary after GVG injection, implantation of testosterone, estradiol, or progesterone, previously shown to regulate the serum GTH-II release response to gonadotropin-releasing hormone and GABA, was also found to modulate GABA synthesis in the brain and pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)