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PubMed1991

GABAA receptor mediated fast synaptic inhibition in the rabbit brain-stem respiratory system.

The involvement of GABA mediated neurotransmission in the central control of respiration was investigated by administration of the specific GABAA receptor agonist muscimol and the specific GABAA receptor antagonist biculline into the fourth cerebral ventricle of the rabbit. Cycle-triggered averaging of the phrenic nerve activity (PNA) was used to quantify drug-induced changes of the central respiratory pattern. Muscimol reduced the peak amplitude of PNA and increased the duration of the respiratory phases. High amounts of muscimol led to a long-lasting but reversible central apnea. Bicuculline very effectively blocked the effects of externally applied muscimol. Blockade of intrinsically active GABAergic neurotransmission by bicuculline resulted in a multitude of effects. Peak amplitude of PNA increased whereas the duration of both inspiration and expiration decreased. In this respect, effects of bicuculline and muscimol were complementary. Bicuculline reduced the slope of the inspiratory ramp, increased postinspiratory activity and induced an augmenting type of discharge activity in the last part of expiration resulting in a smooth transition between expiration and inspiration. In some cases the respiratory modulation was completely lost and PNA became perfectly tonic. This 'apneustic' type of respiratory pattern could be transformed into rhythmic breathing by increasing the respiratory drive. We conclude that neurotransmission via GABAA receptors is important for the maintenance of respiratory rhythm as well as the generation of normal respiratory pattern.

Animals↗
PubMed1990

Modulation of the GABAA receptor by barbiturates and pregnane steroids: differential effects of the influence of assay temperature.

The effect of temperature on the modulation of the GABAA receptor by barbiturates and steroids has been investigated in-vitro using a radioreceptor binding assay. Displaceable [3H]muscimol binding to a crude membrane preparation from rat cerebral cortex was enhanced by the endogenous steroid metabolite, 5 beta-pregnan-3 alpha-ol-20-one, by the synthetic steroid, alphaxalone, and by pentobarbitone in a dose-dependent manner. Hydrocortisone and corticosterone had no significant effect on [3H]muscimol binding. Analysis of binding data using a curve-fitting program ('Ligand') showed that both pentobarbitone (1 mM) and 5 beta-pregnan-3 alpha-ol-20-one (10 microM) increased the apparent number of high affinity binding sites in the membrane but had no effect on the affinity of [3H]muscimol binding (Kd approx. 11 nM). Increasing the assay temperature from 0 degrees C to 35 degrees C decreased [3H]muscimol binding and decreased the enhancement of binding by pentobarbitone but had no effect on 5 beta-pregnan-3 alpha-ol-20-one enhancement of binding. 5 alpha-Pregnan-3 alpha-ol-20-one increased the apparent rate of association of [3H]muscimol binding to its receptor whereas pentobarbitone had no effect. These different effects on the apparent association rate and the different responses to temperature, suggest that the barbiturate and steroid may interact with the GABAA receptor through different binding sites.

Animals↗
PubMed1996

Tonic sympathetic chemoreflex after blockade of respiratory rhythmogenesis in the rat.

1. We sought to determine whether the increase in sympathetic nerve discharge (SND) caused by carotid chemoreceptor stimulation requires the integrity of ventrolateral medullary structures involved in generating respiratory rhythm and pattern. Experiments were done in urethane-anaesthetized, vagotomized, aortic deafferented, ventilated rats except when indicated (see paragraph 3). 2. Brief hypoxia (N2 for 5-12 s) or I.V. NaCN (50-100 micrograms kg-1) activated SND in bursts synchronized with the phrenic nerve discharge (PND). No effect was produced in chemo-deafferented rats. 3. In unanaesthetized vagotomized decerebrated rats, ligation of the internal carotid arteries preserved peripheral chemoreceptor function but abolished baroreflexes. In this preparation, stimulation of peripheral chemoreceptors (N2 for 2-6 s) also activated SND in bursts synchronized with PND. 4. Bilateral microinjection of the GABAA receptor agonist muscimol into the caudal ventrolateral medulla (CVLM) instantly blocked the sympathetic baroreflex, eliminated PND at rest and during chemoreceptor stimulation but did not change the mean increase in SND produced by chemoreceptor stimulation. Sympathoactivation in response to chemoreceptor stimulation became tonic after 1-13 min and was still totally dependent on the integrity of the carotid sinus nerves. 5. Muscimol injection instantly eliminated the respiratory outflow of the Xth and XIIth cranial nerves, both at rest and during chemoreceptor stimulation. 6. Muscimol eliminated the on-off respiratory pattern of neurons in the rostral ventrolateral medulla (RVLM). During chemoreceptor stimulation, these cells became activated or inhibited tonically. 7. Muscimol injection raised the resting discharge rate of vasomotor presympathetic cells in RVLM, blocked their baroreceptor inputs but did not change the magnitude of their excitation by chemoreceptor stimulation. Muscimol injection eliminated their respiratory modulation. 8. In conclusion, the sympathetic response to chemoreceptor stimulation may be due to convergence and integration in RVLM of two processes: respiration-independent excitatory input to RVLM neurons and respiratory patterning of their activities via inputs from the pre-Bötzinger complex.

Anesthesia↗
PubMed1996

Long-term GABAA receptor activation increases [Ca2+]i in single lactotrophs.

Prolactin (PRL) release by pituitary lactotrophs is inhibited by gamma-aminobutyric acid (GABA). We have investigated the effect of long-lasting activation of GABAA receptors on membrane potential and cytosolic free calcium concentration ([Ca2+]i) in single identified lactotrophs. Membrane potential was recorded using the perforated patch-clamp technique and [Ca2+]i using indo 1 as a fluorescent Ca2+ probe. When cells were bathed in muscimol (10 microM) for 30 min, [Ca2+]i unexpectedly increased in 53% of the lactotrophs. This was due to a Ca2+ influx, since it was inhibited by Ca(2+)-free extracellular medium or by Ca2+ channel blockers such as the dihydropyridine PN 200-110. In cells incubated in muscimol, wash of muscimol from the cell membrane potential and reduced [Ca2+]i to the levels found in control cells. This effect was mimicked by picrotoxin, a GABA-operated Cl- channel blocker, thus supporting the involvement of a muscimol-induced Cl- flux. Conversely, under similar experimental conditions, static assays of PRL release revealed an inhibition of release by muscimol, unaffected by the dihydropyridine PN 200-110. Our observations suggest that GABAA, receptors may not regulate the process of exocytosis within the Ca(2+)- regulated steps.

Animals↗
PubMed1987

Sodium-independent, bicuculline-sensitive [3H]GABA binding to isolated rat hepatocytes.

To determine whether hepatocytes possess specific receptor sites for gamma-aminobutyric acid (GABA), a potent amino acid neurotransmitter, [3H]GABA, was added to sodium-free suspensions of Percoll-purified hepatocytes derived from collagenase-perfused rat livers under various experimental conditions and in the presence or absence of specific GABA receptor agonists (muscimol) and antagonists (bicuculline). The effects of GABA, muscimol, and bicuculline on hepatocyte resting membrane potentials were also determined. Specific binding of [3H]GABA to hepatocytes was a consistent finding. GABA-hepatocyte interactions were reversible and temperature dependent. Muscimol and bicuculline inhibited binding in a dose-dependent manner (IC50, 30 nM and 50 microM, respectively), whereas strychnine (1.0-100 microM), a nonspecific central nervous system stimulant, had no appreciable effect. Both GABA and muscimol (100 microM) caused significant hyperpolarization of hepatocyte resting membrane potential (delta PD 5.4 +/- 3.1 and 22.2 +/- 16.2 mV, respectively, means +/- SD, P less than 0.0005). Bicuculline (100 microM) inhibited the effect of muscimol (P less than 0.05). The results of this study suggest that specific GABA receptor sites exist on the surface of isolated rat hepatocytes. The presence of such sites raises the possibility that, in addition to adrenergic and cholinergic innervation, hepatic function may be influenced by GABA-ergic neurotransmitter mechanisms.

Animals↗
PubMed1996

Influence of GABAergic mechanisms on baroreceptor inputs to nucleus tractus solitarii of rats.

The firing frequency of baroreceptive neurons in the nucleus tractus solitarii (NTS) during microiontophoretic application of muscimol, a gamma-aminobutyric acid (GABA)A agonist, or baclofen, a GABAB agonist, was monitored in anesthetized rats. Muscimol decreased the spontaneous discharge of 69 of 73 (94.5%) NTS baroreceptive neurons without affecting the remaining four neurons (5.5%). The statistical comparison on a bin-by-bin basis of the peri-R wave interval histograms of the discharge of each NTS neuron showed that the inhibitory action of muscimol was always exerted on the whole neuronal discharge independently of its correlation to the cardiac cycle. Baclofen inhibited 60 of 73 (82.2%) NTS neurons without affecting the remaining 13 neurons (17.8%). In 31 of 60 (51.7%) neurons inhibited by baclofen, this substance significantly affected only pulse-synchronous peaks of neuronal discharge without significant inhibition of the neuronal firing between cardiac cycle-related peaks. Fifty-eight of 73 (79.5%) NTS neurons studied were inhibited by both muscimol and baclofen, 11 neurons (15%) only by muscimol, 2 neurons (2.7%) only by baclofen, and 2 neurons (2.7%) were unaffected by both substances. These results demonstrate that both GABAA and GABAB receptors mediate inhibition of the spontaneous discharge in the great majority of the NTS baroreceptive neurons studied and suggest different functions of the two types of GABA receptors in influencing baroreceptor inputs to the NTS.

Afferent Pathways↗
PubMed1999

Activation of GABAA but not GABAB receptors in the NTSblocked bradycardia of chemoreflex in awake rats.

In the present study we analyzed effects of bilateral microinjections of muscimol (a GABAA agonist) and baclofen (a GABAB agonist) into the nucleus tractus solitarius (NTS) on bradycardic and pressor responses to chemoreflex activation (potassium cyanide, 40 micrograms/rat iv) in awake rats. Bilateral microinjections of muscimol (25 and 50 pmol/50 nl) into the NTS increased baseline mean arterial pressure (MAP): 119 +/- 8 vs. 107 +/- 2 mmHg (n = 6) and 121 +/- 8 vs. 103 +/- 3 mmHg (n = 6), respectively. Muscimol at 25 pmol/50 nl reduced the bradycardic response to chemoreflex activation 5 min after microinjection; with 50 pmol/50 nl the bradycardic response to chemoreflex activation was reduced 5, 15, 30, and 60 min after microinjection. Neither muscimol dose produced an effect on the pressor response of the chemoreflex. Effects of muscimol (50 pmol/50 nl) on basal MAP and on the bradycardic response of the chemoreflex were prevented by prior microinjection of bicuculline (a GABAA antagonist, 40 pmol/50 nl) into the NTS. Bilateral microinjections of baclofen (12.5 and 25 pmol/50 nl) into the NTS produced an increase in baseline MAP [137 +/- 9 vs. 108 +/- 4 (n = 7) and 145 +/- 5 vs. 105 +/- 2 mmHg (n = 7), respectively], no changes in basal heart rate, and no effects on the bradycardic response; 25 pmol/50 nl only attenuated the pressor response to chemoreflex activation. The data show that activation of GABAA receptors in the NTS produces a significant reduction in the bradycardic response, whereas activation of GABAB receptors produces a significant reduction in the pressor response of the chemoreflex. We conclude that 1) GABAA but not GABAB plays an inhibitory role in neurons of the lateral commissural NTS involved in the parasympathetic component of the chemoreflex and 2) attenuation of the pressor response of the chemoreflex by activation of GABAB receptors may be due to inhibition of sympathoexcitatory neurons in the NTS or may be secondary to the large increase in baseline MAP produced by baclofen.

Animals↗
PubMed2000

Influence of pontine A5 region on renal sympathetic nerve activity in conscious rabbits.

The effects of inhibiting the neural activity in the pontine A5 region on renal sympathetic responses to baroreflex and/or chemoreflex activation were examined in conscious rabbits. Eight rabbits were chronically instrumented with guide cannulas for bilateral microinjections into the A5 area and an electrode for measuring renal sympathetic nerve activity (RSNA). Baroreflex curves were obtained under conditions of normoxia and hypoxia (10% O(2) + 3% CO(2)) after injections into the A5 region of the GABA receptor agonist muscimol or vehicle solution. Under normoxia, injections of muscimol did not affect resting RSNA or blood pressure but increased the range of the RSNA baroreflex by 24 and 33% at doses of 175 or 875 pmol, respectively, without affecting the reflex gain. Hypoxia alone increased resting RSNA by 63%, as well as the range and gain of the RSNA baroreflex by 53 and 89%, respectively, without affecting blood pressure. However, under hypoxia, muscimol increased resting RSNA by 37 and 47% but decreased the gain of the RSNA baroreflex by 19 and 34% at doses of 175 or 875 pmol, respectively, without affecting the reflex range. The effects of muscimol on RSNA were mediated via changes in the amplitude of the sympathetic bursts, whereas burst frequency remained unaffected. These data suggest that the A5 region has a little tonic influence on RSNA in conscious rabbits but serves to limit the renal sympathetic responses to baroreceptor unloading or chemoreceptor stimulation. The different changes in the baroreflex range and gain evoked by muscimol under normoxia and hypoxia indicate that the A5 modulatory action may depend on the activity of the afferent inputs to this region.

Animals↗
PubMed1991

Basal ganglia motor control. III. Pallidal ablation: normal reaction time, muscle cocontraction, and slow movement.

1. Inactivation of the portions of globus pallidus pars interna (GPi) containing the greatest concentration of wrist-related neurons was achieved in two rhesus monkeys with microinjections of muscimol (temporary) and kainic acid (permanent). 2. After muscimol injection, there was onset within 30 s of 1) tonic and phasic coactivation of wrist flexors and extensors; 2) slightly greater activation of the flexors, giving a flexor bias in postural holds and the endpoint of movements; and 3) slowness of all movements with a prolonged movement time. Nevertheless, 4) movements made by lessening prior loaded muscle activity (to move in the direction of the load) were slower than movement made by increasing muscle activity (to move against the direction of the load). Despite marked slowing of all movements, there was 5) a normal reaction time for movement onset. Finally, there was 6) a reduced amplitude of most movements. Open room behavior included 7) spiraling contralateral to the lesion while walking. Effects were reproducible (12 injections), were apparent for 7-8 h and were usually completely gone by the next day's testing. 3. After kainic acid injection, there was a period of mixed effects, followed by a period of permanent defects (observed for up to 24 days) that duplicated the temporary effects of muscimol. 4. By contrast, muscimol inactivation of the cerebellar dentate nucleus resulted in 1) a prolonged reaction time and 2) an increased variability of movement trajectory, but 3) without change in movement time or peak velocity. Open room behavior included overshoot in reaching for fruit with the forelimb ipsilateral to the injection. 5. From the facts that normal pallidal neurons fire constantly, that pallidal neurons inhibit their target neurons, and that the muscimol effect was immediate, we conclude that the release of the target neurons from the tonic inhibition allowed them to fire in patterns that promoted a maintained state of cocontraction of agonist and antagonist muscles. From the fact that movement time was prolonged, we conclude that the maintained state of neural activity that caused the muscle cocontraction interfered with the commands for voluntary movement, which were generated by other mechanisms. From the fact that reaction time for movement onset was normal, we conclude that the pallidal neurons may play little or no role in the voluntary initiation of these movements, which are instead generated by other structures that include the anterior cerebral cortex and the lateral cerebellum.

Animals↗
PubMed1999

Effect of reversible inactivation of macaque lateral intraparietal area on visual and memory saccades.

Previous studies from our laboratory identified a parietal eye field in the primate lateral intraparietal sulcus, the lateral intraparietal area (area LIP). Here we further explore the role of area LIP in processing saccadic eye movements by observing the effects of reversible inactivation of this area. One to 2 microl of muscimol (8 mg/ml) were injected at locations where saccade-related activities were recorded for each lesion experiment. After the muscimol injection we observed in two macaque monkeys consistent effects on both the metrics and dynamics of saccadic eye movements at many injection sites. These effects usually took place within 10-30 min and disappeared after 5-6 h in most cases and certainly when tested the next day. After muscimol injection memory saccades directed toward the contralesional and upper space became hypometric, and in one monkey those to the ipsilesional space were slightly but significantly hypermetric. In some cases, the scatter of the end points of memory saccades was also increased. On the other hand, the metrics of visual saccades remained relatively intact. Latency for both visual and memory saccades toward the contralesional space was increased and in many cases displayed a higher variance after muscimol lesion. At many injection sites we also observed an increase of latency for visual and memory saccades toward the upper space. The peak velocities for memory saccades toward the contralesional space were decreased after muscimol injection. The peak velocities of visual saccades were not significantly different from those of the controls. The duration of saccadic eye movements either to the ipsilesional or contralesional space remained relatively the same for both visual and memory saccades. Overall these results demonstrated that we were able to selectively inactivate area LIP and observe effects on saccadic eye movements. Together with our previous recording studies these results futher support the view that area LIP plays a direct role in processing incoming sensory information to program saccadic eye movements. The results are consistent with our unit recording data and microstimulation studies, which suggest that area LIP represents contralateral space and also has a bias for the upper visual field.

Animals↗
PubMed1984

Involvement of catecholamines and glutamate in GABAergic mechanism regulatory to luteinizing hormone and prolactin secretion.

There is some evidence that a population of estrogen-receptive neurons exists in the preoptic/anterior hypothalamic area which uses gamma-aminobutyric acid (GABA) as neurotransmitter and which is involved in mediating the negative feedback of estrogens on pituitary luteinizing hormone (LH) secretion. These neurons are proposed to be presynaptic inhibitors to norepinephrine (NE) release thereby inhibiting the stimulatory effect of NE on LHRH neurons. Muscimol, a potent GABA agonist, inhibits pituitary LH release in ovariectomized rats after intraventricular injection of 5 nmol. This treatment significantly increased prolactin levels. Catecholamine turnover rates in micropunches of various hypothalamic and mesolimbic structures following intraventricular treatment with muscimol were determined using the method of blocking the activity of tyrosine hydroxylase by alpha-methyl-p-tyrosine. Muscimol did not affect catecholamine, GABA and glutamate concentrations. Turnover rates of NE were significantly reduced in the medial preoptic/anterior hypothalamic area. In this structure as well as in the nucleus accumbens and in the anterior mediobasal hypothalamus turnover rates of dopamine (DA) were also reduced whereas DA turnover in mediocortical amygdalae was increased by muscimol. The selective reduction of NE turnover following muscimol may be explained by a direct or indirect action of the GABA-eric drug on NE axon terminals. The reduced NE and DA turnover in the medial preoptic area may be causally related to reduced serum LH levels whereas the reduced hypothalamic DA turnover may explain increased blood prolactin levels.

Animals↗
PubMed1983

Effects of GABA and some GABA analogues on respiratory regulation in the preterm rabbit.

Preterm neonatal rabbits (gestational age 29 days) were given GABA (750 mg/kg) or the GABA-like drugs muscimol (2 mg/kg) and GHBA (375 mg/kg) intraperitoneally. Basal respiration and the ventilatory response to 10% CO2 were studied, before and after drug administration, in a whole body plethysmograph during halothane anesthesia. The three drugs tested all caused a decrease in minute volume. The decrease in minute volume was mainly due to a decrease in tidal volume after GABA and muscimol, while GHBA reduced minute volume due to a decrease in respiratory frequency. A decrease in respiratory frequency was also seen after muscimol administration. Changes in the respiratory time intervals were seen after muscimol and GHBA both causing significant increases in expiratory and respiratory time. 'Inspiratory drive' and 'respiratory timing mechanisms' were evaluated by VT/TI and TI/TTOT, respectively. GABA and muscimol reduced both VT/TI and TI/TTOT while GHBA only reduced TI/TTOT. Addition of 10% CO2 to the inhalation gas caused an increase in tidal volume and minute volume during control conditions. This response to CO2 was abolished by GABA and GHBA treatment. Our findings demonstrate that GABA and GABA-like drugs cause respiratory depression in the preterm neonate. Central mechanisms are most likely involved in this response. These findings may be relevant to the irregular or apneic breathing sometimes seen in the preterm human infant.

Animals↗
PubMed1994

Combination therapy protects ischemic brain in rats. A glutamate antagonist plus a gamma-aminobutyric acid agonist.

BACKGROUND AND PURPOSE: The excitotoxic effects of glutamate can be blocked almost completely with gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, in cell culture, tissue slices, and in some animal models. After stroke in rats, we showed previously that an agonist of GABA, muscimol, was as neuroprotective as MK-801, an antagonist of glutamate. To obtain further neuroprotection and to avoid the side effects associated with high doses of MK-801, we wanted to assess the efficacy of the two agents in combination. METHODS: Treatment was administered 5 minutes after embolic cerebral ischemia in Sprague-Dawley rats. The subjects were rated using a neurological evaluation 48 hours later. Visual-spatial learning was measured 8 to 10 weeks after stroke, after which we measured the volume of each cerebral hemisphere and several large cerebral compartments. Treatment groups included saline (n = 27), MK-801 1.0 mg/kg (n = 23), muscimol 1.0 mg/kg (n = 17), and both agents together using a dose of 0.5 mg/kg each (n = 25). RESULTS: A probit analysis of the neurological ratings revealed a protective effect of muscimol used alone (MK-801 potency ratio, 2.0; P = NS; muscimol potency ratio, 4.0; P < .05) and a protective effect of the combination (potency ratio, 5.0; P < .05). Focal ischemia caused a moderate to severe delay in the acquisition of visual-spatial information, which was completely eliminated by the combination treatment but only partially ameliorated with MK-801 or muscimol alone. Ischemia reduced the cerebral hemisphere volume from 0.42 mm3 to 0.34 mm3 (P < .0001), the volume density of cortex from 22% to 17% of total cerebral volume (P < .01), and that of hippocampus from 4.3% to 3.0% (P < .05). Only the combination was neuroprotective, as measured by the ratio of the lesioned to the contralateral hemisphere volume (P = .013). The combination treatment and MK-801 protected the hemisphere volume, the cortex, and the hippocampus and reduced the size of visible infarction. CONCLUSIONS: Combination therapy, using a glutamate antagonist and a GABA-A agonist, appeared to protect the brain and ameliorate a defect in learning behavior after stroke. The combination may have been more effective than either agent used alone, although further study of higher doses is needed.

Animals↗
PubMed1986

Evidence for gamma-aminobutyric acid modulation of ovarian hormonal effects on luteinizing hormone secretion and hypothalamic catecholamine activity in the female rat.

Recent evidence suggests that gamma-aminobutyric acid (GABA)-containing neurons may inhibit LH release under certain circumstances. The present experiments tested whether GABA agonists block the LH surge induced in ovariectomized rats by estradiol benzoate (EB) plus progesterone (P) treatment and whether these agents affect the concentration and turnover of hypothalamic catecholamines, assessed from the depletion that occurs after synthesis inhibition. Ovariectomized rats received EB, followed 2 days later by P. Simultaneously with P, rats received either saline or one of the GABA agonists, baclofen or muscimol. Other agonist-treated rats received a second injection 4 h later or were additionally treated with the postsynaptic GABA antagonist bicuculline. Additional experiments tested the effects of these agents on LH release in response to exogenous LHRH. The LH surge induced by EB plus P was blocked by administration of either baclofen or muscimol in a dose-dependent manner. Bicuculline did not prevent the effect of baclofen, but partially prevented the effect of muscimol. Neither baclofen nor muscimol significantly affected LH release in rats receiving LHRH. In a second set of studies in EB plus P-treated rats, baclofen and muscimol decreased the steady state concentrations of norepinephrine in the medial preoptic area and medial basal hypothalamus for several hours and markedly decreased the turnover rate of norepinephrine in these areas. The concentrations and turnover of epinephrine were also decreased by these GABA agonists in the medial basal hypothalamus. The drugs had no effect on dopamine levels or turnover in either structure. These results support the hypothesis that a GABAergic system regulates LH release via modulation of noradrenergic and adrenergic systems that control LHRH secretion.

Animals↗
PubMed1993

Evidence that changes in the function of the subtypes of the receptors for gamma-amino butyric acid may be involved in the seasonal changes in the negative-feedback effects of estrogen on gonadotropin-releasing hormone secretion and plasma luteinizing hormone levels in the ewe.

We have investigated the effects of gamma-amino butyric acid (GABA) agonists and antagonists to GABAA and GABAB receptors microinjected (1 microliter) into the medial preoptic area (MPOA) on LH secretion in ovariectomized (OVX) ewes with or without estrogen (E) treatment, during the nonbreeding season. Guide tubes (19 gauge) were placed into the MPOA of OVX ewes and injections of 1 microgram or 10 micrograms of the GABAA agonist muscimol or the GABAA antagonist bicuculline, and 10 micrograms of the GABAB agonist baclofen or the GABAB antagonist phaclofen were made into conscious animals. Jugular venous blood was collected at 10-min intervals for 3 h, the injection of GABA drug or vehicle was given and samples collected for a further 3 h. The plasma samples were assayed for LH. On completion of the experiments the brains were sectioned to locate the sites of injection. Thirty-four ewes were used, of which 30 had correct guide tube placement. In OVX sheep, both muscimol and bicuculline injection caused suppression of plasma LH concentrations, with a cessation of pulsatile release in many instances. Injection with baclofen or phaclofen into these sheep had no effect on LH secretion. When OVX sheep were treated with 0.5-cm Silastic implants (sc) of E for at least 7 days, there was a variable response to muscimol and bicuculline injection, depending on the degree of suppression of LH secretion by E. When E had little effect on plasma LH levels, muscimol and bicuculline both suppressed LH secretion in a similar manner to that observed in OVX ewes. When E treatment fully suppressed plasma LH levels, muscimol and bicuculline both stimulated LH secretion. This stimulation often took the form of a sustained, nonpulsatile secretion of LH. Baclofen injection into OVX ewes treated with E increased mean plasma LH levels through an increase in pulse amplitude, although there was only an effect on the amplitude of the first pulse after injection. Conversely, phaclofen injection in OVX ewes treated with E resulted in a reduction in LH pulse amplitude. These results provide evidence for a seasonal shift in the regulation of GnRH secretion by GABAergic neurons in the MPOA of the ewe. In contrast to the breeding season, where there was no effect of GABAB ligands, these appear to function in non-breeding season, this may be part of the mechanism for the seasonal shift in the negative-feedback effect of E on LH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Differential regulation of luteinizing hormone release by gamma-aminobutyric acid receptor subtypes in the arcuate-ventromedial region of the castrated ram.

We investigated the effects on LH secretion of infusing gamma-aminobutyric acid (GABA) agonists muscimol and baclofen (GABAA and GABAB receptor agonists, respectively) into either the medial preoptic area (mPOA) or the arcuate-ventromedial region (ARC-VMR) of the hypothalamus of castrated rams during the nonbreeding season. Bilateral microdialysis of artificial cerebrospinal fluid for 4 h followed by treatment with artificial cerebrospinal fluid, baclofen (1 mM), or muscimol (1 mM in the ARC-VMR, 250 microM in the mPOA) for 4 h was carried out on three separate occasions in random order. Simultaneously, jugular venous blood was collected at 10-min intervals, and plasma later was assayed for LH. The estimated dose of baclofen delivered to each unilateral microdialysis site was 7.9 micrograms; for muscimol, it was 1.1 micrograms for the mPOA and 4.5 micrograms for the ARC-VMR. In the mPOA, baclofen had no detectable effect, whereas muscimol had a delayed suppressive effect on mean LH (P < 0.01). In the ARC-VMR muscimol rapidly reduced mean LH (P < 0.01). In contrast, baclofen increased mean LH (P = 0.01) and LH pulse amplitude (P = 0.05) without altering the LH interpulse interval (P > 0.10). These results support the involvement of GABAA receptors in the mPOA in regulating LH secretory patterns. More importantly, both GABAA and GABA(B) receptors in the ARC-VMR appear to differentially modulate LH and, presumably, GnRH release. Whether GABA acts directly on the GnRH neuron or indirectly through other neural systems remains to be determined.

Animals↗
PubMed1994

[Neurochemical and pharmacological studies on brain GABA receptors].

GABAA receptors of the mammalian central nervous system are ligand-gated Cl- ion channels and the sites of action of many pharmacologically important drugs. GABAA receptors were characterized using a potent antagonist, [3H]SR 95531, and agonists such as [3H]GABA and [3H]muscimol. Pretreatment of brain membranes with Triton X-100 or phospholipase A2 increased [3H]GABA and [3H]muscimol binding in the frontal cortex and cerebellum, whereas these treatments significantly decreased [3H]SR 95531 binding. The treatment of rats subacutely with a subconvulsive dose of bicuculline (2 mg/kg, i.p., daily for 10 days) significantly increased the apparent affinity for [3H]muscimol in the frontal cortex, cerebellum, striatum and substantia nigra. On the other hand, the apparent affinity for [3H]SR 95531 binding was significantly decreased in these regions. These results suggest that subacute bicuculline treatment in vivo and treatment in vitro of brain membranes with Triton X-100 or phospholipase A2 bring about a conformational change in the GABAA-receptor molecule, thus resulting in access increase of the GABA agonist and access decrease of the antagonist to GABAA receptors. In the cerebellum, the Bmax values of [3H]muscimol and [3H]SR 95531 binding and Vmax value of muscimol-stimulated 36Cl- uptake were significantly increased following subacute bicuculline treatment with no change in the frontal cortex, with this process involving increased de novo synthesis of GABAA receptors.

Animals↗
PubMed1995

Central GABAergic mechanisms are defective in salt-induced hypertension in borderline hypertensive rats.

We examined the role of central GABAergic mechanisms in salt-induced hypertension and exaggerated responses to stress in borderline hypertensive rats (BHR), the first offspring of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The studies were done in conscious BHR and WKY on high (H) (8% NaCl) or normal (N) (0.3% NaCl) salt diets for 5 weeks. A high-salt diet elevated arterial pressure (AP) (p < 0.01) and augmented pressor responses to shaker stress (p < 0.05) in BHR but not in WKY. Intravenous hexamethonium caused a greater decrease in AP in BHR-H than in BHR-N at rest. Muscimol (a GABA agonist) injected into the central ventricle (i.c.v.) caused a greater decrease in resting AP (p < 0.01) and heart rate (HR) (p < 0.05) and BHR-H than in BHR-N. Renal sympathetic nerve activity (RSNA) did not change in BHR-H, but increased (p < 0.05) in BHR-N during muscimol-induced hypotension, although the magnitudes of muscimol-induced hypotension were greater in BHR-N than in BHR-N. The increases in RSNA in response to intravenous nitroglycerin were similar in BHR-N and BHR-N. Muscimol attenuated pressor and tachycardic responses to stress more in BHR-N than in BHR-N (p < 0.01). Muscimol did not alter AP and HR at rest or their responses to stress in the two groups of WKY. The magnitudes of pressor response to bicuculline (a GABA antagonist) did not differ between the two groups of BHR. These results suggest that a high salt diet may alter the central GABAergic system in BHR, which contributes to salt-induced hypertension and augmented pressor and tachycardic responses to stress.

Animals↗