Cardiovascular effects of 3-mercaptopropionic acid and levels of GABA in regions of the brain of guinea-pigs

3-Mercaptopropionic acid (3-MP), an inhibitor of the synthesis of gamma-aminobutyric acid (GABA), was administered to anesthetized rats and guinea-pigs in order to examine the relationship between the effect of this agent on regional levels of GABA in the brain and cardiovascular function. After a latent period, 3-mercaptopropionic acid (0.16 ml/kg, i.p.) produced initial increases in blood pressure and heart rate in rats followed by vagal bradycardia and hypotension. Guinea-pigs treated with 3-mercaptopropionic acid developed one of three patterns of cardiovascular changes. The type I response consisted of a period of sympathetically-mediated hypertension and tachycardia followed by vagal bradycardia. Type II animals exhibited increased arterial pressure and heart rate, but no vagal activation. Type III and control animals exhibited no significant cardiovascular changes following administration of 3-mercaptopropionic acid or appropriate vehicle. Regional levels of GABA in brain, measured at 90 min after treatment were significantly lower than control in type I and II animals in 3 of 4 areas of the brain measured, but not in type III guinea-pigs. When decreases in levels of GABA were compared to the changes in cardiovascular parameters for individual animals, the decrease in heart rate at the time of sacrifice was directly correlated with the decrease in medullary levels of GABA in type I animals. Conversely, in type II guinea-pigs, decreases in hypothalamic levels of GABA correlated inversely with heart rate at sacrifice. These results suggest that activation of cardiac sympathetic and parasympathetic nervous pathways following the administration of 3-mercaptopropionic acid may result from decreased levels of GABA in different regions of the brain.     

Effect of GABA Analogues on Blood Pressure and Central GABA Metabolism in the Rat

Abstract: Gamma aminobutyric acid (GABA) and different GABA analogues were examined for their cardiovascular actions and their influence on striatal dopamine (DA) levels and GABA accumulation after aminooxyacetic acid (AOAA). Gamma hydroxybutyric acid (GHBA) and baclofen caused hypertension and tachycardia after systemic as well as intracerebroventricular administration, while the opposite was true for GABA and muscimol. The hypertension after GHBA and baclofen was not reduced by picrotoxin or bicuculline and was not influenced by varying GABA levels by 3-mercaptopropionic acid (3-MPA)or AOAA. GHBA and muscimol but not baclofen reduced GABA accumulation induced by AOAA. Picrotoxin in a subconvulsive dose increased GABA accumulation and antagonized the inhibition after GHBA or muscimol. Bicuculline and a moderate dose of picrotoxin tended to decrease GABA accumulation by themselves and if anything augmented the effects of GHBA and muscimol. GHBA and baclofen but not muscimol in combination with AOAA increased DA levels, which was not prevented by picrotoxin or bicuculline. We conclude that the cardiovascular actions of GHBA and baclofen are probably not mediated by mechanisms identical to those of muscimol or exogenous GABA. In view of the biochemical results their actions would however be compatible with a concept of different GABA receptors.     

肾血管性高血压大鼠脑室注射γ-氨基丁酸的心血管效应(英文)

GABA(100和200μg,icv)在肾血管性高血压大鼠(RVHR)产生较伪手术鼠更强的降压作用,尤术后4 wk,GABA降压增强的大部分可被预先icv卡托普利所取消,而ip卡托普利作用较弱,GABA icv还明显改善RVHR已下降的压力感受性反射敏感性,提示RVHR脑内GABA抑制功能不足;外源性GABA降压效应增强可能与其抑制脑内血管紧张素系统有关。     

Comparison of the cardiovascular effects of intravenously administered GABA,THIP, and isoguvacine in the anesthetized rat

Mean arterial blood pressure and heart rate were monitored in pentobarbital-anesthetized rats after intravenous injections of GABA, THIP, or isoguvacine-HCl (all at 0.1–100 mg/kg). GABA produced dose-dependent hypotension and bradycardia; THIP produced no appreciable effect on either parameter; and isoguvacine produced hypotension, but no marked change in heart rate. The transient hypotension and bradycardia produced by GABA (1 mg/kg) were partially blocked by pretreatment of the animals with bicuculline or bicuculline-methobromide. After pretreatment with bicuculline or bicuculline-methobromide, the hypotensive effect of isoguvacine (1 mg/kg) occurred more rapidly (i.e., during the first 5 min, rather than during 5–15 min after injection of isoguvacine). As THIP penetrates the blood-brain barrier more readily than GABA or isoguvacine, as GABA and isoguvacine exerted more pronounced cardiovascular effects than THIP, and as bicuculline and bicuculline-methobromide affected the cardiovascular actions of GABA and isoguvacine, it is suggested that activation of peripheral GABA receptors might explain part of the cardiovascular effects produced by intravenously injected GABA. Further study of isoguvacine and its derivatives might lead to the development of hypotensive (antihypertensive) agents that act on peripheral GABA-ergic systems.     

脑室注射生长抑素或GABA对大鼠痛阈和脑内GABA或生长抑素含量的影响(英文)

目的:研究脑内Som和GABA的相互影响及其与痛觉调制的关系.方法:应用放射免疫,氨基酸分析仪和痛阈测定法.结果:发现Som 10 μg icv可使大鼠海马,脑干内GABA含量显著减少,分别由对照组的2.3±0.3和2.2±0.4 μmol g~(-1)降至1.6±0.4和1.5±0.2μmol g~(-1),痛阈由对照组的4.2±0.2 s升高到7.0±1.1 s;半胱胺600 μg icv降低脑内Som后,海马和脑干内GABA含量也明显减少,但痛阈不变.GABA 1500 μg icv后,痛阈变化不明显,而海马、脑干内Som含量均显著减少,分别由对照组的55±4和84 4 ng g~(-1)降至37±5和55±6 ng g~(-1)这一效应可被荷包牡丹碱10 μg阻断;以异烟肼300 mg kg~(-1)降低脑内GABA后,海马和脑干内Som含量即明显增多.结论:脑内Som和GABA之间存在着相互抑制作用,但与它们在痛觉调制中的作用无关.     

Weak effects of local and systemic administration of the GABA uptake inhibitor,SK&F 89976, on extracellular GABA in the rat striatum

Summary The effects of local and systemic administration of the potent GABA uptake inhibitor, SK&F 89976, on GABA overflow from the striatum of conscious rats were investigated in brain dialysis experiments. Administration of the compound via the dialysis probe at concentrations of 25 or 100 gmol/l significantly increased basal GABA overflow about 2-fold. Overflow evoked by 104 mmol/l K⁺ remained unaltered at the lower and was almost doubled at the higher concentration; this increase did, however, not reach statistical significance.Given systemically at 50 mg/kg i.p., a dose which is severalfold higher than those which exhibit anticonvulsant effects, SK&F 89976 caused a significant enhancement of K⁺-stimulated GABA overflow by about a factor of 2; the lower dose of 20 mg/kg i.p. was not effective. Basal GABA overflow was not significantly increased by either dose. These results suggest that the marked effects of nipecotic acid on basal GABA overflow reported by several authors seem to be related to GABA displacement rather than uptake inhibition, and that uptake inhibition does not improve the interpretability of measurements of GABA release by brain dialysis. They neither support the idea that the relative insensitivity of extracellular GABA to low Ca²⁺ and tetrodotoxin is indirectly due to very efficient removal of GABA by neuronal and/or glial uptake, leaving only residual amounts to be measured. Send offprint requests to P. Waldmeier at the above address     

GABA and hypothalamic feeding systems. II. A comparison of GABA,glycine and acetylcholine agonists and their antagonists

Microinjections of various compounds into the paraventricular hypothalamic nucleus (PVH) were made and the effects on feeding observed. During the light phase of the lighting cycle, injections of 0.3 μl of muscimol (100 ng) and flurazepam diHCl (20 μg) increased feeding. Similar injections of glycine (500 ng) did not influence feeding during the light phase. During the dark phase, 0.3 μl injections of bicuculline methiodide (30 ng) and picrotoxin (160 ng) suppressed feeding. Similar injections of carbachol increased drinking during the dark phase. Injections of strychnine during this phase were without effect. Tilt box activity levels were not altered by injection of picrotoxin (160 ng) into the PVH.     

Pharmacological analysis of the central cardiovascular effects of four GABA analogues

Summary The central cardiovascular effects of 4 structural analogues of GABA were investigated. The drugs were injected intracerebroventricularly (i.c.v.) in cumulative doses into pentobarbital-anaesthetized normotensive rats. Muscimol (0.01–10 g/kg), THIP (0.01–100g/kg), kojic amine (0.1–100 g/kg) and isoguvacine (0.1–100g/kg) produced dose-dependent hypotension and bradycardia. The maximal fall in the mean blood pressure was of about 35% of the initial values. These effects appears to be of central origin since the intravenous (i.v.) injection of the same doses of the drugs did not produce any similar cardiovascular modifications. The hypotensive effects of muscimol and kojic amine were antagonized partly by i.c.v. bicuculline. The combination of bicuculline and kainic acid almost completely prevented the blood pressure lowering effects of muscimol, kojic amine and isoguvacine. THIP however was only slightly antagonized by bicuculline and kainic acid. Atropine i.v. also prevented partly the cardiovascular effects of all these drugs.Thus, the mechanisms of the central cardiovascular actions of GABA analogues appear to be more complex than expected and variable from one drug to another.The involvement of GABA receptors of the A and B types and of cholinergic mechanisms in the hypotensive effect of the drugs is discussed.     

Neurotransmitters in central cardiovascular regulation: glutamate and GABA

1. The role of the amino acids L-glutamate and GABA as neurotransmitters in central pathways regulating cardiovascular function is briefly summarized.     

Circling behavior induced by intranigral injections of GABA and muscimol in rats

Circling behavior induced by unilateral intranigral injections of GABA or muscimol was studied in rats. Both GABA (10–400 g) and muscimol (1–100 ng) evoked the same kind of contralateral circling behavior dose-dependently when injected into the substantia nigra. Muscimol was much more potent than GABA and its effect lasted longer. Neither GABA nor muscimol induced any ipsilateral circling. Pretreatment with bicuculline (3 mg/kg IP) significantly attenuated the intensity of circling behavior induced by intranigral injections of GABA or muscimol. Pretreatment with haloperidol (0.5 and 1.0 mg/kg SC) also significantly antagonized the circling behavior induced by GABA and muscimol. Pretreatment with atropine (10 mg/kg IP) significantly increased the intensity of circling behavior induced by intranigral injections of muscimol and tended to increase the intensity of circling behavior induced by intranigral injections of GABA. Pretreatment with strychnine (0.25 mg/kg IP) did not modify circling behavior induced by GABA, but did to some extent increase that induced by muscimol. These results indicate that the contralateral circling behavior induced by intranigral injections of GABA and muscimol seems to be dependent both on the activation of the dopaminergic nigrostriatal system and on the nondopaminergic nigral output system.     

侧脑室注射蝇蕈醇和荷包牡丹碱对大鼠异氟烷最低麻醉浓度的影响

大鼠侧脑室置管后2 d, 观察icv GABA_A受体激动剂蝇蕈醇和(或)其拮抗剂荷包牡丹碱对麻醉箱内异氟烷最低有效浓度（反映最低肺泡有效浓度）和翻正反射恢复时间的影响. 结果表明icv 5 mmol·L^-1蝇蕈醇2 μL明显降低箱内异氟烷最低麻醉浓度, 延长大鼠翻正反射恢复时间; icv 0.5 mmol·L^-1荷包牡丹碱2 μL对异氟烷的最低麻醉浓度和翻正反射恢复时间皆无影响, 但可部分拮抗蝇蕈醇降低异氟烷最低麻醉浓度和延长翻正反射恢复时间的作用. 以上实验结果提示, 蝇蕈醇和异氟烷间有协同作用, 但脑内的GABAA受体可能不是异氟烷全麻作用的主要靶位.     

Paradoxical blockade of a muscimol response by thip, a GABA agonist and also by GABA-transaminase inhibitors

In a particular strain of mice, relatively large doses of muscimol caused myoclonic jerks of high frequency. This muscimol response was blocked in a dose-dependent manner by a γ-aminobutyric acid (GABA) agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol-hydrate (THIP). Studies using γ-acetylenic GABA and γ-vinyl GABA demonstrated that the blockade of the muscimol-induced jerks caused by these irreversible GABA-transaminase inhibitors closely paralleled the elevation of brain GABA level. It seems that, in this particular strain of mice, muscimol, or one of its metabolites, possibly acts on certain specific binding sites in the central nervous system, eliciting myoclonic jerks and that these receptor sites are different from those to which GABA or THIP binds.

Earlier studies demonstrated the value of the muscimol-induced myoclonic jerks as an animal model for postanoxic action myoclonus. Based on this finding, it is proposed that both THIP and the GABA-transaminase inhibitors might prove to be of value in the management of this clinical condition.     

Ontogeny of muscimol effects on locomotor activity,habituation, and pain reactivity in mice

Three hundred and twenty mouse pups of both sexes of the CD-1 outbred strain received IP muscimol and were subsequently assessed for locomotor activity (single Varimex 30-min session) and for hot-plate responding. Muscimol doses were 0.05, 0.1, or 0.2 mg/kg at 8 and 14 days, and 0.1, 0.5, or 1.0 mg/kg at 21, 28, and 35 days. Activity data showed a shift from an immature pattern at 8 and 14 days to an adult-like pattern from day 21 onwards (high initial activity followed by a marked within-session decrement). Muscimol was ineffective on day 8, and depressed activity from day 14 onwards. At 28 days, however, the higher-dose male group showed a non-monotonic trend of activity; that is, an initial depression followed by a marked rebound hyperactivity. With regard to hot-plate exposure, muscimol was ineffective at 8 days, while it produced maximal analgesic effects on day 14, followed by a progressive decrease in drug sensitivity. Around day 70, mice of the former 0.1 mg/kg and saline groups were re-tested for locomotor activity and pain reactivity without additional drug treatment. Activity was generally higher in males than in females, and two groups habituated significantly less than the others (females tested in the muscimol state at 8 days and males tested in the saline state at 35 days). Moreover, prior testing at the earliest ages and prior muscimol exposure had additive attenuating effects on pain reactivity. These developmental profiles indicate that GABAergic systems contribute to the modulation of pain reactivity by mechanisms which are at least in part separate from those involved in the depression of activity. Developmental changes in³H-muscimol and its metabolite disposition in brain were also assessed.Part of the data reported here was presented at the 1st Convegno Nazionale dei Giovani Cultori di Neuroscienze Rome, 11–12 December 1987     

Release of endogenous GABA in the posterior hypothalamus of the conscious rat; effects of drugs and experimentally induced blood pressure changes

Summary Push-pull superfusion was used to investigate the release of endogenous GABA in the posterior hypothalamus of the conscious, freely moving rat at basal conditions and in response to centrally applied drugs or to peripherally induced blood pressure changes.After an initial, exponential decline, the release rate of GABA remained fairly constant for many hours. Fluctuations in the release rate of GABA point to the existence of an ultradian rhythm with an approximate frequency of 1 cycle/65 min. Hypothalamic superfusion with a potassium-rich (50 or 90 mmol/1) artificial cerebrospinal fluid led to a concentration-dependent increase in the GABA release. The release of GABA was also enhanced by veratridine (1 or 10 mol/1) in a concentration-dependent way. Hypothalamic superfusion with the neutrotoxin tetrodotoxin (1 gmmol/1) led to a long-lasting decrease in the GABA release. The rise in blood pressure (45 mmHg) elicited by an intravenous infusion of noradrenaline was associated with an increased release rate of GABA in the hypothalamus. Hypotension produced by nitroprusside (25 mmHg) led to a counteracting decrease in hypothalamic GABA outflow.The findings suggest that approximately 4510 of the basal outflow of GABA found in the superfusate are released from GABA-ergic neurons of the posterior hypothalamus. The release rate of GABA fluctuates according to an ultradian rhythm. The modified release of GABA in response to experimentally induced blood pressure changes suggests that, in the posterior hypothalamus of the conscious rat, GABAergic neurons are involved in cardiovascular control and possess a hypotensive function.This work was supported by the Fonds zur Förderung der wissenschaftlichen ForschungCorrespondence to N. Singewald at the above address     

卡马西平增强γ-氨基丁酸对大鼠脑片的作用(英文)

目的:研究卡马西平(Car)对γ-氨基丁酸(GABA)在海马区域作用的影响.方法:在海马脑片(350μm)上刺激(0.5 Hz,50μs)Schaffer氏纤维,记录CA1区锥体细胞的诱发场电位.结果:Car 0.2mmol·L~(-1)对CA1区锥体细胞的诱发场电位没有明显影响,但Car 0.2 mmol·L~(-1)和GABA(0.1-1 mmol·L~(-1))同用抑制场电位作用比单用GABA时显著增强.Bicuculline不能翻转被Car加强的GABA的抑制作用.继而,左旋巴氯芬抑制场电位作用强于GABA.Car 0.2 mmol·L~(-1)和左旋巴氯芬(1-5μmol·L~(-1))同用抑制场电位作用比单用左旋巴氯芬时显著增强.结论:Car增强GABA对海马CA1区锥体细胞的抑制作用,其作用机制可能与GABA_B受体有关.     

The chloride-dependent depression by GABA in the frog spinal cord

Spontaneous activities from ventral and dorsal roots of the isolated perfused spinal cord of the bullfrog were inhibited by GABA. β-Alanine showed a strong and glycine a weaker inhibitory effect. The inhibitory effect of GABA was markedly reduced in a chloride-free medium, whereas glycine and β-alanine still showed an inhibitory effect similar to that seen in normal medium. Employing the sucrose-gap method, a marked depolarization in the dorsal root and a small but obvious hyperpolarization in the ventral root were found by the application of GABA. These results support the view that GABA is one of the transmitters involved in pre- and postsynaptic inhibition of the spinal cord. The postsynaptic hyperpolarizing effect of GABA on motoneurones would be caused directly through increased permeability of the membrane to chloride ion. The depolarizing effect of GABA on primary afferent terminals is discussed in connection with chloride dependency.     

Cardiovascular and respiratory effects induced by intracerebroventricular injection of scorpion toxin (tityustoxin) in the rat

The injection of 2·5, 5 and 10 μg of purified scorpion toxin (tityustoxin or TsTX) into the lateral ventricles of anesthetized rats caused dramatic effects on the circulatory and respiratory systems, consisting of hypotension, tachypnea, hyperpnea, ataxic and gasping breathing. Following these initial effects, 5 or 10 μg of TsTX induced hypertension and hyperpnea. The largest dose produced apnea and death about 70 min later. To study the mechanism of action of TsTX the intermediate dose (5 μg) was used. The early respiratory arrhythmias and hypotension were blocked centrally by atropine, but not by hexamethonium. In contrast, the late hypertension was blocked in part by central injection of phenoxybenzamine, but not by atropine or hexamethonium. Intravenous phenoxybenzamine partially antagonized the hypertensive effect, whereas i.v. guanethidine in bilateral adrenalectomized rats prevented the pressor effect induced by central injection of TsTX. The results indicate that the hypotensive effect and the early respiratory arrhythmias induced by intracerebroventricular TsTX are related to central muscarinic mechanisms. It is suggested that the late hypertension is due to the release of catecholamines from adrenal glands and postganglionic nerve fibers, as a consequence of central stimulation.     

Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats

To assess the role of central dopamine on metabolic rate, heat balance and running performance, 2.0 µL of 5 × 10^− 3 M dopamine solution (DA) or 0.15 M NaCl (SAL) was intracerebroventricularly injected in Wistar rats 1 min before running on a motor-driven treadmill, according to a graded exercise protocol, until fatigue. Oxygen consumption (VO₂) and body temperature (T_b) were recorded at rest, during exercise, and after 30 min of recovery. DA induced a marked increase in workload (~ 45%, p < 0.05). At fatigue point, DA-injected rats attained ~29% higher maximum oxygen consumption (VO_2max) and ~0.75 °C higher T_b than SAL-injected rats. Despite the higher VO_2max and T_b attained during exercise, DA-treated rats reached VO₂ basal values within the same recovery period and dissipated heat ~33% faster than SAL-treated rats (p < 0.05). The mechanical efficiency loss rate was ~40% lower in DA than in SAL-treated rats (p < 0.05), however, the heat storage was ~35% higher in the DA group (p < 0.05). Our results demonstrate that increased DA availability in the brain has a performance-enhancing effect, which is mediated by improvements in the tolerance to heat storage and increases in the metabolic rate induced by graded exercise. These data provide further evidence that central activation of dopaminergic pathways plays an important role in exercise performance.     

The antidepressant drug phenelzine produces antianxiety effects in the plus-maze and increases in rat brain GABA

Research on the effects of antidepressant/antipanic drugs in animal models of anxiety has yielded equivocal results, even after chronic drug regimens. In contrast, we found that the antidepressant/antipanic drug phenelzine, given acutely, produced a clear anxiolytic effect in the elevated plus-maze, a widely-used animal model of “anxiety” that is primarily sensitive to benzodiazepine-type anxiolytics (e.g., diazepam). Furthernore, the effective dose of phenelzine (15 mg/kg) administered to rats was associated with more than a 2-fold increase in whole brain levels of γ-aminobutyric acid (GABA), whereas an ineffective dose of phenelzine (5.1 mg/kg) did not significantly change GABA levels. TheN-acetylated metabolite of phenelzine,N ²-acetylphenelzine, produced neither an anxiolytic effect in the elevated plus-maze nor a significant change in whole-brain levels of GABA. However, both phenelzine andN ²-acetylphenelzine potently inhibited monoamine oxidase inhibitors such as phenelzine in the treatment of depression in humans. These results suggest that the mechanism whereby phenelzine produces anxiolytic effects in the plus-maze model is unique to a facilitatory action on brain levels of GABA, in contrast to classical benzodiazepines, which produce anxiolytic effects by enhancing the affinity of the GABA_A-receptor for GABA.