Effect of GABA-ergic substances on the analgesic effect of morphine in rats]

The effect of GABA-ergic compounds on morphine-induced analgesia was studied to reveal probable interaction of GABA and opiates. As an index for morphine effect the reaction of vocalization in response to electrical stimulation of the rat tail was used. It was shown that thiosemicarbazide, the inhibitor of glutamate decarboxylase and bicuculline, GABA-ergic receptor blocking agent, which were proposed to be joined in a group of GABA-negative compounds, reduce and shorten the effect of morphine. Depakine, the inhibitor of alpha-ketoglutarate-GABA-transaminase, as well as GABA itself administered in high doses (GABA-positive actions) make morphine analgesia more pronounced and longer. Probable causes of the described interrelationship between GABA and opiates are discussed.     

A presumptive role for GABA in the stimulatory effects of Des-Gly10, [D-Ala6]-LHRH-ethylamide and pimozide on the gonadotropin release in carp

To investigate the effect of endogenous gamma-aminobutyric acid (GABA) on the blood maturating gonadotropin (GtH) levels, or to study its interaction with pimozide (dopamine antagonist) and a luteinizing hormone-releasing hormone analog (LHRH-a), sexually mature male and female carps were treated with drugs that may either inhibit GABA biosynthesis or GABA degradation. In females the irreversible inhibitor of GABA-transaminase, gamma-vinyl GABA (GVG), which was to increase the endogenous GABA-ergic tone, had no influence on GtH release. On the other hand, the increased GtH response to the combination of pimozide (PIM) and LHRH-a was clearly enhanced by the administration of 3-mercaptopropionic acid (MPA), an inhibitor of the rate limiting enzyme of GABA-biosynthesis. In males the GABA-ergic compound, valproic acid (DPA) decreased LHRH-a stimulated GtH levels. In male carps that received PIM to diminish the dopaminergic inhibition of GtH release, the spermiating response to LHRH-a was increased by administration of MPA. These data suggest that GABA interacts with the action of dopamine and the gonadotropin releasing hormone (GnRH) on the release of GtH.     

The interaction of chlordiazepoxide and sodium valproate in the nucleus accumbens of the rat

Benzodiazepines are known to facilitate GABA-ergic transmission at synaptic sites, while sodium valproate is an anticonvulsant drug which is reported to elevate GABA levels in the brain. In order to determine whether these two drugs interact functionally at GABA receptor sites, graded doses of chlordiazepoxide (CDZ) and sodium valproate were injected bilaterally into the nucleus accumbens and their effect on the dopamine (DA)-induced stimulation of motor activity was studied. Both of these compounds, as well as GABA, produced an inhibition of the hyperactivity induced by the bilateral injection of DA into the nucleus accumbens. Bicuculline, the GABA receptor antagonist, blocked the effect of CDZ on the DA-induced hyperactivity. A low dose of CDZ (2 μg), which by itself did not significantly inhibit the effect of DA, potentiated the inhibition of the hyperactivity produced by valproate. These results suggest that CDZ and sodium valproate can interact functionally at GABA-ergic sites in the central nervous system.     

Anticonvulsant action of di-N-propylacetate combined with benzodiazepines, phenobarbital and phenytoin

The combined use of di-n-propylacetate with phenazepam, diazepam, phenobarbital or phenytoin was shown to be followed by reciprocal potentiation of the anticonvulsant activity of the drugs in a variety of experimental epileptic seizures in mice according to the tests of shock and antagonism with corasole and thiosemicarbazide. The potentiating effect of the subthreshold dose of di-n-propylacetate on anticonvulsant effects of benzodiazepines, phenobarbital and phenytoin was more pronounced than the effect of the drugs administered in the subthreshold doses on the anticonvulsant activity of di-n-propylacetate. Of both combinations, di-n-propylacetate plus benzodiazepines proved to be most efficacious one. The unidirectional effect of the combined drugs on the different stages of the development of GABA-ergic system inhibitory function in the CNS activity is assumed to be of importance in the mechanism of reciprocal potentiation.     

大鼠尾壳核的GABA能传递在条件性行为调控中的作用

本工作采用了行为和脑内注射相结合的方法研究了大鼠尾壳核的 GABA 能传递在条件性行为调控中的作用。在分辨学习的基础上训练大鼠完成条件性回避任务,以比较药物对分辨学习和条件性回避的不同效应。实验结果表明,于大鼠双侧尾壳核内分别注入 γ-氨基丁酸(GABA)(每侧100μg/μl)和 GABA 受体激动剂蝇蕈醇(Muscimol)(每侧0.1μg/μl)后可暂时抑制条件性回避反应的出现,但分辨学习无明显影响。作为对照,于尾壳核内注入等量的生理盐水则既不影响条件性回避反应,也不影响分辨学习。在条件性回避反应被 Muscimol抑制后于尾壳核内再注入 GABA 受体阻断剂印防己毒素(PTX)(每侧0.1μg/μl)则可拮抗Muscimol 的行为抑制效应,即条件反应的出现率可恢复到或接近注射前水平。实验结果表明,大鼠尾壳核的 GABA 能传递在条件性行为调控中的重要作用。     

A neuropharmacological analysis of the compensatory-recovery processes in organic failure of the parafascicular complex of the thalamus]

On the model of biological precursors of thinking in animals (cats), in conditions of free behaviour it has been shown that after neurosurgical lesion of various parts of the parafascicular complex restoration is possible of the disturbed functions of generalization and abstraction by neuropharmacological drugs acting on cholinergic, dopaminergic and GABA-ergic systems. Complex interactions are observed between transmitter structures.     

GABA and endocrine regulation—Relation to neurologic-psychiatric disorders

Data obtained with experimental animals and with humans concerning the involvement of GABA-ergic systems in the control of hormonal secretion have been discussed and analyzed. The available evidence indicates that GABA-ergic systems might modulate the release of several hypothalamic-hypophyseal hormones that are involved in behavioral regulation, either via their endocrine actions or via their direct actions on the brain. Further studies along this line might lead to the development of GABA-ergic drugs that will be useful for treating certain hormonal or neuropsychiatric disorders.     

The effect of the delta sleep-inducing peptide on the development of toxic brain edema-swelling]

Antiedematic effects of the drugs are connected with their action on the mediator systems. DSIP has a wide range of modulatory effects on the brain mediator systems. DSIP antiedematic effect was studied on the toxic brain edema-swelling (BES) model. Physical characteristics of the nervous tissue such as thickness and wetness were used as evaluation criteria. According to the findings, the doses of 75-100 micrograms/kg DSIP were optimal. It is suggested that DSIP effect on BES is multicomponent and rather complicated. Inhibition of serotonin, noradrenaline and histamine systems and activation of GABA-ergic system by DSIP act as a possible antiedematic mechanism.     

Interactions of acoustic and somatosensory evoked responses in a polysensory cortex of the cat

Interactions of acoustic and somatosensory evoked potentials were studied in the anterior suprasylvian gyrus of the cat. The interactions showed dynamic changes and were susceptible to different kinds of influences. The interactions could be influenced by synchronous activation of the acoustic and somatosensory inputs with 2 Hz frequency, or by elevating the stimulus frequency. Interactions could be influenced by amphetamine and gamma-glutamyl-taurine, drugs known as capable of influencing the arousal level of the brain. The antagonists of amphetamine prevented this effect. Drugs acting on the cortical GABA-ergic system proved also to be decisive in the interactions of evoked potentials of different origins. In some experiments unit activity was recorded parallel with evoked potentials.     

Formation of serotonin- and GABA-ergic mechanisms of synaptic transmission in the cat neocortex during early ontogenesis

In acute experiment on 5-20 days kittens, the reactions were studied of neurones in the cortical somatosensory zone to stimulation of the dorsal raphe nucleus (DRN) and application of serotonin, ethanolamine-O-sulphate and bicucullin. The identity is established of the effect of DRN stimulation and serotonin application eliciting inhibition of the background activity and appearance of inhibitory phases in response to sensory stimulation, beginning from the 10-12th day after birth. A suggestion is made about serotoninergic regulation of GABA-ergic interneurones' in young animals. The dynamics of GABA-ergic brain system formation has been studied. Specific sensitivity of neocortical neurones to GABA increased to the end of the second week of life--the period when modulating serotoninergic influences appear.     

Effect of stimulation of GABA-ergic structures of the substantia nigra and caudate nucleus on food-getting behavior in the cat

A study was made of the functional significance of GABA-ergic structures of the substantia nigra (SN) and the caudate nucleus (CN) and their role in food-procuring behaviour of cats. Analysis was made of behavioral and EEG-effects of local GABA and the GABA antagonist, picrotoxin, microinjections into the studied brain structures. Stimulation of the GABA-ergic structures of the SN produced a sedative effect and depression of the cat food-procuring behaviour. Effects of stimulation of the CN GABA-ergic structures were to a great degree reverse. The conclusion has been made that GABA-ergic structures of the SN and the CN play different roles in controlling the CN inhibitory influence upon food-procuring behaviour.     

GABA-ergic structures in the intact and chronically isolated cat association cortex (area 5)

The distribution of GABA-ergic structures in the intact and neuronally isolated cat cerebral cortex in area 5 was studied by the histochemical reaction for GABA-transaminase 2 and 3 weeks after isolation. The overwhelming majority of GABA-ergic fibers of the neuropil and of synaptic terminals was shown to be formed by axons of a few GABA-ergic interneurons, and only a small proportion of them belong to afferent axons of extracortical origin. GABA-ergic interneurons were subdivided into short-axonal, forming connections within an isolated area, and long-axonal, forming horizontal connections with more distant cortical neurons. GABA-ergic axons give numerous projections to bodies and proximal segments of dendrites of many pyramidal neurons not containing GABA-transaminase, and of stellate neurons, which include cells with GABA-ergic and non-GABA-ergic mediator nature. It is suggested that the influence of some GABA-ergic neurons on others is responsible for intracortical spatial regulation of inhibition.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 17, No. 3, pp. 365–371, May–June, 1985.     

The antiepileptic effects of sodium valproate and the calcium antagonist riodipine when used jointly in a model of focal penicillin-induced epileptic activity]

In experiments on 52 freely moving Wistar male rats, 200-220 g in weight, on the model of focal penicillin-induced epileptic activity (EpA) in brain cortex the efficacy of combined application of drugs influencing different mechanisms of epileptogenesis: sodium valproate enhancing GABA-ergic processes, and the calcium antagonist ryodipine (1,4-dihydropyridine) have been studied. It was shown that valproate and ryodipine when used in combination at relatively small doses (150 and 0.8 mg/kg l.p., respectively) produced a more marked antiepileptic effect than each of these drugs given alone. These and previously reported results of studies on the model of generalized pentylenetetrazol-induced EpA, suggest that complex pathogenic therapy (CPT) as a combination of the antiepileptic drugs acting on the corresponding basic pathogenic mechanisms of respective form of epilepsy is reasonable to be used. CPT allows to obtain a better curative effect with a lower dose of each drug used and to reduce the risk of side effects of the drugs applied at large doses in case of monotherapy.     

The antiepileptic effects of sodium valproate and the calcium antagonist riodipine when used jointly in a model of generalized korazol-induced epileptic activity]

In experiments on male Wistar rats on the model of generalized pentylenetetrazol-induced epileptic activity the efficacy of the combination of the drugs influencing different mechanisms of epileptogenesis: sodium valproate enhancing GABA-ergic processes and calcium antagonist, ryodipine (1,4-dihydropyridine), have been studied. Sodium valproate and ryodipine when used in combination at relatively small doses (70 and 0.75 mg/kg, respectively) produced more marked antiepileptic effect than each of these drugs given alone. The results obtained suggest that complex pathogenetic therapy (CPT) as a combination of antiepileptic drugs acting on corresponding basic mechanisms of respective form of epilepsy is reasonable to be used. According to our previous results, CPT can reduce the risk of side effects of each drug due to decreased doses. CPT may be of great importance in case of long-term treatment.     

On neurotransmitter mechanisms of reinforcement and internal inhibition

Experiments reported in this study have been performed in order to investigate cholinergic and GABA-ergic neurotransmitter systems and substance P in the realization of internal inhibition and pain reinforcement. This was accomplished during the elaboration of inhibitory and defensive conditioned reflexes to light flashes in alert, nonimmobilized rabbits. Present results together with a review of past research indicate that the cholinergic system is directly involved in transmitting the effects of pain reinforcement to neocortical neurons. Substance P, a neuropeptide, reduces the background activity of neocortical and hippocampal neurons and the response of cortical neurons to pain and positive conditioned stimuli. The cholinergic system and substance P exert a modulating effect on the elaboration of internal inhibition. Phenybut, a GABA derivative capable of penetrating the blood-brain barrier, enhances inhibitory hyperpolarization in the cerebral cortex and improves discrimination between the inhibitory and reinforcing light flashes. It appears, therefore, that the GABA-ergic system plays a leading part in the elaboration of internal inhibition. Neuronal activity and slow potential changes in response to positive conditioned and pain stimuli occur in the same direction after administering the preparations, and the dynamics of these changes is different from that in responses to inhibitory stimuli. It may be supposed on these grounds that the neurotransmitter and neuromodulator systems studied possess a considerable degree of plasticity.     

GABA representation in hypoxia sensing: a ventilatory study in the rat

Phenibut, a nonspecific GABA derivative, is clinically used as an anxiolytic and tranquilizer in psychosomatic conditions. A GABA-ergic inhibitory pathway is engaged in respiratory control at both central and peripheral levels. However, the potential of phenibut to affect the O2-related chemoreflexes has not yet been studied. In this study we seek to determine the ventilatory responses to changes in inspired O2 content in anesthetized, spontaneously-breathing rats. Steady-state 5-min responses to 10% O2 in N2 and 100% O2 were taken in each animal before and 1 h after phenibut administration in a dose 450 mg/kg, i.p. Minute ventilation and its frequency and tidal components were obtained from the respiratory flow signal. We found that after a period of irregular extension of the respiratory cycle, phenibut stabilized resting ventilation at a lower level [20.0±3.3 (SD) vs 31.1±5.2 ml/min before phenibut; P<0.01]. The ventilatory depressant effect of phenibut was not reflected in the hypoxic response. In relative terms, this response was actually accentuated after phenibut; the peak hypoxic ventilation increased by 164% from baseline vs the 100% increase before phenibut. Regarding hyperoxia, its inhibitory effect on breathing was more expressed after phenibut. In conclusion, the GABA-mimetic phenibut did not curtail hypoxic ventilatory responsiveness, despite the presence of GABA-ergic pathways in both central and peripheral, carotid body mechanisms mediating the hypoxic chemoreflex. Thus, GABA-mediated synaptic inhibition may be elaborated in a way to sustain the primarily defensive ventilatory chemoreflex.     

Respiratory depression by GABA-ergic drugs in the preterm rabbit

Respiratory parameters were studied in preterm rabbits (gestational age 29 days) after intraperitoneal administration of the GABA-like drugs gamma-hydroxybutyric acid and muscimol. The animals were anaesthetized with 0.7% halothane in oxygen and studied in a closed body plethysmograph. Both drugs induced a decreased respiratory frequency and minute volume. Tidal volume decreased after muscimol, but not after gamma-hydroxybutyric acid administration. The present results indicate that an increased GABA-ergic activity causes respiratory depression in the preterm neonatal rabbit, presumably by an action on central nervous frequency and tidal volume modulating systems. Central GABA neurons may thus be involved in the pathogenesis of neonatal respiratory depression and irregular breathing.     

Muscimol differentially facilitates stereotypy but antagonizes motility induced by dopaminergic drugs: a complex GABA-dopamine interaction

Muscimol is the most potent and specific GABA agonist presently available. The influence of muscimol on two behavioral parameters, dependent on dopamine was studied: locomotor activity and stereotyped gnawing induced by apomorphine, cocaine or methylphenidate. In mice pretreated with a non-sedative subcutaneous dose of muscimol, a sedative effect was seen a few minutes after the injection of a stimulant dose of the dopaminergic drugs; the combination muscimol - apomorphine being most sedative. Contrastingly, muscimol strongly facilitates the development of stereotyped gnawing induced by higher doses of cocaine, methylphenidate or apomorphine. Pretreatment with α-methyltyrosine, an inhibitor of the catecholamine synthesis given before muscimol, did not antagonize the stereotyped gnawing after cocaine or methylphenidate. This finding suggests that the muscimol effect primarily depends on a direct GABA-ergic mechanism facilitating stereotyped gnawing.     

大鼠脊髓胶状质内GABA能神经元突触联系的超微结构研究

本文用免疫电镜方法对脊髓胶状质内ＧＡＢＡ能神经元的突触联系进行了超微结构研究。结果表明;脊髓胶状质内有许多ＧＡＢＡ能神经元胞体和末梢分布;标记的ＧＡＢＡ能神经末梢可作为突触前成分与未标记的ＧＡＢＡ形成输一树突触。未标记的末梢可与标记的ＧＡＢＡ末梢形成输一轴突触。此外,标记的ＧＡＢＡ能神经末梢还可作为突触前成分与标记的ＧＡＢＡ能轴突、树突或胞体形成输－轴、轴－树或轴－体突触,即自调节突触。上述结果揭示：ＧＡＢＡ能末梢可对脊髓胶状质内其它神经元产生抑制或脱抑制作用。值得注意的是胶状质内含ＧＡｎＡ的神经结构可形成各种形式的自调节突触,并借此实现其对脊髓功能的复杂调节。     

Effect of changing the frequency of conditioning tetanus on depressor responses evoked by stimulation of the aortic nerve.

The effect of changes in frequency of the conditioning tetanus on the magnitude of the testing depressor response was studied in rabbits anaesthetized with urethane. Conditioning and testing stimulations were applied to the same aortic nerve. The duration of the conditioning tetani was set at 3 and 60 sec and the interval between stimulations amounted to 40 and 120 sec. At the testing interval of 40 sec the increase in frequency both of short and long conditioning tetani reduces the magnitude of the testing response which attains a minimum at frequency of about 30 cycles/sec. Conditioning stimulations of higher frequency are gradually less effective and cause the testing response to increase. Similar depression is observed at the testing interval of 120 sec but only following long-lasting conditioning tetanus. Short conditioning trains at the testing interval of 120 sec facilitate the testing response. The frequency of the conditioning stimulation which produces the greatest reduction of the depressor response indicates the range of control exerted by the conditioning tetanus over the testing blood pressure effect. The size of this control is determined by the lowest level of depression and the highest value of facilitation of the testing response.