Neuropharmacologic analysis of the process of generalization in the cat

Processes of generalization and abstraction were studied in intact cats before and after systemic administration of dopamine-, cholin- and GABA-ergic substances in conditions of free behaviour with food reinforcement by a developed method. It is shown that only inhibition or activation of dopaminergic system disturbs the function of generalization in animals. Some possible neurochemical mechanisms of generalization in animals are being analyzed.     

The role of substantia nigra in the cognitive activity in cats

The role of substantia nigra (SN) in the cat cognitive activity of different complexity degree, was investigated by original technique. Neurosurgery or neurochemical SN switching off leads to reliable disturbances of condition, reflexes, generalization and abstraction. Rehabilitation was possible after pharmacological stimulation of dopaminergic, partly GABA-ergic, and cholinergic systems. Stimulation of serotonin system was ineffective.     

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-ergic Inhibition in the CNS: Types of GABA Receptors and Mechanisms of Tonic GABA-Mediated Inhibitory Action

This review considers such aspects of the problem of GABA-ergic inhibition in the CNS as the fundamental molecular mechanisms of GABA-ergic synaptic transmission, current questions on the principles underlying the classification of the GABA receptors, the diversity of the types of GABA-ergic inhibition, as well as possible mechanisms and functional importance of the tonic GABA-mediated inhibitory action.     

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.     

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.     

Role of GABA-ergic and dopaminergic mechanisms in the withdrawal syndrome after discontinuation of long-term phenazepam administration

It has been shown that depakin, a GABA-ergic agonist, and alpha-methyl-DOPA that inhibits catecholamine synthesis are capable of removing the withdrawal syndrome (disturbed pavlovian behavior pattern and aggressiveness) occurring after discontinuance of long-term administration (30 days) of phenazepam to rats in a dose of 2 mg/kg. In contrast, bicucullin, a blocker of GABA-ergic receptors, thiosemicarbazide that inhibits GABA synthesis by the brain, disulfiram and 3,4-dioxyphenylalanine that increase dopamine and noradrenaline content in the barain aggravate the withdrawal syndrome after phenazepam is discontinued. The data obtained suggest a role of GABA-ergic and dopaminergic mechanisms in the emergence of the withdrawal syndrome after discontinuance of long-term administration of benzdiazepins.     

Post-Tetanic and Depolarization-Induced Suppression of Inhibition in Hippocampal Cell Cultures: Are Similar Mechanisms Involved?

Several forms of short-term synaptic plasticity of GABA-ergic synaptic transmission selectively expressed only in a fraction of synaptic connections have been described earlier. In particular, this is the phenomenon termed “depolarization-induced suppression of inhibition” (DSI), a transient suppression of GABA-ergic synaptic transmission evoked by postsynaptic spike firing or brief depolarization of the membrane of postsynaptic neurons. On the other hand, the same tetanic stimulation (30 sec⁻¹, 4 sec) of the presynaptic neuron also revealed the heterogeneity of GABA-ergic synaptic connections: about 45% of the connections were facilitated, while 55% were depressed. In this work, we show that post-tetanic depression is predominantly expressed in neuronal pairs susceptible to DSI, and that both phenomena have a similar time course. Considering our own results and the retrograde involvement of endocannabinoids in DSI, we hypothesize that post-tetanic depression is also due to the release of endocannabinoids acting, in the latter case, on their autoreceptors.     

Distinct origin of GABA-ergic neurons in forebrain of man, nonhuman primates and lower mammals

In this mini-review we present recent data about origin of GABA-ergic (gama-aminobutyric acid) neurons in the mammalian forebrain, including the diencephalon and telencephalon. The interest in GABA-ergic neurons, which in cerebral cortex mostly correspond to local circuit neurons (interneurons), has increased in the past decade. Many studies have shown that in lower mammals all hippocampal and almost all neo-cortical GABA-ergic neurons are born in the specific region named ganglionic eminence, and not locally in proliferative layers all around telencephalic vesicle. The ganglionic eminence, that represents a region with thick proliferative-subventricular layer in the ventral (basal) part of telencephalon, was classically thought to give neurons to basal ganglia and septal nuclei, whereas proliferative layers of dorsal telencephalon give neurons to cerebral cortex including hippocampus. It was thought that neurons migrate from proliferative layer to their target region following a radial orientation. However, data in lower mammals showed that this is the case only for glutamatergic principal cells, i.e. projection neurons. GABA-ergic neurons use long distance tangentional migration, parallel to pial surface to reach, from ganglionic eminence, their targeting layer in the cerebral cortex. Especially intriguing, but frequently neglecting, several studies suggest that mammalian evolution might use different developmental rules to provide GABA-ergic neurons to an expending brain. In this review we focus on specific events underlying GABA-ergic neuron development in human and non-human primates. Disturbances of the GABAergic network are found in many neurological and psychiatric disorders, some of them might result from altered production or migration of these neurons during development. Therefore, it is crucial to understand human-specific mechanisms that regulate the development of GABA-ergic neurons.     

Complex effects of GABA-ergic agents on anxiety

The paper reviews the role of GABA-ergic mechanisms in anxiety and summarizes the data on complex bimodal effects produced by GABA-ergic agents on receptors and behavioral measures of anxiety. Possible physiological mechanisms of such effects on anxiety have been discussed. The paper reviews some paradoxical anxiotropic effects produced by certain GABA-ergic agents in behavioral tests of anxiety. Currently existing traditional views on GABA-ergic mechanisms that underlie anxiety and anxiety-related states are critically re-considered.Neirofiziologiya/Neurophysiology, Vol. 28, No. 6, pp. 267–272, November–December, 1996.     

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 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.     

An unexpected effect of capsaicin on spontaneous GABA-ergic IPSCS in hippocampal cell cultures

Vanilloid receptors 1 (VRs1) expressed in a subpopulation of sensory neurons and responsible for processing of chemical and thermal noxious stimuli were also shown to be expressed in several cerebral structures and to be involved in the regulation of glutamatergic synaptic transmission. In this study, we started to investigate the possibility that VRs1 are also involved in the regulation of GABA-ergic synaptic transmission. For this purpose, the effect of a VR1 agonist, capsaicin, on spontaneous GABA-ergic inhibitory postsynaptic currents (IPSCs) was studied in hippocampal cell cultures using a patch-clamp technique. It was found that capsaicin (10 μM) decreased both the frequency and amplitude of spontaneous IPSCs. This finding suggests the involvement of VRs1 in the regulation of neuronal firing in some GABA-ergic interneurons and in the modulation of the efficacy of GABA-ergic synaptic transmission. However, considering the direction of the effect (a decrease in the IPSC frequency) and lack of its desensitization, the involvement of other receptor(s) also cannot currently be ruled out. Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 364–367, July–August, 2006.     

Inhibitory processes in the cerebral cortex and the anticonvulsive action of benzodiazepine derivatives]

A comparative study of the effect of some benzodiazepine deprivatives (chlonazepam, lorazepam, diazepam, and medazepam) on the recovery cycles of the interzonal response was carried out on unanesthetized curare-immobilized cats. These drugs proved to selectively inhibit the testing potential within the range of 20 to 100 msec. between the conditioning and the testing stimuli. This indicates that potentiation of GABA-ergic inhibition in the cerebral cortex. The threshold doses of the drugs inducing the depression of the test response and of ED50, preventing the development of convulsions, caused by GABA deficiency or by GABA-ergic receptor block, were compared; a correlation between the mentioned effects was demonstrated. The significance of GABA-positive effect of benzodiazepines in the mechanism of their anticonvulsive activity is suggested.     

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.     

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.     

Modulation of Oscillatory Synchronization in an Interneuronal Network under the Influence of Tonic GABA-ergic Inhibition: a Model Study

The influence of a tonic GABA-ergic current on the processes of network synchronization was examined using a computer model of the neural network with shunting GABA-ergic synapses and tonic excitation that initiated spiking. The tonic inhibitory current was characterized by two parameters, the reversal potential and the conductance introduced. We found that tonic current with a reversal potential more negative than the threshold for spike generation reduces the network spiking frequency and synchronization. A monotonic decrease in the network synchronization with augmentation of the tonic current conductance was shown. We also found that a particular range of tonic current conductance leads to a bistable character of the network dynamics. Depending on the initial conditions of the network examined, spontaneous synchronous oscillations similar to epileptiform activity could appear.     

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.     

The effect of lesions of the dorsal acoustic stria on the levels of glutamic acid decarboxylase and GABA transaminase in the inferior colliculus and cochlear nucleus of the guinea-pig

The levels of glutamic acid decarboxylase (GAD) and γ-amino butyric acid-α-oxoglutarate transaminase (GABA-T) have been investigated in the cochlear nucleus and inferior colliculus of the guinea-pig after hemilateral section of the dorsal acoustic stria. Animals were cerebellectomised and the stria on one side cut. Eleven days later the animals were killed and GAD and GABA-T assayed in the respective nuclei. There was no change in the enzyme levels of the inferior colliculi showing no direct GABA-ergic fibres ascending through the stria and terminating in the inferior colliculi. The levels of both GAD and GABA-T in the cochlear nucleus on the operated side decreased significantly. It is concluded that about 30% of the GAD containing terminals in the cochlear nucleus arise from fibres descending through the dorsal acoustic stria. The bulk of the GABA-ergic transmission in the cochlear nucleus is assumed to involve an intrinsic system of short axoned neurones, the majority of which have their nerve endings in the dorsal part of the nucleus.