Neurophysiological mechanisms of the action of GABA-tropic agents on brain structures

The effect of systemic administration of agonists and antagonists of GABA system on excitability and intracentral relationships of the brain structures was found during chronic experiments on rabbits with bipolar electrodes implanted in the region of the frontal cortex, dorsal hippocampus, midbrain reticular formation and central gray matter. The changes of the functional state of the cerebral formations were suggested to be related to a different degree of the involvement of GABA receptors of types A and B.     

Role of cholinergic and adrenergic mechanisms in the action of ketamine and thiopental sodium on the structures of the hippocampal-reticular complex and the neocortex

Under conditions of free behaviour of rabbits with electrodes implanted into the brain structures it was found that ketamine and sodium thiopental decrease the excitability in the dorsal hippocamp, reticular formation and periaqueductal gray matter of the midbrain. Excitability of the frontal neocortex increases during general anesthesia with ketamine and decreases during thiopental narcosis. Changes in excitability of the studied cerebral structures during general anesthesia can be determined by common N-cholinoblocking and alpha-adrenomimetic properties of ketamine and thiopental at the level of the dorsal hippocamp, cholinoblocking and adrenoblocking properties at the level of the reticular formation and central gray matter. In the frontal cortex ketamine presented properties of an M-cholinomimetic and adrenomimetic agent, sodium thiopental--those of a M-cholinoblocker and beta-adrenoblocker.     

Effect of gamma-aminobutyric acid analogs on the brain GABA-ergic system participating in cardiovascular regulation

In pentobarbital-anesthetized cats GABA methylester (MEG) and beta-phenyl-GABA methylester (MEF) administered intravenously in doses of 1/100, 1/30, 1/10 of LD50 and injected intracerebroventricularly in doses of 0.1 and 0.5 mg produce hypotension, These effects are significantly suppressed by picrotoxin. These compounds administered intracerebroventricularly in larger doses increase blood pressure, heart rate and sympathetic impulse outflow. Picrotoxin does not decrease these effects. MEG and MEF inhibit the GABA-transaminase activity of mouse brain in vivo. MEF increases and MEG decreases GABA concentration in the whole mouse brain.     

Effects of electroconvulsive shock on central GABA-ergic mechanisms

A single electroconvulsive shock (ECS) has no influence on seizures induced by picrotoxin and bicuculline, although it decreases the level of GABA in the cortex. A repeated ECS (once daily for 7 days) does not change the level of GABA in the cortex, brain stem, and cerebellum, but depresses seizures induced by both compounds. It prolongs the time of their occurrence and decreases their intensity. This effect is stronger in the case of bicuculline. It manifests itself in the increase of the number of animals protected from seizures and decrease of their lethality. Baclofen does not change ECS action on seizures induced by picrotoxin and bicuculline whereas it enhances catalepsy caused by ECS. Bicuculline does not change the time-course of catalepsy. The obtained results suggest that repeated ECS reduces the seizures induced by GABA antagonists probably y increasing GABA-ergic transmission or/and by increasing dopaminergic and serotoninergic transmission which significantly modify the activity of GABA-ergic neurons.     

The characteristics of the action of GABA-ergic agents on the brain microcirculation during motor activity and hypodynamia]

Changes in the microcirculatory bed of the rat brain cortex during motor activity and hypodynamia under the action of piracetam, GABA and bicuculline were studied. The possibility of the development of compensatory processes due to the cerebral blood flow increase under the influence of GABA agonists at a disturbance of the cerebral hemodynamics in combination with increased locomotor activity and also due to the improvement of the microcirculation at early stages of hypodynamia induced by administration of GABA agonists opens up new perspectives in the use of GABA-positive drugs.     

GABAergic mechanisms of the function of hippocampal-reticulo-neocortical system structures of the brain under thiopental anesthesia

In experiments on rabbits with electrodes chronically implanted in the brain structures thiopental exhibited properties of a pronounced GABA receptor agonist. Muscimol potentiated the suppressive effect of the general anesthetic agent on electrographic and behavioral correlates of excitability of the periaqueductal gray matter, mesencephalic reticular formation and especially dorsal hippocampus and frontal neocortex. On the contrary, bicuculline reduced the anesthetic effect of thiopental but potentiated the inhibitory action of the cortex and hippocampus on the midbrain formations as compared with the effects of the barbiturate proper.     

Molecular mechanisms of the brain reward system

The brain possesses a reward system which produces positive emotion. To reveal the mechanisms of the brain reward system, investigation of mechanisms underlying actions of substances of abuse can be one of the promising research approaches. Various behavioral tests using animals and methods in genomic science are also useful for these studies. I introduce our findings obtained by these ideas and techniques as follows: (i) Inhibition of methamphetamine preference by G-protein activated inwardly rectifying potassium (GIRK) channel inhibitors. (ii) Essential role of NMDA receptor channel GluN2D subunit in phencyclidine effects on animal behavior. (iii) Association of polymorphisms in the mu-opioid receptor and GIRK genes with opioid sensitivity.     

GABA-ergic component in the mechanism of action of the psychostimulant sidnocarb

The psychostimulant sydnocarb administered in single doses of 15 and 25 mg/kg provokes a dose-dependent decrease in the brain GABA content without affecting the concentration of glutamate and aspartate. This effect remains unchanged but does not get potentiated after combined use of sydnocarb and thiosemicarbazide. During chronic 2-week administration of sydnocarb, a significant reduction in the GABA and aspartate content in the brain is detected. The GABA-positive substance valproate does not prevent the stimulant effect of sydnocarb on the motor and orienting activity of animals under "open field conditions". However, the research behavior remains in this case depressed. Sydnocarb reduces, whereas amphetamine prolongs the latent period of GABA-deficient seizures induced by thiosemicarbazide. The biochemical and behavioral data suggest that the GABA-ergic component is involved into the mechanism of the psychostimulant action of sydnocarb.     

Effect of certain GABA-ergic substances on dopamine metabolism in the rat brain

Effect of the GABA-ergic drugs, sodium hydroxybutyrate, n-dipropylacetate (n-DPA) and piracetam, has been studied on the level of homovanillic acid (HVA) and activity of GABA-transaminase in the striate body of the rat brain. It has been established that piracetam in doses of 500 and 400 mg/kg, n-DPA in a dose of 200 mg/kg and sodium hydroxybutyrate in a dose of 500 mg/kg do not affect the HVA level or activity of GABA-transaminase. The data obtained are likely to support a suggestion about a possible relationship between the GABA-ergic and dopaminergic mediator system.     

Down-regulation of the GABA-ergic system in selected brain areas of spontaneously hypertensive rats (SHR)

The relevance of GABA-ergic system in hypertensive state has been studied. GABA content, GAD activity and GABA-A receptor binding in various brain areas in age-matched spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY) was compared. Out of 9 brain areas studied the GABA content was significantly lower in the substantia nigra, hypothalamus, hypothalamus posterior and hippocampus of SHR rats. GAD activity was lowered in the hypothalamus and hippocampus of young SHR and adult SHR rats (4, 8, 14 weeks old). Scatchard analysis of the binding isotherms indicated a lower Bmax of the binding sites in the hypothalamus and hippocampus of 8 and 14 weeks old SHR rats. These results suggest that activity of GABA-ergic system differs substantially in SHR and WKY rats brain. Furthermore, these differences appear already in young prehypertensive SHR rats as well as in the early stages of hypertension.     

Participation of brain cholinergic mechanisms in the action of neuroleptics]

Tests conducted with mice demonstrated the neuroleptics droperidol, galoperidol and aethaperazine capable of subduing in mice greatly the agressive reaction provoked by an electric stimulation of pain and to distinctly raise at the same time the sensitivity of the M-cholinoreactive systems of the brain to the tremor-inducing effect of arecoline. Amizyl (benactyzil) and cyclodol, by abolishing this M-cholinopositive action of the neuroleptics, greatly reduce, at the same time, their antiagressive activity, Il may be presumed that in the antiagressive activity of neuroleptics the activation of the M-cholinergic plays a definite part in cerebral mechanisms produced by them.     

The action of benzodiazepine antagonist Ro 15-1788 on the effects of GABA-ergic drugs

Summary The interaction of Ro 15-1788 (5 mg kg^–1 i.p.), a benzodiazepine antagonist, with GABA-ergic drugs muscimol (1.4 mg kg^–1 i.p.), fenibut (100 mg kg^–1 i.p.) and baclofen (5 mg kg^–1 i.p.) was examined in behavioural and biochemical studies in rats. All the above-mentioned GABA-ergic drugs produced motor depression and with the exception of muscimol, where anti-aggressive effect was evident, fenibut and baclofen showed only slight antiagressive properties. Ro 15-1788 attenuated the motor depression produced by these compounds but potentiated their antiaggressive effect. Moreover, it was found that Ro 15-1788 itself possessed dose-related antiagressive properties. Fenibut increased, whereas muscimol and Ro 15-1788 decreased, the GABA content in the rat striatum. Ro 15-1788 and all the studied GABA-ergic compounds increased the level of the dopaminc metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. In spite of this no further increase of DOPAC was observed after concomitant use of Ro 15-1788 with GABA-ergic drugs. The action of investigated GABA-ergic drugs via GABA receptors linked to benzodiazepine receptors is suggested.     

The mechanism of action of ketamine on the myelinated nerve membrane

Ketamine is an intravenous anaesthetic that has been reported to react with a number of synaptic and non-synaptic receptors at both the spinal and supraspinal level. The present investigation was undertaken to analyse the effects of ketamine on the myelinated axon under voltage clamp conditions. Both sodium and potassium channels were affected. The effect may be described as mainly a reduction of the permeability constants. No effect on inactivation was observed. The effects were described by a first order binding to receptors within the ion channels that may be identical with the receptors for other anaesthetics. It was concluded from experiments with naloxone that no opiate receptors were involved in the axonal ketamine effects.     

Effect of chronic lead treatment on GABA-ergic receptor function in rat brain

The effect of chronic lead treatment on brain gamma-amino-butyric acid (GABA)-ergic function has been studied in an attempt to correlate the clinical aspects of the chronic exposure to the metal with specific neurochemical alterations. [3H]GABA-specific binding and cyclic guanosine monophosphate (GMP) content have been measured in various rat brain areas and have been found to be increased in cerebellum and decreased in the striatum of rats after chronic lead treatment. The changes found in the GABA-ergic neurons were correlated with the different levels of lead exposure in rats. Our results indicated that lead selectively affects GABA-ergic function in various rat brain areas, inducing effects which are dose-dependent.     

Anti-arrhythmic properties of GABA and GABA-ergic system activators

Clinical and experimental data available in the literature are summarized, which are indicative of the antiarrhythmogenic properties of GABA and substances possessing GABA-positive activity (phenibut, piracetam, sodium hydroxybutyrate, lithium hydroxybutyrate, etc.). The antiarrhythmic effects are manifested in various cases of the heart rhythm violation. The mechanism of this action is related to activation of the central and peripheral retarding GABAergic system, as well as to antihypoxant, antioxidant, and antistressor effects.     

Classical and non-classical neuroleptics induce supersensitivity of nigral GABA-ergic mechanisms in the rat

The present study compared the ability of neuroleptic and non-neuroleptic agents to modify the sensitivity of nigral, GABA-sensitive, non-dopaminergic efferents in the rat after sub-chronic administration. Pre-treatment with haloperidol or clebopride, 1.0 mg/kg PO for 10 days, induced dupersensitivity to the behavioural effects of unilateral intranigral muscimol, 5.0 ng, on withdrawal day 1. This effect was no longer significant in other rats tested on withdrawal day 7. In contrast, similar pre-treatment with sulpiride, 20 mg/kg PO, led to significantly enhanced responses to intra-nigral muscimol on both withdrawal days. Pre-treatment with clozapine, 20 mg/kg, or thioridazine, 12 mg/kg PO, did not lead to supersensitivity on withdrawal day 1, but did so on withdrawal day 7. Pre-treatment with amitriptyline, 20 mg/kg PO, or metoclopramide, 1.0 mg/kg PO, failed to result in supersensitivity on either withdraway day. The data confirm previous biochemical and behavioural findings suggesting that repeated administration of neuroleptics can induce nigral GABA-ergic supersensitivity in the rat, but demonstrate that this action is not an exclusive property of classical, cataleptogenic agents.