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90 alcoholic patients (II stage of alcoholism) with secondary affective disorders (anxiety, depression) were divided into 4 groups. The patients of the first group received the GABA receptor ligand baclofen during 3 weeks. Sybazon preparation was used in the second group, while the patients of the third group were treated with amitriptyline. Placebo was applied in the forth group. The clinical psychological tests demonstrated that all drugs caused quite effective relief of affective disorders. Psychosemantic tests application showed that the pharmacotherapy caused positive changes in patients of 1-3 groups. These changes touched on both system of personal estimations and relations of personality to himself and to the world around i.e. psychosemantic sphere. Such changes in psychosemantic sphere were not observed in the 4-th group of patients (placebo). Besides it was revealed that each drug caused some specific changes in psychosemantic sphere. The result obtained were supposed to have some theoretical value in comprehension of brain-psychics relations as well as the applied significance for adequate choice of affective disorders pharmacotherapy of alcoholic patients.

90 patients with alcoholism stage II suffering from secondary affective disorders (anxiety, depression) were divided into 4 groups: treated with GABA-B-receptor ligand baclofen (group 1), with sibazon (group 2), amitriptylin (group 3), placebo (group 4). As shown by clinical, experimental psychological and electrophysiological examinations, baclofen is not inferior in efficacy to sibazon and amitriptylin, but is free of side effects and complications typical for the above drugs (central deprivation, addiction, etc.). MAO activity was unaffected in all the patients, so were dopamine, serotonin and GABA blood concentrations after the treatment. This does not allow to relate the peripheral metabolism of GABA and monoamines to emergence of secondary affective disorders in alcoholism. The authors think promising to seek for drugs effective against affective disorders among ligands of GABA-B receptors.

RNA-synthesizing activity of neuronal nuclei in the neocortex of rats increases after the termination of conditioning depending on the degree of learning. RNA synthesis shifts induced by propylnorantifein and the demethylated derivatives of ethylnorantifein are correlated only with the influence of the drugs on the retention but not the learning. Participation of RNA synthesis by the neurons of the neocortex in the mechanisms of long-term memory is discussed.

The authors review different mechanisms of mnemotropic and cerebroprotective effects of nootropic drugs. The data concerning the molecular mechanisms of action of the structural analogs of the memory stimulant ethylnorantifeine (etimizol) have been summarized and analyzed. It is shown that the effects of antifeines on the retention of the conditioned reflexes are independent of their effects on the cAMP system and structural-functional condition of the neuronal membrane. The key role in the action of these compounds on the long-term memory is played by the activity of the genetic apparatus. The existence of nootropic receptors in neuronal chromatin is assumed.

Catalase, superoxide dismutase (SOD) activity and level of lipid peroxidation in embryo brain of 13-17-th day were evaluated during ethanol consumption by pregnant rats. The level of lipid peroxidation was more higher in alcohol groups, than in control groups. At the same time the reduced glutathione content was decreased by 13% in the brain of 15-th day embryos under the same conditions. One can draw a conclusion that the elevated level of lipid peroxidation may be a consequence of activated free radical mechanisms or consequence of reduced activity of a non-enzymatic antioxidant system.

It has been shown that ethylnorantifein and its structural analogues with opposite effects on long term memory reduce the activity of membrane bound phosphodiesterase cAMP with high and low affinity and exert the same directed influence on lipids peroxidation in membranes. A positive correlation was observed only between the action of these substances on the long term memory and their influence on the RNA synthesis in the rat brain nuclei. Ethylnorantifein and its demethylated analogues increased RNA synthesizing activity while allyl- and propylnorantifeins decreased it. The molecular mechanisms of memory effects of neuroactive substances are discussed.

The two cAMP-independent protein kinases (PK I and PK II) were obtained from neuronal chromatin of rat brain. Nonhistone HMG-proteins were used as phosphorylation substrates. The possibility of antifeines direct action on PK II was revealed. Ethylnorantifeine and its demethylated analogues increased enzyme activity whereas allylnorantifeine decreased it. The action of ethylnorantifeine and its structural analogues were similar to its influence on neuronal RNA-synthesizing activity and long-term memory. The conclusion was made that cAMP-independent PK II may be the target of antifeines action during realization of its mnestic effects.

It has been demonstrated by a double blind placebo-controlled study that transcranial electric treatment (TET) by means of combination of direct current and pulse current and pulse current at a frequency of 70-80 Hz is an effective method of correcting affective disorders (anxiety, depressions) in patients suffering from alcoholism. The therapeutic effects of TET are coupled with changes in GABA and monoamine metabolism rather than in beta-endorphin as well as with a decrease of the latent period of the occurrence of alpha-rhythm after eyes closing.

Red cell aldehyde dehydrogenase (ALDH, EC 1.2.1.3) activity was measured by spectrophotometry in normal subjects and alcoholics after various periods of alcohol abstinence. ALDH was measured in all red cell hemolysate fractions; red cells were purified from hemoglobin by Sephadex CM-50 chromatography. The enzyme activity was found reduced in alcoholics' red cells as against that in controls. ALDH activities were somewhat increasing and approaching the normal values in the patients not using ethanol for 4 weeks or longer. These results recommend ALDH measurements in human red cells as a test for the detection of subjects abusing alcohol.

Three main directions of neuropharmacology developing at the S. V. Anichkov Department of Pharmacology of the Institute of Experimental Medicine, include the pharmacology of neurogenic damages of visceral organs, the pharmacology of memory disorders and the psychoneuropharmacology. The evolution of the outlook and the main achievements are described. The perspectives are analysed.

The ethanol-preferring (EP) rats have a higher level of lipid peroxidation in the brain and blood serum than the water-preferring rats. At the same time it was found that EP rats have a decreased antioxidant enzyme activity in the brain tissue (catalase and superoxide dismutase) and blood serum (ceruloplasmin and superoxide dismutase). This antioxidant status can lead to a greater sensitivity of the EP rat brain to ethanol toxicity. The increased catalase activity in blood of EP rats reflects the elevated metabolic tolerance of this group of animals to ethanol.

Basic strategic and tactical principles of neuropharmacological studies are outlined, whose aim is to find and explore new synthetic neuro-blocking agents and substances simulating the structure of natural metabolites. The basic research has resulted in the development of new highly effective drugs and experimentally substantiated recommendations for their clinical application. The conceptions of the action mechanism of adrenergic and cholinergic agents, stimulants of tissue energy exchange, which have been formulated in the department, suggested new approaches to the pharmacological treatment of diseases of the central and peripheral nervous systems and neurogenic diseases of the gastrointestinal and cardiovascular systems.

In chronic experiments on rabbits, in initial period of single action of ethanol, reduction was observed of the dominating frequency of the theta-rhythm and synchroneity of summated bioelectrical activity of homotopic zones and suppression of EEG manifestation but preservation of parameters of the interhemispheric zeta-wave and of temperature asymmetry in the dorsal hippocampus in response to electro-cutaneous stimulation. Late period of ethanol action was characterized by lowering of the amplitude of superslow activity, its inversion in symmetrical areas of the visual neocortex and instability of other parameters.

The time course of 14C-etimizol distribution in cell structures of the rat cerebral cortex was studied. Two minutes after intraperitoneal injection etimizol penetrates brain cells. At this time the greater portion of the drug is found in cytosol. In five minutes the maximal part of the label gets bound with cell nuclei and microsomal protein fraction extracted with 0.14 M NaCl. These two cell fractions show the highest radioactivity throughout the entire observation period (up to 7 days). Since these fractions are reported to be capable of calcium accumulation, a suggestion is made that metabolic effects of etimizol are likely to be related to calcium metabolism.

In animals, an increase in glycolysis intensity and processes of oxidative phosphorylation in the brain correlated with the steady potential shifts within the range of 0--1.0 Hz in the neocortex, dorsal hippocampus, and thalamic nuclei. The neurotropic drug ethymizol revealed two effects depending on the initial functional state of the rabbit: 2.5 mg/kg of the drug enhanced the amplitude of the minute waves in the frontal neocortex and dorsal hippocampus, increasing the metabolic rate in the unsteady period of conditioning, whereas after the fast conditioning the drug rendered background values to the minute oscillations and elongated the extinction of conditioned reflexes. The ethymizol appears to be an unspecific connector.

Alcohol dehydrogenase activity (ADH; KP 1.1.1.1.) in blood serum of rats and rabbits is 1 and 2 orders of magnitude higher than in humans. In chronic alcoholics, blood ADN is activated with an increase in alcoholism standing. Twelve hours after acute alcoholic intoxication alcoholics and heavy drinkers manifest a significant reduction in blood ADH activity. Acute alcoholic intoxication does not influence blood ADH in men who do not abuse alcohol. Chronic exposure of rabbits to ethanol leads to a decrease in ADH activity in the liver and to its rise in the blood. ADH activation is observed only in those animals which demonstrate the signs of fatty and protein liver dystrophy. It is concluded that chronic exposure to ethanol does not induce ADH synthesis in the liver. The blood ADH content ascends as a results of an increase in ADH transport from hepatocytes to the bloodstream.

Cross immunoelectrophoresis was used to study antigenic composition of the brain of rats preferring water, or 15% ethanol and of intermediate group animals. The rat brain showed 6 antigens, one of them was found to be neurospecific. The intermediate group animals and those preferring ethanol differed from those preferring water in that they demonstrated two antigens which were found to be neuro-nonspecific. The content of the neurospecific protein S-100 in the cerebellum measured by rocket immunoelectrophoresis was demonstrated to be the same in animals preferring water and ethanol. A single intraperitoneal injection of 25% ethanol (2.5 g/kg) to the intermediate group rats brought about a change in the composition of neuro-nonspecific soluble antigens of the brain.

White rats were divided into water-preferring (WP) and ethanol-preferring (EP) groups, on the basis of their preferable drink: either water or 15% solution of ethanol. Each of these groups was then subdivided into groups which were given to drink for 1 year 15% solution of ethanol (ethanol-treated) or water (controls). Alcohol dehydrogenase/aldehyde dehydrogenase activity ratios (ADH/AlDH) in livers of WP controls were considerably higher than those in EP controls. The difference in ADH/AlDH has somewhat decreased after ethanol treatment. However, this ratio remained the highest in the WP alcohol-treated group. The signs of proteinic and lipid dystrophy of the liver in alcohol-treated WP rats were expressed much more clearly than in all other groups. It is concluded that in the liver of animals with a high ADH/AlDH ratio there are favourable conditions for accumulation of a toxic hepatocyte-damaging acetaldehyde.

Behavioral reactions induced in white rats by propylnorantifein were studied by the tests of an open field, passive avoidance and self-stimulation from the medial bundle of the fore brain and Raffe suture. Biochemical analysis was done on the content of corticosteroids in blood plasma and that of glycogen and creatine phosphate in brain tissue. Propylantifein in a dose of 5 mg/kg was shown to decrease the self-stimulation, to change the emotional memory in response to pain stimulation, to increase the concentration of corticosteroids in blood plasma. During 3 hr after the drug administration brain tissue demonstrated the decreased glycogen content and particular, drastically reduced the drug action. It is suggested that propylantifein may activate the adenylcyclase system in brain tissue.

One-minute oscillations of the infraslow activity were recorded within the range of 0 to 1 Hz with indwelled electrodes in the rabbit hippocampus. The oscillations disappeared for 5-hour period after L-DOPA administration. The phenomenon could be prevented with ethimisol. A correlation was found between the amplitude of the infraslow oscillations and the temperature of the dorsal hippocampus in different states of the c. n. s. induced by catecholaminergic serotoninergic and cholinergic neurotropic substances.

A study was made of the effect of diamide derivatives of imidazole- and pyrazole-dicarboxylic acids on blood glycolysis in rabbits depending on structural and conformational features of the molecules. It was shown that glycolysis is affected by the position and magnitude of an alkyl substituent in the heterocyclic part of the molecule. An essential role in the manifestation of metabolic activity is played by structural similarity of the test compounds to the adenine molecule.

Principal possibilities and limits of using the pharmacological approach for control of memory in studies of neurophysiological and neurochemical mechanisms of learning and memory in humans and animals are reviewed as well as its place in experimental and clinical therapy of memory disorders. Using an unspecific connector aethimizol as a pharmacological probe aided to assess changes accompanying the formation and consolidation of memory traces. The significance of fast and slow bioelectrical brain activity in the memory processing, the role of enzymes involved in transcription and template chromatine activity of the neurons under the effect of drugs on memory and learning, the correlation between time-depending learning and the pattern of RNA synthesis in brain cells, as well as possibilities and pathways of utilization of drugs in the correction of the long-term memory matrix formed by a stable pathological state of the brain, are discussed.

It has been ascertained that alkyl derivatives of imidazoledicarboxylic acid diamides produce different effect on respiration and acid-base balance (ABB) of animal body. Antiphein and ethymisole stimulate respiration and change ABB. Ethirazol does not affect respiration, producing only insignificant changes in the respiratory component of ABB. Differences in the biological activity of the test drugs may be related to the structure or position of the alkyl radical in the heterocyclic ring.

Activity of alcohol dehydrogenase (ADH) was estimated using highly sensitive spectrophotometric procedure with p-nitrose dimethylaniline as a substrate in blood serum of control healthy persons without a history of alcohol abuse and of the patients with chronic alcoholism. The ADH activity in the control group was about 0.55 +/- 0.04 microM/min/L and in the patients it was 2.5-5-fold higher. A direct correlation was found between the ADH activity and duration of alcohol abuse. In the patients with alcohol abstention syndrome the activity of ADH was 4.2-fold higher as compared with controls. During the remission, from 2 months up to 5 years, the enzymatic activity decreased, but was still distinctly higher than the control values.

Superslow electrical activity was studied after the action of neurotropic drugs on curarized rabbits with gold electrodes implanted in the deep brain structures. Intramuscular administration of 1/5 mg/kg dose of ethimizol, of 5 mg/kg of ethipyrol, or of 1/5 mg/kg of metamizyl led to a reciprocity of the oscillation amplitudes between the field CA-3 of the dorsal hippocampus and the medial nuclear groups of the reticular formation. Ethimizol and ethipyrol, though producing a similar final effect, act differently on the duration and phases of slow oscillations. Micropolarization of the dorsal hippocampus field CA-3 with a 2.5 microampere current lengthened the action of the neurotropic drugs, up to six hours in the case of ethimyzol. A mathematical vector analysis has shown that the angle of the wave amplitude vector in space depends both on the characteristics of the neurotropic drug and the excitability level of field CA-3 of the dorsl hippo-campus. A slow electrical potential reflecting the capacity of the electric field of a brain structure is likely to be one the major components controlling the conformation position of the receptor proteins.

The influence of intracisternal administration of antiserum to the neurospecific brain gamma gamma-enolase (aS-gamma gamma) on the consumption of 7.5% ethanol solution by rats was studied. Injection of aS-gamma gamma decreased the ethanol intake by the rats which had been drinking 15% solution of ethanol for 7 months as a single source of liquid. In vitro aS-gamma gamma caused 4-fold inhibition of the gamma gamma-enolase activity while it did not influence the alpha alpha-enolase activity. Intracisternal administration of aS-gamma gamma shifted enolase isoenzyme spectra in the direction of the decrease of gamma gamma-enolase content. It is suggested that the effect of aS-gamma gamma on ethanol consumption is due to inhibition of the activity of gamma gamma-enolase which participates in energy metabolism in neurons.

Formation of encephalogenic shortened reflex in rabbits induced specific local changes of amplitudes of the 1-min waves. Etimizol rapidly stabilized the level of the 1-min waves and fixed the reflex, keeping the local character of the response. Propylnorantiphein enhanced corticofugal projections to the thalamus. The shifts in the brain energy exchange (the creatin--phosphate, glycogen contents) coincided in time with the amplitude shifts of the 1-min waves and occurred within 20--30 min after administration of neurotropic drugs lasting 2--3 hrs. The etimizol recruited both alpha-and beta-adrenoreceptors whereas the propylnorantiphein involved mainly the alpha-adrenoreceptors. Etimizol, being an unspecific connector, enhanced consolidation of the shortened reflex increasing the local response to electric stimulation, whereas propylnorantiphein aided to spreading of the responses over to the thalamic nuclei.

In chronic experiments on rabbits it was shown that the hypothermic effect appears in the series of antipheins after the addition of ethyl radical in the first position of imidazole ring. The hypothermic effect of etimizol is more pronounced in the brain than in the body, whereas caffeine equally increases the temperature of the brain and body.

The authors have demonstrated the effect of ethimizol on the processes of training and consolidation, the duration of memory traces, and process of reproduction in adult and old mice and rats. It has been found that ethimizol in doses of 1.5-5 mg/kg facilitates the formation of passive avoidance behavior in old animals difficult to be trained and raises the duration of storing the reflex formed in both the age groups. The improvement of reproduction of passive avoidance behavior after ethimizol administration has been discovered to be characteristic for old animals.

A study was made of the RNA biosynthesis intensity in the brain cortex depending on the rate of the learning of the conditioned active avoidance and food reinforcement alteration responses in ethanol or water preferring rats placed in a complex maze. The level of the brain RNA biosynthesis in ethanol preferring rats was lower as compared with that in rats preferring water. In ethanol preferring rats, the rate of the learning of the conditioned active avoidance response was lower, whereas that of the learning of the alternation response was greater than in water preferring rats. The data are discussed in accordance with the concepts that disorders in the interaction of transmitter and genetic structures of brain cells form the basis of the behavior of ethanol preferring animals.

In rabbits with indwelled gold electrodes, multiminute oscillations of infraslow activity were recorded within the range from 0 to 1 Hz. The temperature of cerebral structures was recorded from symmetrical areas with the aid of thermocouple. Changes of the functional state were induced by means of 1) unilateral microstimulation of frontal neocortex with 1.5-2.5 microA; 2) administration of neurotropic activators: aethimizole and its analogue: and 3) prolonged administration of ethanole. All these influences sharply increased the natural functional interhemisphere assymmetry inducting a rearrangement of intracentral interrelationships. Use of the neurotropic activators (aethimizole and IEM-476) temporarily restored the normal interaction between the cerebral hemispheres even if the functional interhemisphere asymmetry was still obvious.

It has been shown in the experiments on rats that subcutaneous administration of central alpha-adrenoblockers IEM-611 (30 mg/kg and 15 mg/kg) and phenoxybenzamine (10 mg/kg) for one or two weeks brings about a decrease in voluntary ethanol consumption at early stages of experimental alcoholism (3-week alcoholization). In rats with chronic alcoholization for 6 months only IEM-611 had a remarkable inhibitory effect on alcohol consumption. Moreover, it has been stated that IEM-611 reduced threefold the activity of liver aldehyde dehydrogenase (AlDH) by the inhibition of AlDH isoenzymes with low and high Km for acetaldehyde. Phenoxybenzamine inhibited slightly only low Km AlDH. It is suggested that differences in IEM-611 and phenoxybenzamine effects may be associated with specific drug inhibition of AlDH isoenzymes.

The composition of water-soluble antigens in the brain of rats preferring ethanol or water was studied. A significant difference was found in the content of two antigens in rats preferring water or ethanol. Administration of IEM-611 changed the antigen content ot the level characteristic for animals preferring water.

The effect of IEM-611 (30 mg/kg) on alcohol consumption in rats under the conditions of voluntary choice between water and 15% ethanol was studied as that on alcohol dehydrogenase (ADH) in postmitochondrial supernatant and in NAD-dependent aldehyde dehydrogenases (A1DH) in liver mitochondria. Administration of IEM-611 during 6 or 12 days reduces ethanol consumption by 29 and 30%, respectively, activates ADH and appreciably decreases overall activity of NAD-dependent A1DH. At the same time the ADH/A1DH ratio increases. Activation of ADH and A1DH and the decreased ADH/A1DH ratio were disclosed in alcohol preferring rats as compared to water preferring animals. IEM-611 shifts enzymatic activity of ethanol metabolism towards the level characteristic for water preferring rats. It is suggested that variation of the ADH/A1DH ratio is one of the mechanisms responsible for the decreased ethanol consumption in rats.

Spontaneous superslow electrical brain activity and its changes were studied in acute experiments on curarized rabbits after administration of etimysol in doses of 1.0, 1.5 and 2.5 mg/kg. The effect of the drug persisted for three hours. Two oscillation phases were recorded in the medial group of mesencephalic reticular nuclei and the lateral nucleus of the hypothalamus: a short positive phase and a prolonged negative one. In other brain structures only negative waves were recorded. A significant functional rearrangement of correlative connections of brain structures took place in 90 minutes after the drug administration. The factor analysis showed that the most subtle connections were preserved in the neocortex and the dorsal hippocampus.