Effect of M4-cholinoceptor blockade on haloperidol-produced catatonic syndrome in rats.

We studied the relationship between the efficiency of muscarinic receptor antagonists in preventing haloperidol-induced catatonia and their activity in tests for the interaction of ligands with various subtypes of muscarinic receptors (M1-M4) in rats. Mathematical modeling showed that affinity of the ligand for M4 receptors positively affects its ability to correct extrapyramidal disorders (catatonic syndrome) produced by haloperidol, while affinity for M2 receptors had a negative effect on this characteristic.

Effects of cholinoblockers on acetylcholine content in rat striatum in neuroleptic-induced parkinsonism.

Correction of neuroleptic-induced parkinsonism in rats with two central cholinoblockers atropine and pentifine (acetylene aminoalcohol synthesized at Institute of Toxicology) were studied by measuring the content of acetylcholine in the striatum. The content of the transmitter secretion was estimated from the content of bound acetylcholine fraction in homogenates of the above-mentioned compartment of the brain. The results indicate that atropine and pentifine in doses equally effectively preventing catalepsy in rats had different effects on acetylcholine secretion in the striatum. Hence, cholinolytics with different pharmacological selective effects differently interact with central muscarine receptor subtypes.

[Differences in prooxidant effect of neuroleptics haloperidol and aminazine]. / Razlichiia prooksidantnogo deistviia neiroleptikov galoperidola i aminazina.

In the in vitro experiments with hydrobiont Daphnia magna Straus as the test-object the comparative evaluation of the prooxydant activity of two neuroleptics galoperidol and aminazine, was performed. It was shown that galoperidol possesses the pronounced prooxydant activity compared with hydrogen peroxyde. Aminazine didn't display such an action. The exogenios reduced glutathione is capable to protect Daphnia from the prooxydant action of galoperidol may be used for the investigation of anti- and prooxydant effects of toxicants and medicines in vivo.

Qualitative assessment of selective blockade of M(4)-cholinoreceptors in the whole organism.

Quantitative assessment of selective blockade of M4-subtype muscarinic receptors was performed by the number of pilocarpine-induced movements of lower jaw in rats. Three antagonists (atropine, cyclodol, and glipin) were used in the experiments. Glipin produced the most potent blockade of M4 receptors in the whole organism compared to other test antagonist.

Mathematical analysis of subtypes of muscarinic receptors modulating heart and respiratory rhythms in rats.

Mathematical analysis of the data obtained in experiments on the whole organism revealed that blockade of M(2)-cholinergic receptors increased both heart and respiratory rates. Blockade of M(1)-cholinergic receptors alleviated tachycardia induced by M(2)-receptor blockade.

[The role of M-cholinoreceptor subtypes in heart rhythm disturbances of various etiology]. / Izuchenie roli otdel'nykh podtipov M-kholinoretseptorov v narushenii serdechnogo ritma razlichnoi étiologii.

The experiments on rats showed different activities of pilocarpine, arecoline, and DDVF in tests for the onset of bradycardia and hypersalivation. A comparative study of the activity of selective M-cholinoblockers in preventing the arrhythmias induced by phosphacol and potassium cyanide showed that the activity of M1-antagonist pirenzepine is higher as compared to that of the M2-antagonist AF-DX-116; at the same time both drugs showed equal activity with respect to arrhythmias induced by aconitine, calcium chloride, and carbachol. It is suggested that the arrhythmias of various etiology involve different subtypes of M-cholinoreceptors.

[Daphnia magna for studies of cholinergic preparations]. / Daphnia magna kak ob''ekt pri issledovanii preparatov kholinergicheskogo tipa deistviia.

Published data and original experimental results are summarized to justify biochemically the use of Daphnia magna Straus as an additional or alternative test object for the study of cholinotropic substances. The data of radioligand analysis provide direct evidence that the organism of Daphnia contains M-cholinoreceptors identical (with respect to pharmacodynamic parameters) to those in the human and animal organism.

[Effect of M3-choline receptor blockade on the ability of muscarinic antagonists to prevent catalepsy induced by haloperidol in rats]. / Vliianie blokady M3-kholinoretseptorov na sposobnost' muskarinovykh antagonistov preduprezhdat' katalepsiiu, vyzvannuiu galoperidolom u krys.

A relationship between the indices of efficacy of the muscarinic antagonists in preventing the haloperidol catalepsy and their activity in the tests characterizing the interaction of these ligands with various subtypes of m-cholinoreceptors was studied in rats. A mathematical model was formulated that confirmed the previous conclusion concerning the role of of the m1- and m2-cholinoreceptor blockade in the antiparkinsonian activity of muscarinic antagonists. It was established that blocking of the m3-cholinoreceptors decreases the anticataleptic activity of m-cholinoblockers with respect to haloperidol. It is suggested that the high antihaloperidol activity of pentiphine (an acetyleneamine alcohol) is explained by its dopaminomimetic properties rather than by the anticholinergic activity.

[Effect of pH on muscarinic antagonist selectivity]. / Vliianie pH na retseptornuiu izbiratel'nost' muskarinovykh antagonistov.

The results of in vitro experiments showed that the receptor selectivity of the M-cholinoblocker tropacin (in contrast to that of amedine) is pH-dependent. A difference observed in the characteristics of tropacin selectivity in vivo and in vitro is probably explained by dissimilar conditions for the ligand interaction with M-cholinoreceptors in the organism and in the in vitro experiments. It is suggested that certain short-time (transient) local pH changes capable of affecting the ligand--receptor interaction parameters may take place in the synaptic cleft in the course of the neurotransmission.

[New approaches to analysis of the interrelationship between cholinergic and dopaminergic mediator systems]. / Novye podkhody k analizu vzaimootnoshenii kholinergicheskoi i dofaminergicheskoi mediatornykh sistem.

Intermediatory relationships between the cholinergic and dopaminergic neurotransmission systems were analyzed using published data and the original experimental results obtained on Daphnia magna Straus, a new test object. Based on these results, the antihaloperidol activity of a series of M- cholinoblocking agents with different receptor selectivities were studied in comparison to the new cholinoblocker pentifin exceeding in the activity the classical antiparkinsonian drugs such as cyclodol, amedin, and norakin.

[Subtypes and neuronal localization of muscarinic receptors in rat cerebral hemispheres]. / Otsenka tipovoi prinadlezhnosti i neironal'noi lokalizatsii muskarinovylh retseptorov bol'shikh polushrii golovnogo mozga krys.

The subtypes of pre- and postsynaptic muscarinic receptors in rat cerebral hemispheres were determined using a new approach based on the radioligand analysis.

[Effect of biotransformation on the receptor selectivity of muscarinic antagonists in vivo]. / Vliianie protsessov biotransformatsii na retseptornuiu izbiratel'nost' muskarinovykh antagonistov v usloviiakh tselostnogo organizma.

In the experiments in vivo it is found that the receptor selectivity of muscarine antagonist glypine is time-dependent unlike atropine, amedine, benzhexol, benactyzine, and thropacin. Using modulation of the metabolic system activity it is shown that upon biotransformation glypine forms active metabolites that differs in receptor selectivity of the action.

[The evaluation of the specific activity and side effects of the m-cholinergic blocker pentifin compared to other antiparkinson agents]. / Otsenka spetsificheskoi aktivnosti i pobochnykh éffektov m-kholinoblokatora pentifina v sravnenii s drugimi antiparkinsonicheskimi sredstvami.

Experiments on rodents showed that pentifin, a muscarine antagonist belonging to the group of acetylene amines, possesses a pronounced antiparkinsonian activity. Pentifin is superior in the breadth of therapeutic action and tolerance characteristics to the conventional agents used for Parkinson's disease treatment.

[Characteristics of effects of acetylene amino alcohols M-cholinoreceptor blockers on the dopaminergic system in Daphnia magna]. / Osobennosti mekhanizma deistviia m-kholinoblokatorov iz gruppy atsetilenovykh aminospirtov na dofaminergicheskuiu sistemu Daphnia magna.

Haloperidol and dimethpromide exhibit the properties of dopamine antagonists in the experiments on Daphnia magna Straus (Crustaceae family). Haloperidol, in contrast to dimethpromide, does not significantly influence the toxic effect of apomorphine. It is suggested that acetylene aminoalcohol derivatives are selective ligands for one of the subtypes of dopamine receptors.

[The effect of selective m-cholinopositive substances on the antiparkinson activity of atropine]. / Vliianie izbiratel'nykh m-kholinopozitivnykh veshchestv na antiparkinsonicheskuiu aktivnost' atropina.

The effect of the selectivity of cholinopositive compounds on atropin antiparkinsonian activity was compared in experiments on rats. The selectivity of the effect of two new synthesized cholinopositive compounds of the phenylcarbamate group was evaluated in preliminary experiments. It was determined by means of these compounds that stimulation of m1-cholinoceptors reduces while stimulation of m2-cholinoceptors has no effect on the ability of atropin to prevent haloperidol-induced catalepsy.

[The role of the blockade of separate subtypes of muscarinic receptors in realizing the antidotal effect of m-cholinolytics in dimethyl dichlorovinyl phosphate poisoning]. / Rol' blokady otdel'nykh podstipov muskarinovykh retseptorov v osushchestvlenii antidotnogo éffekta m-kholinolitikov pri otravlenii dimetildikhklorvinilfosfatom.

On comparison of the values of receptor selectivity of a series of m-cholinoblockers in vitro with those of the selectivity of their effect in in vivo experiments, pharmacological tests characterizing the interaction of ligands with m1, m2, and m3-subtypes of muscarine receptors were determined. Analysis of the protective effect of m-cholinoblockers in poisoning with organophosphorus compounds (OPC) depending on their activity in the determined tests showed that blocking of the m1-cholinoceptors is responsible for the antidotal effect of the antagonists, whereas block ing of m2-cholinoceptors prevents it. It is suggested that the negative effect of m2-cholinoceptor blocking on the protective effect of the drugs in OPC poisoning is mediate d by increased excretion of the mediator into the synaptic cleft as a result of interaction of the ligands with the presynaptic autochol inoceptors.

[The role of acetylcholine in the pathogenesis of seizure states of different etiologies]. / Rol' atsetilkholina v patogeneze sudorozhnykh sostoianii razlichnoi étiologii.

Experiments were performed on rats to study the dynamics of changes in some parameters characterizing the state of the cholinergic part of the nervous system during the development of convulsions induced by various convulsants. It is concluded that, depending on its concentration in the synaptic space, acetylcholine may contribute to the development of convulsions or to their arrest. These effects of the mediator are probably due to its interaction with muscarine receptors of various localization and type.

[The possibility of using Daphnia magna as an alternative test object for evaluating the receptor selectivity of cholinotropic substances]. / Vozmozhnost' izpol'zovaniia Daphnia magna v kachestve al'ternativnogo test-ob''ekta dlia otsenki retseptornoi izbiratel'nosti kholinotropnykh veshchestv.

The results of study of the selectivity of the effects of cholinonegative and cholinopositive agents obtained on Daphnia magna hydrobionts were compared with the results of investigations on rats. This allowed Daphnia to be recommended as an alternative test object for studying the selectivity of the effect of cholinotropic agents in relation to some subtypes of muscarine receptors in an intact organism.

[The mechanism of the transport of organophosphorus compounds across the histo-hematic barriers]. / K voprosu o mekhanizme transorta fosfororganicheskikh soedinenii cherez gisto-gematicheskie bar'ery.

It was demonstrated in experiments on mice [correction of rats] that the transport of organophosphorus compounds (OPC) through membranes of the histohematic barriers (HHB) of the organism occurs by means of diffusion. The rate of this process depends on the interaction of OPC with the specific sites of binding with the tissues, among which the enzyme carboxylesterase plays an important part. It is suggested that both the rate and direction of OPC diffusion are determined by the relationship between the values of affinity of the ligands for the sites of their specific binding found on both sides of the HHB.

[The antiparkinson activity of muscarinic antagonists depending on their selectivity for individual m-cholinoreceptor subtypes]. / Antiparkinsonicheskaia aktivnost' muskarinovykh antagonistov v zavisimosti ot ikh izbiratel'nosti k otdel'nym podtipam m-kholinoretseptorov.

The dependence between the activity parameters of muscarine antagonists in the prevention of haloperidol catalepsy in rats and those in tests characterizing the interaction of ligands and various subtypes of m-cholinoceptors was studied. It was established by constructing the mathematical dependence that blockade of m1-cholinoceptors increases, while that of m2-cholinoceptors reduces the antiparkinsonian activity of the drugs. The activity of the muscarine antagonist pentiphan in the prevention of haloperidol-induced catalepsy in rats exceeds the activity of such traditional antiparkinsonian drugs as cyclodol and amedin.