Neurotropic Drugs Research Articles

The center for advanced training in cell and molecular biology: an opportunity for biomedical scientists

The Center for Advanced Training in Cell and Molecular Biology has been established as a national center to provide expert training for scientists and technicians in the biomedical sciences. Its focus is on those new and established biomedically related concepts and technologies that provide the major impetus for contemporary research, innovative industrial applications and sophisticated laboratory techniques. The Center sponsors diverse programs such as workshops, conferences, and symposia. Its primary emphasis is on 1-week programs that combine principles with laboratory practice. This unique endeavor is designed to serve society by providing scientists with opportunities to exploit effectively new and alternate technologies and by relieving industry and government of the burden of training its technical staff. Toxicologists will benefit from such programs as in vitro toxicology, receptors, epithelial cell culture, neurotropic drugs, and inflammatory responses.

A probable site of action of diazepam in rat cerebellar gaba system

Diazepam and some neurotropic drugs were examined for their effects on the cyclic guanosine 3′, 5′-monophosphate (cyclic GMP) content in rat cerebellum. Diazepam caused a marked decrease of cerebellar cyclic GMP content in a dose-dependent manner. Elevation of cerebellar gamma-aminobutyric acid (GABA) level by aminooxyacetic acid also caused a decrease in the cyclic GMP content. On the other hand, dl-amphetamine, oxotremorine, picrotoxin, and GABA-reducing agents such as isoniazid or thiosemicarbazide increased the content of this nucleotide. The increase of cyclic GMP content elicited by isoniazid was blocked completely by the premedication of diazepam in doses causing partial reduction of dl-amphetamine or oxotremorine action. Changes of cerebellar GABA level, which were caused by aminooxyacetic acid or thiosemicarbazide, did not influence the effect of diazepam. Moreover, the inhibitory action of diazepam on the picrotoxin-induced increase of cyclic GMP was a competitive type. These results suggest that diazepam facilitates the GABAergic function by acting on a picrotoxin-sensitive site of the GABA receptor complex in vivo.

Lytic action of neurotropic drugs on retroviruses in vitro

Certain widely used nervous system drugs as chlorpromazine, promazine, haloperidol, propranolol and chlorphenethazine show a lytic action on retroviruses of both C-type and D-type in vitro. Some of the drugs also display moderate inhibitory activity on virion-associated reverse transcriptase.

Some features of modern pharmacology

INTRODUCTION I.P. Pavlov indicated in the last century that the action of many pharmacological substances begins after their contact with the endings of afferent nerves. Clark was ~he first to carry out quantitative calculations of the action of a phgrmacological substance on a ce~l; he showed that oubain occupies only 3% of frogcardiac cells during the period of maximum effect, l.e° during cardiac arrest. Later, Ari~ns introduced the concepts of affinity of a pharmacological substance for cellular receptors and of its efficiency, or intrinsic activits, independent of the affinity, proportional to the number of receptors occupied by the drug. A number of authors have demonstrated lately the presence, in the structures of the central nervous system~ of receptors specific for some neurotropic drugs, opiate anal~esics included. Pert and Snyder ((973) have shown in experiments on homogenates of the J

Influence of neurotropic drugs on neurogenic damages of internal organs induced by stress

Summary Drugs which promote restoration of sympatho-adrenal system activity and of sympathetic mediators, normalize the energy resources in tissues. Key enzyme synthesis of metabolic processes can be used not only for preventing but also for pharmacotherapy of diseases of internal organs where the nervous factor is the most significant.

MALFORMATIONS OF THE CENTRAL NERVOUS SYSTEM INDUCED BY NEUROTROPIC DRUGS IN MOUSE EMBRYOS.

Out of a sample of fifteen neurotropic drugs consisting of seven antidepressants and anti-psychotics, two antianxiety drugs, one anticonvulsant, three opiates and two synthetic analgesics, twelve were found to be teratogenic for mouse embryos, causing malformations of the central nervous system. After single injections of the teratogenic dose administered at the very beginning of the ninth day of gestation, four days later, i.e. in 13-day-old embryos, the induced defects appeared to make up a recurring syndrome of malformations which consists of several abnormalities present in various frequencies either individually or in combination in the same embryos. These malformations are: exencephaly, craniorachischisis, cervical and thoraco-lumbar myeloschisis, hydrocephalic dilatation of the fourth brain ventricle, Z-shaped kinking of the spinal cord and lumbar hydromyelia. In addition, after administration of some of the drugs, branchyury or anury with or without lumbar myeloaplasia were recorded. In general the results reported here seem to suggest that because of their possible affinity neurotropic drugs are potentially teratogenic for the embryonic central nervous system if applied at the time of the neural tube closure although it is known that there are drugs in this group which do not cause any malformations of the central nervous system and that many non-neurotropic agents do cause such malformations. Secondly, the results seem to suggest also that the position of the malformations along the cerebro-spinal axis may be depending to some extent on the pharmacological properties of the drugs tested. These conjectures are treated here as entirely provisional pending further investigations.

Bioenergetics of thermogenesis: Effects of some neurotropic drugs on heat production

1. 1. DDT is able to stimulate heat production in rats independently on central thermal receptors. 2. 2. Chlorpromazine and imipramine decreased the hyperthermic effect of DDT on intact as well as decapitated rats. 3. 3. DDOH blocked completely oxygen consumption by mitochondria pretreated with chlorpromazine or imipramine. 4. 4. DDOH reversed the passive swelling of mitochondria induced by chlorpromazine or imipramine in KCl and NaCl solutions. 5. 5. Dearrangement of mitochondrial membrane permeability to osmotically active cations as a mode of anti-hyperthermic action of chlorpromazine or imipramine on peripherial heat production stimulated by DDT is discussed.

Factors influencing the serum cholesterol and ?-lipoprotein levels in fasting rabbits

The effect of starvation under ordinary conditions, in the presence of a deficiency of pyridoxine (administration of 4-deoxypyridoxine) and thiamine (administration of hydroxythiamine), and also during administration of neurotropic drugs 9amphetamine, diazepam) was studied in male rabbits. Starvation for 7–10 days led to an increase in the serum cholesterol and β-lipoprotein concentration. Pyridoxine deficiency and administration of amphetamine caused a greater increase in the level of cholesterol and, in particular, of β-lipoproteins. Thiamine deficiency and administration of diazepam, on the other hand, had a restraining effect on the increase in the cholesterol and β-lipoprotein levels in hunger stress. Prophylactic administration of the preparation Aerovit helped to reduce the severity of the metabolic changes. The cholesterol concentration in the liver of the fasting animals was increased by an especially marked degree during amphetamine administration and pyridoxine deficiency; administration of Aerovit prevented the increased accumulation of cholesterol in the liver. Differences in the serum and liver cholesterol concentrations must be attributed to changes in cholesterol biosynthesis in hunger stress.

Effect of neurotropic drugs on sleep disturbance caused by electrical stimulation of the hypothalamus in cats

A state of stress induced in cats by electrical stimulation of the hypothalamus was shown to reduce the total duration of sleep at the expense of its paradoxical phase. Haloperidol (1, 2, or 3 mg/kg), diazepam (0.5 or 1 mg/kg), nitrazepam (1 or 6 mg/kg), Noxyron (glutethimide) (10, 30, and 60 mg/kg), and pentobarbital (5, 15, and 30 mg/kg) did not restore the structure of sleep when disturbed by stress, and lithium hydroxybutyrate (100 and 150 mg/kg), dimedrol (diphenhydramine) (1, 5, and 6 mg/kg), and imipramine (1, 3, and 6 mg/kg) increased the total duration of sleep on account of the slow-wave phase. Sodium hydroxybutyrate (100 mg/kg) restored the normal electrophysiological pattern of sleep, reduced the latent period, and increased the total duration and number of episodes of the paradoxical phase, and also reduced the number of awakenings.

Nonparallel changes in brain monoamines of pyridoxine-deficient growing rats.

The effects of a large number of neurotropic drugs have been attributed to changes in the metabolism of 5-hydroxytryptamine. The aromatic amino acid decarboxylase considered to decarboxylate both dihydroxyphenylalanine and 5-hydroxytryptophan requires pyridoxal phosphate as coenzyme. Thus, in pyridoxine deficiency one would expect a decrease of serotonin as well as the catecholamines of the brain. In the present study we have found a very significant decrease in brain serotonin of the pyridoxine-deficient growing rat. However, the brain levels of norepinephrine and dopamine were not altered. This decrease in serotonin does not result from a decrease either in the brain level of trytophan or the activity of tryptophan hydroxylase. Increased degradation of serotonin measured by the levels of its metabolite, 5-hydroxyindoleacetic acid is also excluded, thus suggesting the possibility that the decarboxylation of 5-hydroxytryptophan is decreased in pyridoxine deficiency.

Action of some neurotropic drugs and Cu 2+ cations on mitochondrial membrane permeability

1. 1. Chlorpromazine (2.5 × 10 −4−1 × 10 −3M) and imipramine (5 × 10 −4−3 × 10 −3M) caused rapid swelling of rat liver mitochondria suspended in isotonic NaCl and KCl solutions, but not in isotonic sucrose. 2. 2. Copper cations added (6.66 × 10 −5M) reversed effects of chlorpromazine and imipramine on freshly prepared mitochondria. 3. 3. Imipramine protected mitochondrial membranes against lytic action of triton X-100 in manner similar to chlorpromazine. 4. 4. Neurotropic drug-copper cation interaction at the level of mitochondrial membranes is discussed.

Effect of some neurotropic drugs on differential enzyme secretion by the pancreas

The basal secretion of the pancreas and the secretion stimulated by duodenal perfusion were investigated in chronic experiments on dogs. A protein digest stimulated pancreatic enzyme secretion to a greater degree than protein itself. Amobarbital, chlorpromazine, and benactyzine inhibit both basal and stimulated pancreatic secretion. The differential character of pancreatic secretion was disturbed most by chlorpromazine and benactyzine; this is evidence of the essential role of central adrenergic and cholinergic structures in the adaptation of pancreatic secretion to food stimuli.

Effects of neurotropic drugs on hypothalamic self-stimulation

Imipromine-like antidepressants (10(-7)--10(-5) M) significantly inhibited the uptake of serotonin by the human blood platelets. Among the neuroleptics haloperidol alone depressed the uptake of serotonin in the concentration of 10(-5) M. Amphetamine and cholinolytics failed to affect the uptake of serotonin even in a concentration of 10(-4) M. The data obtained supported the hypothesis on mediation of the thymoanaleptic action through the intensification of the central serotoninergic processes. Serotonin uptake by the human blood platelets can be used for screening the antidepressants.

Effects of neurotropic drugs on Drosophila melanogaster

Drosophila melanogaster is sensitive to a variety of psychotropic and neurotropic drugs that alter neurotransmitter metabolism in humans. For many drugs the activity is a function of the stage of development of the organism. An example is the convulsant allylglycine (2-amino 4-pentenoic acid). Larvae were unaffected by a dose of allylglycine that was lethal for adults. Larvae that had been exposed to the drug continuously through three instars were able to pupate. In the pupae, which were no longer exposed to the drug, the pharate adults appeared to mature normally but subsequently died, usually before emerging from the puparium case. Allylglycine is known to inhibit mammalian glutamate decarboxylase. This enzyme is present in homogenates of Drosophila. Larvae possess a much smaller amount of glutamate decarboxylase than do adults. Allylglycine has a minimal effect on glutamate decarboxylase in vivo or in vitro. Several drug-resistant strains have been isolated.

Effect of neurotropic drugs on motor hyperactivity induced in dogs by benactyzine

Quantitative recording of motor activity in dogs showed that benactyzine (2 mg/kg intramuscularly) led to an increase in this activity which persisted for 2–3 h. The effect of benactyzine was abolished by intramuscular injection of galanthamine in a dose of 3 mg/kg. The most effective of the neuroleptics and tranquilizers studied was perphenazine. Chlorpromazine and diazepam not only did not abolish the hyperactivity induced by benactyzine, but they also caused the animals' condition to worsen. A further increase in hyperactivity was observed after diazepam and haloperidol. Levomepromazine abolished hyperactivity in some animals but potentiated other symptoms induced by benactyzine. It is postulated that motor hyperactivity produced by benactyzine is connected with anticholinergic mechanisms; the use of the drug for blocking the action of neuroleptics with marked cholinolytic properties is thus contraindicated.

Effects of neuropharmacological agents on microsomal membrane: Influence on deoxyribonucleic acid-membrane interactions in vitro

Over 20 neurotropic drugs were tested for their ability to interact with microsomal membrane and for their influence on membrane-deoxyribonucleic acid (DNA) associations in vitro. About 85% of the compounds tested altered the density of the membrane in caesium chloride equilibrium density gradients, the macroscopic appearance of the membrane band, and the extent of DNA binding. In three out of five cases studied in greater detail, the decrease in membrane density was correlated with a reduced protein content of the membrane. Theoretical significance and potential practical applications of these observations are considered.

Effects of neuropharmacological agents on in vitro formation of complexes between nucleic acids and proteins

Effects of neurotropic drugs on the formation of sodium dodecyl sulphate (SDS)—insoluble complexes between proteins and nucleic acids were investigated. Several drugs interfered with this reaction, either increasing or decreasing the final yield. Certain regularities in the interference patterns were observed. The neuropharmacological agents were found to inhibit binding of DNA to methyl-esterified bovine serum albumin (MBSA) and RNA to calf thymus histone. The less toxic drugs tend to be active predominantly under conditions when the compound is pre-incubated with either the protein or the nucleic acid tested. While the relevance of the observed phenomena to the in vivo effects remains to be established, the available data suggest that this simple and reproducible technique may be utilized for drug screening.

Conditioning of successive adaptive responses to the initial effects of drugs.

Data in the literature indicate that conditioned responses (CRs) generated by repeated pairing of conditional stimulus (CS) with administration of a neurotropic drug may resemble its unconditional effects or they may be opposite in direction; furthermore, the CRs may change as such pairings are continued. In explanation, it is hypothesized that as in conditioning of physiological reflexes, a CS repeatedly paired with administration of a neurotropic drug eventually comes to activate central“processing” events that are evoked by the“stimulus” properties of the drug,i.e., the effects of the drug at receptor sites inside or outside the pia mater which lie in the afferent arms of“reflex” neural circuits; or, the CS comes to activate central processing events that are evoked by centripetal feedback responses to the effects of the drug at receptor sites in the processing or efferent arms of reflex neural circuits. Depending on the receptor site action of the drug, the conditioned autonomic and/or neuromuscular responses that are observed may be in the same direction as, or opposite in direction to the unconditioned effects of the drug. With continued pairings of CS and drug, the unconditioned processing events evoked by the stimulus properties of the drug, and hence the CRs also, change in consequence of compensatory (sometimes“overshooting”) biochemical alterations proximal to the receptor site of action of the drug, induced by negative or positive neuronal feedback mechanisms. These concepts are utilized in a theory of opiate addiction and relapse.

Control of synthesis and release of radioactive acetylcholine in brain slices from the rat. Effects of neurotropic drugs

1. Studies of the synthesis and release of radioactive acetylcholine in rat brain-cortex slices incubated in Locke-bicarbonate-[U-(14)C]glucose media, containing paraoxon as cholinesterase inhibitor, revealed the following phenomena: (a) dependence of K(+)-or protoveratrine-stimulated acetylcholine synthesis and release on the presence of Na(+) and Ca(2+) in the incubation medium, (b) enhanced release of radioactive acetylcholine by substances that promote depolarization at the nerve cell membrane (e.g. high K(+), ouabain, protoveratrine, sodium l-glutamate, high concentration of acetylcholine), (c) failure of acetylcholine synthesis to keep pace with acetylcholine release under certain conditions (e.g. the presence of ouabain or lack of Na(+)). 2. Stimulation by K(+) of radioactive acetylcholine synthesis was directly proportional to the external concentration of Na(+), but some synthesis and release of radioactive acetylcholine occurred in the absence of Na(+) as well as in the absence of Ca(2+). 3. The Na(+) dependence of K(+)-stimulated acetylcholine synthesis was partly due to suppression of choline transport, as addition of small concentrations of choline partly neutralized the effect of Na(+) lack, and partly due to the suppression of the activity of the Na(+) pump. 4. Protoveratrine caused a greatly increased release of radioactive acetylcholine without stimulating total radioactive acetylcholine synthesis. Protoveratrine was ineffective in the absence of Ca(2+) from the incubation medium. It completely blocked K(+) stimulation of acetylcholine synthesis and release. 5. Tetrodotoxin abolished the effects of protoveratrine on acetylcholine release. It had blocking effects (partial or complete) on the action of high K(+), sodium l-glutamate and lack of Ca(2+) on acetylcholine synthesis and release. 6. Unlabelled exogenous acetylcholine did not diminish the content of labelled tissue acetylcholine, derived from labelled glucose, suggesting that no exchange with vesicular acetylcholine took place. In the presence of 4mm-KCl it caused some increase in the release of labelled acetylcholine. 7. The barbiturates (Amytal, pentothal), whilst having no significant effects on labelled acetylcholine synthesis in unstimulated brain except at high concentration (1mm), diminished or abolished (at 0.25 or 0.5mm) the enhanced release of acetylcholine, due to high K(+) or lack of Ca(2+). The fall in tissue content of acetylcholine, due to lack of Ca(2+), was diminished or abolished by pentothal (0.25 or 0.5mm) or Amytal (0.25mm).

Effect of neurotropic drugs on cortical evoked potentials

In acute experiments on unanesthetized, curarized cats and rabbits and also on animals anesthetized with chloralose, recordings were made of direct cortical and transcallosal responses, responses in the pyramids of the medulla to peripheral stimulation and stimulation of the motor cortex, primary responses in area S-I, and interzonal somatomotor responses. The effect of narcotics on these cortical responses was shown to persist under conditions partially or completely excluding effects mediated through the reticular formation and other subcortical structures (intracarotid injection of the drugs or their local application to the cortex, experiments after premesencephalic section or on the isolated cortex). Neuroleptics have only a slight effect on these cortical evoked responses, mainly due to their blocking action on the reticular formation. Tranquilizers of the benzodiazepine series are active against the cortical responses studied, and this effect is due to their direct action on the cortex.