Neurotropic Drugs Research Articles

The absence of teratogenic effects of some analgesics used in anaesthesia.

The possibility exists that agents used in anaesthesia may have adverse teratogenic effects on staff, patients, and developing fetuses. It has been shown that a range of neurotropic drugs, when injected into pregnant mice on the 9th day of gestation, produce a characteristic group of central nervous system malformations in their fetuses. We have studied the possible teratogenicity of pethidine, fentanyl, phenoperidine and lignocaine when tested in this way and conclude that they appear to have less effect than other neurotropic drugs previously tested.

Subcellular localization of two neurotropic drugs in three varieties of central nervous system cells by secondary ion mass spectroscopy (SIMS) microscopy

The intracellular localization of two neurotropic drugs, flunitrazepan (benzodiazepine) and triflupromazine (phenothiazine), was studied by secondary ion mass spectrometry microscopy (SIMS) in three varieties of cells. The images of the intracellular distributions of the two drugs are easily obtained by selecting the fluorine atom of the molecules. These images show that the drug from the benzodiazepine group is mainly located in the nuclei, whereas the phenothiazine is exclusively located inside the cytoplasm.

Some aspects of the use of liposomes to store neurotropic drugs

Some aspects of the use of liposomes to store neurotropic drugs

Interaction between neurotropic drugs and the phosphatidylcholine bilayer effect on sorption of polyvalent cations

Interaction between neurotropic drugs and the phosphatidylcholine bilayer effect on sorption of polyvalent cations

Nociceptive quality of the orbicularis oculi reflexes as evaluated by distinct opiate- and benzodiazepine-induced changes in man

The corneal reflex and the three components of the blink reflex (R1, R2, and R3) were recorded electromyographically in volunteers. The area of these responses was measured before and after administration of the narcotic-analgesic fentanyl (1.5 mg i.m.) and its antagonist naloxone, and after administration of the benzodiazepine diazepam (10 mg i.v.) and its antagonist flumazenil. Saline was given as a control placebo. The corneal reflex was 71% reduced by fentanyl, 43% by diazepam. R1 was 35% reduced and R2 was 60% reduced by diazepam. R3 was abolished by both drugs. Whereas the fentanyl-induced changes were completely reversed by naloxone, the diazepam-induced changes were only partly reversed by flumazenil. The corneal reflex appears to be a ‘nociceptive’ reflex under all points of view. Recording of the orbicularis oculi reflexes in man may be valuable in the evaluation of central-acting neurotropic drugs.

SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [ 3H]dextromethorpan and σ ligands to guinea pig brain.

The DM 1 σ 1 site binds dextromethorphan (DM) and σ receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [ 3H]dextromethorphan, [ 3H]3-(-3-Hydroxyphenyl)-N-(1-propyl) piperidine and (+)-[ 3H]1,3-Di-o-tolylguanidine ([ 3H]DTG) to the guinea pig brain. SKF 525-A, 1-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM Ki values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM 1 σ 1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed Ki values of 9–13 and 3–4 μM respectively against the three labeled ligands. These results, the broad specificity of the DM 1 σ 1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor. These findings may have important implications for the understanding of the therapeutic, side effects and toxicity of several neurotropic drugs.

Neurotropic drugs block calcium activated K channels from rat brain synaptosomal membranes

Neurotropic drugs block calcium activated K channels from rat brain synaptosomal membranes

Ontogenic studies of the neural control of adenohypophyseal hormones in the rat: gonadotropins.

1. Serotonergic, dopaminergic, and opioid systems controlling luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion develop with particular characteristics in the male and female prepubertal rats. 2. Serotonergic pathways evoke a maximal release of LH and FSH in female rats from day 12 to day 20 of age, but not in males of the same age. 3. Antidopaminergic drugs increase LH and FSH levels only in the female infantile rats. This effect is absent at birth and disappears after 20 days of age. 4. Naloxone markedly increases gonadotropins in 12-day-old females. 5. On the other hand, in 12-day-old male rats some neurotropic drugs such as diazepam could enhance LH levels, the effect being absent at other ages or in female littermates. 6. A period of high sensitivity of gonadotropins to neurotropic drugs is present during the second and third weeks of life of the rat and it is related to the sexual differentiation of the brain.

Teratogenic potential of two neurotropic drugs, haloperidol and dextromoramide, tested on mouse embryos

Potential teratogenic activity of two neurotropic drugs, haloperidol and dextromoramide tartrate, was tested by using the mouse embryo experimental model. Like numerous other drugs of this class these two are also embryotoxic. After treatment 1 hour into the 9th gestation day they induce the neurotropic syndrome of malformations comprising exencephaly, craniorachischisis, kinking of the spinal cord, brachyury, and dilation of the fourth brain ventricle. In addition, dextromoramide tartrate was found to induce one more, so far unknown, neural tube defect, namely the ectopia of the neural tube. Delay of treatment by 1 or 2 hours tends to displace the location of the neural tube defects along the length of the neural axis towards the anterior and posterior directions. Even after accumulating these results at relatively high doses, it is difficult to estimate human reproductive risks from this animal data for human therapeutic doses.

Developmental changes in FSH secretion induced by 5-hydroxytryptophan, naloxone and haloperidol in male and female rats

Follicle-stimulating hormone (FSH) secretion is increased in the immature female rat from day 5 to days 17–18 of life, and decreases steadily thereafter until puberty. It has been reported that estradiol negative feedback and inhibin-like peptides are low during this period, while luteinizing hormone (LH) and FSH sensitivity to LH-releasing hormone (LHRH) are maximal. It was therefore of interest to study the effects of some neurotropic drugs on FSH release at 12 days of age, and to compare their effects at 1 and 20 days. Besides, as developmental patterns and regulation of FSH are different in male and female rats, the experiments were carried out using male and female littermates. The drugs chosen were haloperidol, 5-hydroxytryptophan and naloxone. These drugs release LH in the infantile female rat, the effect decreasing or disappearing as the animal matures; no effects of these drugs have been reported on FSH release in infantile rats to the present time. It was found that haloperidol (0.25 mg/kg), naloxone (2 mg/kg) and 5-hydroxytryptophan (50 mg/kg) markedly increased the already high titers of FSH in the 12-day-old female rat. This effect could not be discerned in newborn rats, and had disappeared at 20 days of age. Male littermates failed to respond at any age. When adult male and female rats in diestrus were tested, all drugs at the chosen doses were ineffective in altering FSH release. These data suggest that the infantile female rat represents an interesting physiological model to evaluate the neural regulation of FSH in a situation in which inhibitory signals provided by inhibin and estrogen in later life are diminished.

Brain cell acquisition and neurotropic drugs with special reference to functional teratogenesis

This chapter describes brain cell acquisition and neurotropic drugs with special reference to functional teratogenesis. The chapter also talks about the effects of psychotropic drugs on cell acquisition in the rat brain, but it must be emphasized that effects on cell differentiation may be of no less importance because normal brain development depends on the formation and differentiation of neural cells in an interrelated fashion. Much evidence indicates that substances which act as neurotransmitters in the developed brain may also function as neurohumoural agents, involved in the regulation both of the early phases of embryogenesis and of the subsequent stages of development in the nervous system. Persistent changes in higher nervous function are often seen in experimental animals after exposure to neurotropic drugs during the period of rapid brain development. The chapter also examines the possibility that such abnormalities have a structural basis and may be because of drug-induced perturbations of cell acquisition in the brain.

Transcallosal response (TCR) in the chronic photosensitive baboon preparation, Papio papio. I. Premotor cortical stimulation, recovery cycle and neurotropic drug effect

Transcallosal response (TCR) and its recovery cycle were studied in the chronic photosensitive baboon, Papio papio. Bipolar premotor intracortical stimulation evoked early positive (P1) and negative (N1) sequences followed by late small positivity (P2) and large negativity (N2) in the contralateral homotopic site. The sequential pattern of P1 and N1 was similar to that previously described in acute preparations. The recovery cycle as measured by means of paired stimuli with varying inter-stimulus intervals (ISI) showed a marked supernormality of P1 and N1 at an ISI of 15–200 msec with maximal facilitation up to 250–300% of the conditioning response at an ISI of 30–50 msec. Pentobarbital (10 mg/kg) suppressed this supernormality without causing a constant TCR amplitude change. In contrast, a significant increase in both the TCR amplitude and the supernormality of the recovery cycle was observed with a subconvulsive dose (3 mg/kg) of Megimide, a presumed antagonist of pentobarbital. Our results suggest that (a) the recovery cycle is a more sensitive measure than amplitude for assessing the effect of neurotropic drugs on TCR, and (b) the P1, N1 amplitudes and the supernormality may represent different neuronal processes involved in the TCR.

Synthesis of N-(1-phenyl-2-propyl)-2,5-diphenylpentylamine and some related compounds as potential neurotropic and cardiovascular drugs

Heating of 2,5-diphenylvaleric acid with 2-phenylethylamine, 1-phenyl-2-propylamine, 1-phenyl-2-butylamine (IX), 1-(4-methoxyphenyl)-2-propylamine, 1-(4-methoxyphenyl)-2-butylamine (X) and 1-(4-dimethylaminophenyl)-2-propylamine to 200-210 °C resulted in the amides IIb-VIIb which were reduced with lithium aluminium hydride in boiling dibutyl ether to give the amines IIa, IIIa, and Va - VIIa. A similar two-step sequence starting from 4-phenyl-4-(phenylthio)-butyric acid and the amine IX gave compound VIIIa. The salts of the title amines revealed some central stimulating, antireserpine, thiopental potentiating, anticonvulsant, and antiarrhythmic effects. 1-(4-Dimethylaminophenyl)-2-butylamine (XI), prepared in this connection, proved anoretic activity.

An auditory psychophysical correlate of depression

In this study, we examine the possible relation between depression and a diminution of subjective pleasure experienced during sensory stimulation. A subjective evaluation of 5 pure sounds presented at random 5 times to each subject was carried out with 10 depressive subjects, 10 non-depressive psychiatric subjects, and 10 non-depressive subjects, the three groups being matched for sex and age. In depressed subjects, the results showed no reduction in the number of experiences of subjective pleasure but a significant reduction in the repeatability of subjective pleasure associated with a given sound. These modifications seems to be specific to depression since psychiatric patients receiving neurotropic drug behave as control subjects. On the other hand, no such significant difference is found in the repeatability of a subjectively unpleasant experience. Finally, when all subjects are considered on the same continuum of depression, a significant negative correlation is found ( P < 0.01) between the degree of depression as measured by the Beck Depression Inventory and the number of sounds for which repeatability of subjective pleasure is obtained over 5 trials. Our results extend into the sensory realm the reduction in the repeatability of subjective pleasure already established for depressed subjects in the social realm; this is discussed in terms of positive reinforcement reduction associated with depression.

Quantitative imaging of neuroreceptors in the living human brain

Positron emission tomography (PET) makes it possible for the first time to examine in living humans the chemistry of the brain, which relates the structures of the brain to the functions of the mind. PET scans make it possible to assess the state of neurotransmitter receptors, such as the dopamine, serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptors, in different regions in normal persons and patients with neuropsychiatric diseases. One of the most striking findings to date is that dopamine receptors fall significantly between the ages of 19 and 73 years, to a greater degree in men than in women. The effects of neurotropic drugs, such as haloperidol and methadone, can be assessed in an individual patient, providing for the first time an objective indicator of the specific desired effects of such drugs in the treatment of nervous or mental disease. Studies of patients with diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, bipolar disease, and schizophrenia are in progress. At present, the patients are being examined as part of research protocols, but it is likely that clinical trials will not be far off.

Use of neurotropic drugs to prevent aphthous stomatitis

Use of neurotropic drugs to prevent aphthous stomatitis

Action of neurotropic drugs on K+-induced GABA release from brain synaptosomes

It was shown previously that psychotropic drugs of different classes have varied effects on active GABA transport through the synaptosomal membrane [6-8]. Compounds which are the most active inhibitors of GABA uptake by synaptosomes also caused the greatest release of this mediator [8]. Neuroleptics and antidepressants,which behaved like depolarizing agents, inducing GABA release from synaptosomes in the same way as during K+-depolarization [8], were most effective from this point of view. Some of these compounds (chloropromazine and imipramine), in effective concentrations, were shown in fact to reduce the transmembrane potential in syn-? aptosomes [9].

Isaxonine base is a strong perturber of phospholipid bilayer order and fluidity—A differential scanning calorimetry and spin labeling study

The effects of the neurotropic drug isaxonine on fully hydrated dipalmitoyl-phosphatidylcholine (DPPC) bilayers has been studied in the temperature range 0°–60°, using differential scanning calorimetry and electron spin resonance spectroscopy, with two stearic acid spin labels. At low concentration (1% mol/mol), isaxonine is trapped in the polar interface and enhances the phospholipid multibilayers organization in the gel state. In contrast, at high concentration (30% mol/mol), the drug disorganizes the phospolipidic structures and may induce domain formation by phase separation. The strong interactions of isaxonine at the lipid-water interface change the ionization state of the stearic acid spin labels which become totally ionized. Then isaxonine acts as a modifier of the surface pH of the bilayer. The strong membrane effects of isaxonine may explain in part its pharmacological properties in vivo.

Neurotropic drugs and brain cell replication

International Journal of Developmental NeuroscienceVolume 1, Issue 3 p. 210-210 Roundtable 1 Neurotropic drugs and brain cell replication A.J. Patel, A.J. Patel MRC Developmental Neurobiology Unit, Institite of Neurology, 33 John's Mews, London, WC1N 2NS U.K.Search for more papers by this author A.J. Patel, A.J. Patel MRC Developmental Neurobiology Unit, Institite of Neurology, 33 John's Mews, London, WC1N 2NS U.K.Search for more papers by this author First published: 1983 https://doi.org/10.1016/0736-5748(83)90266-6AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume1, Issue31983Pages 210-210 RelatedInformation

Further studies on the effect of cimetidine and other neurotropic drugs on rat serum prolactin.

The hyperprolactinemic effect of H2 histamine receptor antagonists has been described in the rat and in humans. The present study was undertaken to explore more fully the hyperprolactinemic action of cimetidine, and its interrelationship with other neurotropic agents. Adult ovariectomized estrogen-primed rats were injected with mepiramine, diphenhydramine, pilocarpine, atropine, dopamine, cimetidine or saline as control, at different sequences and the effect on serum prolactin was determined. The effect of cimetidine on prolactin release "in vitro" by hemipituitaries of estrogenized male rats during a short time incubation period, was also investigated. Our results indicate that cimetidine is able to release prolactin and that this effect is not prevented by atropine or the classical antihistaminergic agents mepiramine and diphenhydramine. Both pilocarpine and dopamine inhibit the prolactin release due to cimetidine. The hypoprolactinemic action of pilocarpine was completely blocked by atropine, but not by mepiramine or diphenhydramine. Finally, cimetidine was unable to modify significantly the prolactin release by incubated pituitaries. It is postulated that cimetidine acts mainly at the brain and that the hyperprolactinemic effect is not mediated by muscarinic or H1 histaminergic receptors. This action can be prevented by drugs such as dopamine that are able to act on the lactotroph, and also by pilocarpine, probably by stimulating a prolactin inhibiting pathway.