Effect of tranquilizers on the total acetylcholine content and acetylcholinesterase activity in the brain tissue of Arvicanthis niloticus

The effect of reserpine and meprobamate on the total acetylcholine content and acetylcholinesterase activity in the brain tissue of the kusu rat, Arvicanthis niloticus, was studied. The total acetylcholine content and acetylcholinesterase activity were determined 1 hr after i.p. injection of different doses of reserpine (0.25, 0.5 and 1 mg/ml/100 g body wt) and meprobamate (6.25, 12.5 and 25 mg/ml/100 g body wt). The effect of different time intervals (1, 10, 30 min, 1, 2.5, 5, 8, 12, 24 and 48 hr) on the total acetylcholine content and acetylcholinesterase activity was investigated after i.p. injection of 0.5 mg of reserpine and 12.5 mg of meprobamate/ml/100 g body wt. Both reserpine and meprobamate caused an increase in the total ACh content in the brain tissue of Arvicanthis niloticus which was suggested to be due to a decrease in the release of ACh, since both reserpine and meprobamate inhibited AChE activity after some tested periods. The effect of meprobamate was observed to be stronger than that of reserpine.     

Mg2+-ATPase activity of brain mitochondria fractions in chronic stress and its correction by psychotropic agents

The activity of Mg2+-ATPase was determined in the cortex mitochondrial fraction, limbic system and medulla oblongata under conditions of chronic stress as well as against a background of preliminary therapy by psychotropic drugs. At the inanition stage of animals the chronic stress is shown to inhibit sharply the process of respiration and phosphorylation (by dissociation) and to decrease the content of brain macroergs. The activity of Mg2+-ATPase in the mitochondrial fractions is lowered. It practically restores to the control level against a background of stress with preliminary course of administering nicotinic acid and GABA derivatives (lithonite, nicogamol and phenibut) to rats in average therapeutic doses. Mebicar, meprobamate and chlorodiazepoxide produce a less pronounced normalizing effect on the activity under study. It is substantiated to be expedient to apply psychotropic drugs as stress-protectors for normalization of energy metabolism of brain neurons.     

Effect of diazepam, meprobamate and amizyl on the emotional reactions of the rabbit to hypothalamic stimulation

The influence of minor tranquilizers (diazepam, meprobamate and beuactizine) on the hypothalamically elicited emotional responses was studied in chronic experiments on rabbits. The positive self-stimulation elicited from the lateral hypothalamus was facilitated by all used tranquilizers. On the first day of administration of the drugs the rate of self-stimulation increased markedly. The rate of self-stimulation was still mildly enhanced on the second day and returned to its initial value on the third day. The avoidance behaviour elicited from the medial hypothalamus changed to obvious self-stimulation after the administration of diazepam and meprobamate. The reversed behaviour preserved on the second day, while on the third day the animals resumed their avoidance behaviour. It was depressed by benactizine injection and some activation of exploratory behaviour was observed.     

An analysis of the differences in the effects of diazepam on the EEG of noninbred white rats with high and low expression of anxiolytic action in a conflict situation]

The effects of diazepam (5 mg/kg, i.p.) on the EEG power spectra of the sensorimotor cortex and the dorsal hippocampus were studied in albino rats with different types of conflict behaviour. "Active" rats were characterized by domination of the theta-activity in their background cortical EEG-spectra, "passive" ones--by that of the delta-activity. No differences were revealed in the background hippocampal EEG-spectra. Diazepam produced slowing of the theta-activity and increased the beta-activity in a band of 12-32 Hz in "active" rats and that in a band of 12-16 Hz in "passive" ones. The finding is usefull for studying individual animal sensitivity to drugs effects.     

Recurrent Conditioning in the Cat Spinal Cord : Differential effect of meprobamate on recurrent facilitation and inhibition

The action of cumulative doses of meprobamate on antidromic conditioning has been studied in spinal cats. Recurrent facilitation is greatly reduced or completely abolished by total doses ranging from 210 to 400 mg./kg. The depth of recurrent inhibition is not affected in a consistent manner by meprobamate, but the duration of inhibition is markedly increased in all experiments. This differential action of meprobamate on facilitation and inhibition can be utilized to study conditioning effects consisting of combined inhibition and facilitation. If conditioning starts with an inhibitory phase, variable in duration, followed by facilitation, meprobamate depresses the facilitation and reveals an extended inhibitory curve. Facilitation, however, is not always accompanied by inhibition, since in some cases facilitation is depressed and no inhibition is uncovered. The results of these experiments are discussed in relation to the various types of conditioning that have been produced by antidromic stimulation.     

The non-sedating anxiolytic CGS 9896 produces discriminative stimuli that may be related to an anxioselective effect

Sprague Dawley albino rats were trained to discriminate an internal stimulus associated with CGS 9896, a non-sedating pyrazoloquinoline that exhibits anxiolytic activity in animals. Classical anxiolytics (diazepam and meprobamate) and proposed anxiolytic drugs having low sedative potential (CL 218,872 and tracazolate) generalized to the CGS 9896 discriminative cue. The CGS 9896 cue appeared to be mediated by a pure anxiolytic action as previous research has shown that this compound does not produce sedation or muscle relaxation. As such, the CGS 9896 stimulus would have both research and clinical application in the investigation of selective anxiomodulation. This is the first report of discriminative stimuli established on one of the newer atypical anxiolytics in which the discriminative cue appeared related to an anxiolytic effect.     

Cross tolerance when benzodiazepines are administered with other substances

It has been demonstrated in experiments on rats that only the drugs of benzodiazepine structure are responsible for complete cross tolerance as regards the myorelaxant effect under application with phenazepam. Other substances such as neuroleptics (chlorpromazine, triftazin), ethanol, phenobarbital, tranquilizers of non-benzodiazepine structure (meprobamate, ataractic), and an agonist of GABA receptors, muscimol, in doses that produce myorelaxation are not capable to replace phenazepam under conditions of this drug tolerance development. Partial cross tolerance under application with phenazepam arises from the use of supposed endogenous ligands of benzodiazepine receptors, nicotinamide and inosine, as well as of the use of the GABA-mimetic calcium valproate. The mechanisms of benzodiazepine tolerance development are discussed.     

Involvement of neuroleptic drugs in selenium deficiency and sudden death of cardiac origin: study and human post-mortem examination

The involvement of psychotropic drugs in sudden deaths has been highlighted. The objective of this work was to establish a link between selenium levels in heart tissue, psychotropic treatment and sudden death. Selenium levels were measured by electrothermal atomic absorption spectroscopy post-mortem in heart, brain and liver. Histological examination evidenced dilated cardiomyopathy in 45% of cases, left ventricular hypertrophy in 36%, and ischemic coronaropathy in 18%. A significant reduction of myocardial selenium levels compared to controls was seen in patients treated with neuroleptic drugs or meprobamate. No changes in brain or liver selenium levels were seen. These results suggest that selenium deficiency can facilitate sudden death in patients on psychotropic drugs. The reduced activity of glutathione peroxidase due to selenium deficiency can result in augmented oxidative stress in myocardial cells and myocardiopathy leading to sudden death.     

Effects of antianxiety and antipsychotic drugs on DRL responding for brain stimulation

Satiated rats could be trained to give stable rates of responding for rewarding stimulation of the lateral hypothalamus delivered on differential reinforcement of low rate (DRL) schedule requiring 2 to 8 sec interresponse intervals for reinforcement (DRL-2 to 8). The performance on a DRL-8 schedule was tested 30 min after the oral administration of benzodiazepines. Diazepam (5 and 10 mg/kg) and meprobamate (200 mg/kg) caused significant increases in response rates during the first 5 min of a session, but not thereafter. Bromazepam (1 and 5 mg/kg) also caused a significant increase in the rates during the first and second 5 min. On the other hand, chlorpromazine (20 mg/kg) caused no effect in the first 5 min but decrease in second and third 5 min. These results indicate that DRL schedules with a brain stimulation reward provided a useful tool for evaluation of antianxiety drugs. The advantage of the brain stimulation reward over food reward is that the possible effects of the drugs on hunger motivation need not be considered.     

Action of meprobamate on spinal monosynaptic reflexes and on inhibitory pathways

Meprobamate was administered intravenously to spinal cats, in cumulative doses of 30 to 40 mg./kg. each. Initial doses may have a variable action on monosynaptic reflexes. At times some reflexes are depressed, while others are enhanced or unaffected. When dose levels of 100 mg./kg. or higher are reached, monosynaptic reflexes, both flexor and extensor, are depressed. Monosynaptic reflexes can be strongly depressed by meprobamate, their input-output relations often remaining unchanged. In such cases there is thus no change in the spatial summation requirements of those motoneurons remaining in the excitable zone. Inhibitory pathways, both direct and disynaptic, are highly resistant to the action of meprobamate. The drug does not distinguish between the direct and disynaptic pathways. It is suggested that meprobamate acts as a general depressant of excitatory synaptic transmission.     

Effect of psychotropic drugs on the development of experimental gastric ulcer produced by different stress-inducing factors in rats

The anti-ulcer activity of three different doses (1/10, 1/30 and 1/90 of LD50) of imipramine, amitryptyline, chlorpromazine, amphetamine, ephedrine, chlordiazepoxide and meprobamate was studied in two types of stress-produced gastric ulcers in rats. It was found that these drugs given in doses of 1/10 or 1/30 LD50 inhibited in the same degree the development of gastric ulcer-produced by the method of Senay, in spite of differences in their psychotropic activity. On the other hand, when the method of Rossi was used for ulcer production the ulcer-preventing activity of these drugs has been varied. Thymoleptics were most effective and ataractics least effective against ulcers produced by the method of Rossi.     

Characteristics of drug pharmacodynamics in irradiated rats

A whole-body exposure of rats to 8 Gy radiation is ineffective in 3 days, and in 6 days, it prolongs considerably the effect and increases the pharmacological activity of hexenal, meprobamate, ethylmorphine, and amidopyrine, inhibits the activity of amidopyrine demethylase, aniline hydroxylase, NADPH-cytochrome c reductase, and reduces the content of protein, cytochromes P-450 and b5 in a microsomal liver fraction.     

HPLC MS/MS method for quantification of meprobamate in human plasma: application to 24/7 clinical toxicology

We described the development and full validation of rapid and accurate liquid chromatography method, coupled with tandem mass spectrometry detection, for quantification of meprobamate in human plasma with [(13)C-(2)H(3)]-meprobamate as internal standard. Plasma pretreatment involved a one-step protein precipitation with acetonitrile. Separation was performed by reversed-phase chromatography on a Luna MercuryMS C18 (20 mm×4 mm×3 μm) column using a gradient elution mode. The mobile phase was a mix of distilled water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. The selected reaction monitoring transitions, in electrospray positive ionization, used for quantification were 219.2→158.2 m/z and 223.1→161.1m/z for meprobamate and internal standard, respectively. Qualification transitions were 219.2→97.0 and 223.1→101.1 m/z for meprobamate and internal standard, respectively. The method was linear over the concentration range of 1-300 mg/L. The intra- and inter-day precision values were below 6.4% and accuracy was within 95.3% and 103.6% for all QC levels (5, 75 and 200 mg/L). The lower limit of quantification was 1 mg/L. Total analysis time was reduced to 6 min including sample preparation. The present method is successfully applied to 24/7 clinical toxicology and demonstrated its usefulness to detect meprobamate poisoning.     

The effect of neurotropic substances on the self-stimulation reaction at the thalamic level]

The effect of d-amphetamine, cocaine, caffeine, morphine, imipramine, phenobarbital, LSD-25, benactyzine, meprobamate, diazepam, chloridiazepoxide on the lateral hypothalamic self-stimulation of rats was investigated. D-amphetamine, cocaine, caffeine, morphine, imipramine decreased the threshold of selfstimulation. Meprobamate, diazepam, chlordiazepoxide failed to influence this index, but increase the intensity of self-stimulation during the threshold, the optimum and more than the optimum cirrent intensity. Benactyzine, LSD-25, phenobarbital decreased the threshold and increased the frequency of self-stimulation during all the current intensities. A comparative study of the above results showed the agents of the first group to exert a direct stimulating action on the positive reinforcement system. Tranquillizers activated this system due to their depressive action on the negative reinforcement system. Benactyzine, LSD-25, phenobarbital activated the system and depressed the system of negative reinforcement.     

Use of tranquilizers in diseases of the skin; a preliminary report

Tranquilizing agents such as chlorpromazine and reserpine were used in various diseases of the skin in which the psychogenic factors were considered important etiologic agents. While a tranquilizing effect was obtained in the majority of instances, the side reactions and variation in response were so great as to render these agents unsatisfactory for routine use as tranquilizers. Meprobamate (marketed under the trade names Miltown and Equanil) was then used on a group of dermatologic patients with more consistent tranquilizing effect and comparatively little unpleasant side reactions. It is felt that further study of the use of meprobamate as a tranquilizing agent in dermatology is worth while.     

Effect of various neurotropic drugs on chronic hyperreflexia in rats after cordotomy]

Substances modulating calcium permeability of cell membrane (verapamil imidazol, 4-aminopyridine), decreasing motor activity (meprobamate) and blocking adrenoreceptors (clophelin, propranolol, droperidol, aminazine++ have been studied for their action on the monosynaptic discharge of the ventral roots (MD VR) reinforced due to chronic cutting of the spinal cord. It is found that verapamil and meprobamate depress more strongly MD VR of rats with chronic cutting of the spinal cord than of those with the acute one. Imidazol and 4-aminopyridine reinforcing MD VR of rats with acute cutting of the spinal cord have no influence on the analogous index of rats with chronic cutting of the spinal cord. Adrenoblockers do not change the amplitude of MD VR in both groups of the animals.     

USE OF TRANQUILIZERS IN DISEASES OF THE SKIN—A Preliminary Report

Tranquilizing agents such as chlorpromazine and reserpine were used in various diseases of the skin in which the psychogenic factors were considered important etiologic agents. While a tranquilizing effect was obtained in the majority of instances, the side reactions and variation in response were so great as to render these agents unsatisfactory for routine use as tranquilizers. Meprobamate (marketed under the trade names Miltown and Equanil) was then used on a group of dermatologic patients with more consistent tranquilizing effect and comparatively little unpleasant side reactions. It is felt that further study of the use of meprobamate as a tranquilizing agent in dermatology is worth while.     

Psychopharmacological analysis of hypothalamically-induced emotions

The effect of minor tranquilizers and neuroleptics was compared on self-stimulation and escape behaviourelicited by electrical stimulation of the hypothalamic nuclei in rabbits. It was shown that while tranquilizers (diazepam, oxazepam and meprobamate) increased the rate of self-stimulation elicited from the lateral hypothalamus, neuroleptics considerably suppressed such behaviour. Tranquilizers caused a remarkable reversal of the escape behaviour into a high-rate self-stimulation, both responses being induced from the same electrodes within the medial hypothalamus. Neuroleptics (chlorpromazine, reserpine and haloperidol) had not such an influence, though they somewhat increased the general activity of the animals. The reversing effect of the tranquilizers was compared with similar findings obtained after electrolytic ablation of the ventral hippocampus. It is suggested that the hippocampus has an inhibitory influence on the hypothalamic motivational system thus providing substantially for the animals' survival in a hostile environment.     

The effects of naloxone and picrotoxin on the sedative and anticonflict effects of benzodiazepines

Interactions between naloxone and the benzodiazepine, chlordiazepoxide (CDP), were investigated in rats in a Conditioned Suppression of Drinking Test (CSD), which is a model of experimental conflict behavior. Naloxone reversed the anticonflict activity of CDP in this test. Naloxone and picrotoxin were then tested against CDP in rats using the Geller Conflict Test, which is an operant model of conflict behavior. Both naloxone and picrotoxin antagonized the anticonflict effects of CDP. Naloxone and picrotoxin were also tested for their abilities to reverse CDP-induced loss of righting reflexes in mice. Both naloxone and picrotoxin antagonized the loss of righting reflexes induced by CDP. Naloxone had no effect on the loss of righting reflexes induced by barbiturates or meprobamate. These results suggest that naloxone may be useful in the management of benzodiazepine overdoses.