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Meprobamate is a schedule IV anxiolytic and the primary metabolite of the muscle relaxant carisoprodol. Meprobamate modulates GABAA (γ-aminobutyric acid Type A) receptors, and has barbiturate-like activity. To gain insight into its actions, we have conducted a series of studies using recombinant GABAA receptors. In αxβzγ2 GABAA receptors (where x=1-6 and z=1-3), the ability to enhance GABA-mediated current was evident for all α subunit isoforms, with the largest effect observed in α5-expressing receptors. Direct gating was present with all α subunits, although attenuated in α3-expressing receptors. Allosteric and direct effects were comparable in α1β1γ2 and α1β2γ2 receptors, whereas allosteric effects were enhanced in α1β2 compared to α1β2γ2 receptors. In "extrasynaptic" (α1β3δ and α4β3δ) receptors, meprobamate enhanced EC20 and saturating GABA currents, and directly activated these receptors. The barbiturate antagonist bemegride attenuated direct effects of meprobamate. Whereas pentobarbital directly gated homomeric β3 receptors, meprobamate did not, and instead blocked the spontaneously open current present in these receptors. In wild type homomeric ρ1 receptors, pentobarbital and meprobamate were ineffective in direct gating; a mutation known to confer sensitivity to pentobarbital did not confer sensitivity to meprobamate. Our results provide insight into the actions of meprobamate and parent therapeutic agents such as carisoprodol. Whereas in general actions of meprobamate were comparable to those of carisoprodol, differential effects of meprobamate at some receptor subtypes suggest potential advantages of meprobamate may be exploited. A re-assessment of previously synthesized meprobamate-related carbamate molecules for myorelaxant and other therapeutic indications is warranted., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, meprobamate, a controlled substance that produces sedation via GABA(A) receptors (GABA(A)Rs). Given the structural similarities between carisoprodol and meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABA(A)R function. In whole-cell patch-clamp studies, carisoprodol allosterically modulated and directly activated human alpha1beta2gamma2 GABA(A)R function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric rho1 GABA or glycine alpha1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 min after injection. Intraperitoneal administration of meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist, flumazenil. The results of our studies in vivo and in vitro collectively suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, meprobamate. Furthermore, the functional traits we have identified probably contribute to the abuse potential of carisoprodol.

The dried extracts of aerial parts of Cynodon dactylon Pers. (Graminae) were evaluated for CNS activities in mice. The ethanol extract of aerial parts of C. dactylon (EECD) was found to cause significant depression in general behavioral profiles in mice. EECD significantly potentiated the sleeping time in mice induced by standard hypnotics viz. pentobarbitone sodium, diazepam, and meprobamate in a dose dependant manner. EECD showed significant analgesic properties as evidenced by the significant reduction in the number of writhes and stretches induced in mice by 1.2% acetic acid solution. It also potentiated analgesia induced by morphine and pethidine in mice. EECD inhibited the onset and the incidence of convulsion in a dose dependent manner against pentylenetetrazole (PTZ)-induced convulsion. The present study indicates that EECD has significant CNS depressant activities.

Rationale: The active placebo hypothesis states that placebo effects are potentiated when an active drug is administered., Objective: This hypothesis was tested in an experiment where information about the effect of a drug was combined with administration of an active drug or placebo., Methods: Information that a drug acted as a relaxant, a stimulant, or as a placebo was crossed with oral administration of a relaxant drug (700 mg carisoprodol), a stimulant drug (400 mg caffeine) or placebo (lactose) in healthy volunteers ( n=94). Dependent variables were subjective and physiological measures of arousal, as well as serum carisoprodol and caffeine levels. Data were collected from 15 to 280 min after administration of drug or placebo., Results: Caffeine increased alertness, systolic and diastolic blood pressure, startle blink reflexes, and skin conductance responses. Subjects were calmer after carisoprodol, and heart rate was increased. There was a positive correlation between increased arousal and carisoprodol levels when stimulant information had been provided. However, this was only seen when carisoprodol levels were very low. There was no evidence that caffeine modulated the placebo response., Conclusions: Active placebo responses were seen only transiently when carisoprodol levels were low, and only in the subjective arousal data. Caffeine did not support active placebo responses. The overall findings did not favour the active placebo hypothesis.

Implementation of regulations to control the prescribing of benzodiazepines in New York State in 1989 resulted in a 55% decrease in benzodiazepine prescribing, with a concomitant increase in the rates of prescribing older sedative-hypnotic compounds such as butabarbital (30% increase) and meprobamate (125% increase). In a double-blind, crossover, placebo-controlled study, we compared the behavioral and pharmacological effects of triazolam, meprobamate, and butabarbital in 14 recreational drug users. Placebo and three doses each of triazolam, meprobamate, and butabarbital were administered to each subject in a random order. Objective tests (motor performance, concentration) and subjective response questionnaires measured drug effects. Triazolam, meprobamate, and butabarbital showed comparable negative dose-response slopes on the objective measures. On the basis of these objective data, equivalent doses for the three compounds were determined to be as follows: 0.5 mg triazolam = 2,400 mg meprobamate = 400 mg butabarbital. Subjective effects data on equivalent doses show that butabarbital produced the highest peak score on Cole/ARCI Abuse Potential, ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG), and "drug strength" scales. Triazolam and butabarbital produced equivalent results on ARCI Morphine Benzedrine Group (MBG), Cole/ARCI Euphoria, and "drug liking" scales. Meprobamate was indistinguishable from placebo on euphoria and abuse potential scales. Behavioral economics analysis indicated a price crossover point two times higher for butabarbital (400 mg) than for any other drug condition. These data indicate a comparative abuse liability of butabarbital > triazolam > or = meprobamate, suggesting that the prescribing restrictions on benzodiazepines had little net benefit on abuse risk in the population and may have increased the risk of overdose morbidity and mortality.

This paper considers the pharmacology of the centrally acting muscle relaxant carisoprodol, and its metabolite meprobamate, which is also administered as an anxiolytic in its own right. Literature implicating these drugs in impaired driving is also reviewed. A series of 104 incidents in which these drugs were detected in the blood of drivers involved in accidents or arrested for impaired driving was considered, with respect to the analytical toxicology results, patterns of drug use in these subjects, the driving behaviors exhibited, and the symptoms observed in the drivers. Symptomatology and driving impairment were consistent with other CNS depressants, most notably alcohol. Reported driving behaviors included erratic lane travel, weaving, driving slowly, swerving, stopping in traffic, and hitting parked cars and other stationary objects. Drivers on contact by the police displayed poor balance and coordination, horizontal gaze nystagmus, bloodshot eyes, unsteadiness, slurred speech, slow responses, tendency to doze off or fall asleep, difficulty standing, walking or exiting their vehicles, and disorientation. Many of these cases had alcohol or other centrally acting drugs present also, making difficult the attribution of the documented impairment specifically to carisoprodol and meprobamate. In 21 cases, however, no other drugs were detected, and similar symptoms were present. Impairment appeared to be possible at any concentration of these two drugs; however, the most severe driving impairment and most overt symptoms of intoxication were noted when the combined concentration exceeded 10 mg/L, a level still within the normal therapeutic range.

The elevated plus-maze test was used to determine if the opiate antagonist naloxone could potentiate the anxiolytic-like effects of the benzodiazepine diazepam, the barbiturate pentobarbital, the propanediol carbamate meprobamate and the partial benzodiazepine receptor agonist [R]-1-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl) carbonyl]-2-pyrrolidine-methanol (Ro19-8022) in the rat. A subeffective dose of each of these compounds was combined with naloxone, 10 mg/kg. Naloxone had no effect by itself, but potentiated all drugs except Ro19-8022. The proportion of entries on the open arm increased while the total number of arms entries was not modified. These results coincide with and extend data previously obtained in the mouse. One possible explanation for naloxone's effect could be that it blocks opioid inhibition of GABAergic (gamma-aminobutyric acid) neurons thereby enhancing the effects of benzodiazepines. Another possibility is that naloxone blocks opioid effects on adenosinergic systems.

Naloxone has previously been shown to block the effects of benzodiazepines in the Swiss but not in the BALB/c strain. We have also reported that naloxone potentiates subeffective doses of benzodiazepines in Swiss mice. In the present studies we first determined whether naloxone could block anxiolytic-like effects of meprobamate in Swiss and BALB/c mice. Then we evaluated if subeffective doses of meprobamate could be potentiated in Swiss as well as in BALB/c mice. The elevated plus-maze test and the light/dark choice procedure were used. The lowest dose of meprobamate with anxiolytic-like effects was 60 mg/kg in the BALB/c mice. This dose was effective in both the plus-maze and in the light/dark choice procedure. In Swiss mice the same dose was effective in the plus-maze, whereas 120 mg/kg was required in the light/dark choice procedure. When an effective dose of meprobamate was combined with naloxone, 10 mg/kg, no blockade of anxiolytic-like effects was obtained in any strain in any procedure. To the contrary, when a subeffective dose of meprobamate was combined with naloxone, 10 mg/kg, an anxiolytic-like effect was obtained in both strains in both procedures. The present series of experiment shows that the ability of naloxone to block anxiolytic-like drug effects do not apply to meprobamate. However, the naloxone-induced potentiation of subeffective doses previously observed after treatment with benzodiazepines or buspirone was present also after treatment with meprobamate. Moreover, although blockade of anxiolytic-like drug effects with naloxone has not been observed in BALB/c mice, potentiation was as evident in that strain as in the Swiss. This suggests that the mechanisms behind naloxone's blockade of anxiolytic-like effects are independent from those behind its potentiation of such effects.

The discriminative stimulus effects of benzodiazepines often have been indistinguishable from those of barbiturates or other sedative/anxiolytics. However, baboons and rats trained to discriminate lorazepam did not reliably generalize to pentobarbital in previous studies, although animals comparably trained to discriminate pentobarbital reliably generalized to lorazepam. The present study investigated the generalization profile for a variety of anxiolytic, sedative and other drugs in baboons trained to discriminate oral lorazepam (1.8 mg/kg). Triazolam, alprazolam, diazepam, midazolam, bromazepam, temazepam and nordiazepam occasioned >80% of total responses on the lorazepam-paired lever, in that order of potency, 60 min after oral dosing; chlordiazepoxide did so in three of five baboons. However, barbiturates (amobarbital, hexobarbital, methohexital, pentobarbital, phenobarbital, secobarbital) and methypryIon occasioned lorazepam-appropriate responding in only one or two baboons. Testing barbiturates at different pretreatment times (amobarbital, hexobarbital, pentobarbital or secobarbital) or by an i.m. route of administration (methohexital, pentobarbital) did not produce an increase in generalization. Neither other classic sedatives/anxiolytics (chloral hydrate, clomethiazole, ethanol, methaqualone, meprobamate, triclofos), nor anticonvulsants (phenytoin, valproic acid), nor drugs from other pharmacological classes shared discriminative-stimulus effects with lorazepam. These results, together with those from previous studies in which lorazepam or another benzodiazepine served as the training stimulus, indicate that lorazepam training results in a more selective generalization profile with respect to sedative/anxiolytic drugs than does training with other benzodiazepines.

The anticonvulsant effect of felbamate and meprobamate were compared in a series of models for seizure activity and regarding their neurotoxic action. In the MES test, felbamate was active below neurotoxic doses. Meprobamate had an ED50 in the range of neurotoxic doses. The s.c. PTZ test was influenced by meprobamate in a fairly low dosage (ED50 66 mg/kg), but for felbamate no clearly dose-related effect could be shown up to 150 mg/kg. Reflex epilepsy in gerbils was stronger suppressed by meprobamate (ED50 34 mg/kg) than by felbamate (ED50 63 mg/kg). In amygdala kindled rats, meprobamate proved to be the most active compound, both regarding treatment of fully kindled rats, development of kindling and independent discharges from a mirror focus (secondary epileptogenesis), which were fully suppressed by oral treatment with 80 mg/kg for 30 days. Both drugs were weakly effective in a model for absence epilepsy in rats. The unexpectedly high activity of meprobamate justifies a second look at the anticonvulsant properties of the drug, especially since it was extensively used as an anxiolytic drug in the past with few obvious serious side effects.

Felbamate and meprobamate are structurally related propanediol dicarbamates that possess distinct pharmacological profiles. Felbamate is a minimally sedative, broad-spectrum anticonvulsant, whereas meprobamate is a strong sedative-anxiolytic agent. Previously, we reported that felbamate potentiates gamma-aminobutyric acid(A) (GABA(A)) receptor Cl- currents and inhibits N-methyl-D-aspartate (NMDA) receptor currents. Here we further characterized the interaction of the two dicarbamates with GABA(A) receptors to determine the basis for their pharmacological differences. In whole-cell voltage-clamp recordings from cultured rat hippocampal neurons, meprobamate enhanced GABA-evoked responses in a concentration-dependent manner and, at high concentrations (>1 mM), exhibited a separate channel-blocking effect that limited the magnitude of GABA(A) receptor potentiation. At equivalent concentrations, meprobamate produced substantially greater potentiation than did felbamate. Furthermore, meprobamate (but not felbamate), in the absence of GABA, directly activated Cl- currents that could be attenuated by the GABA(A) receptor antagonists bicuculline and picrotoxin. The mean deactivation time constant of whole-cell currents evoked by 10 mM meprobamate (110 ms) or 1 and 3 microM GABA (180 ms) were faster than the deactivation time constant of 10 mM meprobamate (490 ms) or 3 mM felbamate (470 ms) in the presence of GABA. Meprobamate and felbamate prolonged the mean burst duration of GABA-activated unitary currents in excised outside-out membrane patches. In addition, at high (supratherapeutic) concentrations, meprobamate blocked NMDA-activated currents. We conclude that felbamate and meprobamate have barbiturate-like modulatory actions on GABA(A) receptors, but meprobamate has greater activity and, unlike felbamate, is able to directly activate the receptor.

Hexenal, meprobamate, amidopyrine and ethylmorphine produced a significantly marked effect in animals under hypokinesia as compared with normal rats. When phytin, benzonal and their combination were used for preventive purposes, impaired pharmacodynamics of the tested drugs metabolizing in the liver disappeared. The investigations demonstrated that the preventive use of phytin in combination with benzonal is the most optimal in correcting the impairments of drug pharmacodynamics in hypokinesia.

The action of diazepam, meprobamate, trioxazine and mexidol on bioelectrical activity of sensorimotor cortex and dorsal hippocamp of the left and right hemisphere of the brain in conscious rat in free behavior has been studied. All the drugs produced a decline in the frequency of the dominant peak of EEG power spectra. Diazepam and meprobamate increased beta-activity. It is concluded that the decreased frequency may be due to an anxiolytic effect of the tranquilizers, whereas high beta-activity is related to muscle relaxant effect of some drugs.

To evaluate whether antianxiety drugs enable guilty subjects to appear innocent on polygraph tests, we compared the effects of diazepam, meprobamate, and propranolol on the outcome of a guilty knowledge test (GKT). Seventy-five undergraduate students were evenly divided among one innocent and four guilty groups. Subjects in each of the guilty groups received either one of the drugs or a placebo prior to the administration of the GKT and after viewing a videotape that depicted a burglary as seen from the perspective of the burglar. The results showed that drug status had no influence on the outcome of the GKT. Innocent subjects who coincidentally obtained high scores on a recognition memory test covering details of the mock crime tended to obtain higher guilt scores on the GKT.

The effect on the pentobarbital sleep time by olfactory stimulation with various odorants was investigated using mice to appraise the physiological or psychological significance of olfactory information. The sleep time was determined as the time elapsed between intraperitoneal pentobarbital administration and the first time that the animal was able to spontaneously right itself. The sleep time was affected by inhalation of some odorants compared to pure air controls, but not by others. The sleep time was prolonged by terpinyl acetate and phenethyl alcohol, and was shortened by lemon oil and jasmin oil. However, neither potentiation nor attenuation of pentobarbital action by odorant inhalation was observed when using anosmic mice produced by intranasal zinc sulphate treatment. In conclusion, olfactory stimulation associated with odorant inhalation influences the pentobarbital sleep time, suggesting that olfactory information may have a more potent influence on the physiological and psychological status than has previously been thought.

Each animal was chronically implanted with bipolar electrodes in dorsal central gray matter (DCG) and was trained to press a lever to decrease the DCG-stimulation current. Chlordiazepoxide (5-20 mg/kg, PO), diazepam (2-10 mg/kg, PO) and bromazepam (1-5 mg/kg, PO) produced dose-dependent increases in the DCG-stimulation threshold 1-4 h after administration without affecting motor performance. Meprobamate (200 mg/kg, PO) and pentobarbital (10 mg/kg, PO) also slightly increased the stimulation threshold. Their potency was in the order of bromazepam greater than diazepam greater than chlordiazepoxide greater than pentobarbital greater than meprobamate. The increase in the threshold induced by diazepam (10 mg/kg, PO) was inhibited by the GABA antagonists, bicuculline (1 mg/kg, IP) and picrotoxin (0.1 mg/kg, IP). These results suggest that decreased susceptibility to brain stimulation is involved in suppressing effects of anxiolytic drugs on the escape behavior, and also that the antiaversive action of benzodiazepines may be related to a GABAergic mechanism.

A comprehensive analysis of the cat brain electrograms (EG) by computer has revealed that the derivatives of 1,4-benzodiazepine (chlorodiazepoxide, diazepam) selectivity increase the modules of brain transients within the ranges of 8-12 and 10-12 Hz largely on the EG of the proreal gyrus and paleocortical structures and raise in the same spectral region the level of coherence between biopotentials of the limbic structures, displace the coefficients of asymmetry and excess unidimensional distributions of the instantaneous values of the EG amplitudes towards negative magnitudes. The indicators in question may be used as differential criteria of the tranquilizing effect of neurotropic substances. It is suggested that the increase in the modules of brain transients within the ranges of 8-10, 10-12 Hz during exposure to neurotropic substances is likely to mirror their central GABA-ergic mechanisms and to be an integral electrophysiological correlate of tranquilization as a psychophysiological state.

From the research results given we may conclude that the flicker fusion frequency is reduced not only by tranquillisers but also by neuroleptic drugs. The records obtained of the effect of the dosage can be seen as a measure of the efficiency of this method. It should be established by means of similar experiments, by including additional substances, in which regions of the cortico-retinal system the site of action should be presumed to be.

The behavioral interaction of intraperitoneal (i.p.) injections of meprobamate with intracerebroventricular (i.c.v.) injections of adenosine or 5'-N-ethylcarboxamidoadenosine (NECA) was examined on spontaneous locomotor activity in mice. The locomotor depressant effect of meprobamate, an adenosine uptake inhibitor, was potentiated by adenosine, but not by NECA, an uptake-resistant adenosine analogue. These findings suggest that heightened endogenous adenosine levels could mediate some of the central actions of meprobamate.

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.

The design, analysis and conclusions of the series of experiments by Carpenter et al., Ashford and Cobby, and Cobby and Ashford [J. Stud. Alc., Suppl. No. 7, pp. 54-176, 1975] are reviewed. Mathematical models of the joint action of drugs were developed and data obtained to test the models by studying the action of alcohol and meprobamate singly and in combination in human subjects. The data proved to be too limited in the range of drug concentrations in the blood necessary to identify the single most appropriate model. Carpenter et al. analyzed the data by analysis of variance, which involves assumptions about the structure of the observation and the form of the distribution of the error terms. The analyses of Ashford and Cobby and Cobby and Ashford used the mathematical models, which represented pharmacological and physiological actions of the drugs. The majority of the results of the two analyses agreed; however in Experiment V Carpenter et al. combined drugs, doses and blood samples in one analysis anf found a significant influence of meprobamate dose on blood alcohol concentration (BAC) and homogeneous error terms. Cobby and Ashford analyzed absorption and elimination phases of each alcohol dose separately and found no influence of meprobamate on BAC and significant heterogeneity in the residual error terms. Both sets of analyses found a complex interaction between the pattern of abosorption and elimination of meprobamate and dose of alcohol. Carpenter et al. related the results of behavioral measures to drug doses, Ashford and Cobby to the concentrations of the drugs in the blood. Theoretically the models can analyze the pattern of behavioral results at each combination of doses but the data available were insufficient for the purpose. The modifications in experimental design and analytical techniques necessary to continue research in developing mathematical models are discussed.

In the simultaneous administration of meprobamate and ethanol to rabbits, the blood meprobamate concentration (BMC) increased greatly when the maximum blood ethanol concentration (BECmax) exceeded 1.0 mg/ml. Thus, we subjected the rabbits to continuous infusion of ethanol so as to make the blood ethanol concentration (BEC) constant and administered meprobamate by intravenous injection. Elimination of meprobamate became slow at about the BEC of 0.5 mg/ml and the degree reached almost maximum around the BEC of 1.0 mg/ml. The elimination rate did not change any more even when the BEC was raised higher. In the study conducted to elucidate the relationship between the BMC and brain meprobamate concentration (BrMC) using rats, it was found that meprobamate would show similar movements and its level would rise extremely by an acute administration of ethanol. It was indicated that the effect of ethanol on reinforcement of meprobamate activity would appear strongly by potentiation effect.

A conflict model is described in which clinically effective antianxiety agents exhibit pronounced anticonflict activity. Male squirrel monkeys were trained to depress a bar for 5 sec to obtain food reinforcement. The 6 hr test session was comprised of an initial 3 hr period in which each 5 sec response was punished and then a 3 hr unpunished period. Trained monkeys would rarely be shocked and would make most of their responses during the non-punished period. Both benzodiazepine (chlordiazepoxide and diazepam) and non-benzodiazepine (meprobamate and phenobarbital) anxiolytics produced pronounced and unequivocal increases in punished responding. Other psychoactive agents (damphetamine, chlorpromazine, ethanol, morphine, amitriptyline and imipramine) did not produce an increase in punished responding. Sensitivity (i.e., large magnitude effects), selectivity, stable baseline performance and fully automated features make this test useful in identifying potential anxiolytic agents in primates.

The effects of minor tranquilisers and of stimulant drugs were studied in the Social Interaction test of anxiety in which the illuminance and unfamiliarity of the test arena are manipulated. Acute administration of sodium phenobarbitone (25 mg/kg) was without effect. Acute administration of sodium phenobarbitone (35 mg/kg) and of meprobamate (60 mg/kg) produced sedation: both locomotor activity and social interaction were reduced. On the other hand, amphetamine sulphate (2 mg/kg) and caffeine citrate (20 mg/kg) reduced social interaction, but increased locomotor activity. Chronic administration dissociated the pattern of results produced by sodium phenobarbitone (35 mg/kg) from that produced by flurazepam (0.5 mg/kg). With chronic treatment (5 days) neither drug reduced motor activity, but whereas phenobarbitone increased social interaction regardless of the test illuminance and unfamiliarity, the increase produced by flurazepam was limited to the more stressful test conditions, i.e., when the arena was unfamiliar or brightly lit.

The considerations necessary to describe the effects of combinations of drugs in a biological system are reviewed. The terms which express these effects-additive, potentiative, antagonistic, synergistic-have not had specific operations applied to them and mathematical models have been sought to define these operations. The models should (1) describe the nature of the action of single drugs, (2) classify the results of drug combinations, (3) provide a set of operations for deciding the outcome of combinations, and (4) predict all possible results of a combination from a knowledge of each drug acting alone. Research on the effects of alcohol and meprobamate and their interactions is reviewed, including behavioral and pharmacological studies and also some studies of the interaction of alcohol with other drugs. The task of characterizing the relation between the drug and response is formidable because complex physiological and biochemical processes determine the relationship between administered and effective dose and are further complicated by route of drug administration and various time relations. The descriptions of biochemical and physiological events seem well advanced; those of behavior are not. Much of the behavioral research assumes that a single dose is representative of all doses of the drug, and that combinations of the drugs and additivity of effects can be determined without a rigorous definition or means of application. [Bibliography of 249 items.]

Electroencephalograms were recorded from the parietal and frontal cortex of freely moving rats held in constant vigilance by placing them in a slowly turning drum. The effects of 5 clinically effective anxiolytics, buspirone, meprobamate, phenobarbital, chlordiazepoxide and diazepam, were studied after intraperitoneal injection of different doses. After on-line fast Fourier transformation of the EEG signal, the drug effects were quantified by an Analysis of Variance. This resulted in a t profile for each drug dosage. Averaging the t profiles of all dosages of a drug results in a 'drug profile'. Averaging the drug profiles of the 5 anxiolytic drugs tested results in an 'anxiolytic profile'. This profile is characterized by a power decrease from 8 to 11 Hz and above 70 Hz and a power increase from 20 to 60 Hz. The anxiolytic profile is compared with the formerly defined antidepressant and neuroleptic profiles and can be clearly distinguished from the latter two.

The combination of meprobamate and diphenhydramine increased tyrosine hydroxylase activity in the rat nucleus locus coeruleus after twice daily injections, whereas neither compound alone had an effect. Increased activity occurred using a variety of medication ratios and absolute doses.

Oxazepam (2.5-80 mg/kg) induced significant mouse killing among large samples (N = 100/dose) of Holtzman strain albino rats. Meprobamate (2.5-80 mg/kg) and Chlorpromazine (0.5-4 mg/kg) did not induce killing. Despite its lesser tendency to induce aggression in humans, Oxazepam is as potent as Chlordiazepoxide for inducing killing by rats. Induction of mouse killing by rats appears to the predict clinical potency rather than the aggressive side-effects of anxiolytic benzodiazepines.

Diazepam and meprobamate significantly attenuated the increases in grooming behavior induced by peptides. Significant increases in total grooming frequency over a thirty minute observation period were produced by intraventricular administration of 1 microgram ACTH1-24 and by 1 microgram bombesin to awake rats. Diazepam 1 mg/kg IP blocked the peptide-induced increases in grooming. Non-sedating doses of diazepam also completely reversed the grooming seen when rats were placed in a novel environment. The functional antagonism between anxiolytics and stress-related peptides supports the concept of interacting brain mechanisms mediating stress and anxiety.

Pentobarbital (30 and 60 mg/kg) and chloral hydrate (300 and 600 mg/kg) administered in anesthetic/hypnotic doses produced significant increases in acetylcholine concentration in the cerebral cortex, striatum, hippocampus and brainstem. Hypnotic/anxiolytic agents like diazepam, flurazepam (100 mg/kg each) and triazolam (30 mg/kg) significantly increased the acetylcholine concentration only in the cerebral cortex and striatum. Alprazolam and ketazolam had no significant effect on regional distribution of acetylcholine in the brain. The results have been discussed with respect to the role of central cholinergic system in anesthetic and hypnotic actions of these drugs.

A critical review of some relevant literature concerning the effects of prenatal administration of drugs and several other substances on postnatal behavior. Significant variables and problems in the adequate design of experiments to assess these effects are discussed. Although the evidence concerning prenatal drug effects on behavior is equivocal, sufficient data exist to indicate that this will continue to be a viable and important area of research in the future. Present results demonstrate the complexity of drug interactions with other variables.

The take up time of a standardized alimentary material is a simple component of hamster hoarding behaviour. This value was modified by administrations of the following compounds: diazepam, chlorpromazine, meprobamate, apomorphine, d-amphetamine, piribedil, fenfluramine, sulpiride, imipramine, phenobarbital, clonidine and morphine. The change consisted of a varying increase in the take up time, dependent upon the substance and dosage. High doses of chlorpromazine, apomorphine and fenfluramine inhibited the take up. A behavioural study connected with alimentary take up was included in the experiment. Some behavioural modifications (increase or decrease in motor activity, myorelaxation, stereotyped exploration, reciprocating movements) demonstrated differences between the studied compounds related to their pharmacological properties. The immediate consumption of food, without take up and hoarding behaviour, observed with meprobamate treatment, was an interesting and unexpected change in hamster behaviour. The measurement of the take up time and analysis of behavioural modifications may be useful in comparing and preliminary screening of new psychopharmacological compounds.

Two behaviors related to nonreward (omission of water in an enclosure where the rats were habituated to drink) were studied. The time spent licking the bottles during water omission and the time spent drinking during a subsequent 5-min drinking session (water available) were recorded. The drinking session was performed 30 min after the water-omission session. Rats subjected to water omission showed an enhanced drinking time that varied with the length of the water omission session, with the motivational state of the animals, and with the previous number of water-omission sessions. Diazepam, chlordiazepoxide, lorazepam, and meprobamate (i.p., 30 min before water omission), increased the time spent licking the empty bottles, but failed to abolish subsequently enhanced drinking. However, some of our data suggested that minor tranquilizers weakly reduced the increased drinking induced by nonreward, despite their direct stimulation on water drinking. It is proposed that either minor tranquilizers are devoid of general antifrustration activity or nonreward-induced frustration and nonreward-induced drive enhancement may not be correlated.

Electromyographic response evoked by stretches is registered in the rat gastrocnemius muscle. Stretch is caused by the forced flection of the paw on the leg by a solenoid. Intensity of the electromyographic signal is measured by an electronic integrator. We studied the dose/effect correlation of some psycotropic drugs on the stretch reflex in stressed rats by contention: Pentobarbital, Meprobamate, Chlorpromazine, Sulpiride, Amitriptyline, D-Amphetamine. Chlorpromazine abolishes the myoelectric stretch response while Meprobamate and Amitriptyline reduce it only a little. Pentobarbital and Sulpiride produce a biphasyc effect of opposite sign: at small doses Pentobarbital increases the stretch response while Sulpiride reduces it. At high doses we can see an opposite effect. Amphetamine, at least, at all studied doses decreases the myoelectric stretch response.

The demonstration of specific recognition sites for benzodiazepines in the mammalian CNS has altered current thinking on the mechanisms of action of the benzodiazepines as well as the neurochemical events which are associated with anxiety. Recent studies suggest that the physiological regulation of the benzodiazepine receptor is far more complex than initially believed and includes a functional coupling to both a GABA receptor and an associated chloride ionophore. It now appears that a number of other psychopharmacologic agents, including minor tranquilizers other than the benzodiazepines as well as several convulsants and anticonvulsants, may exert their pharmacologic effects by affecting one or more regulatory sites on the benzodiazepine receptor complex. In addition to a number of drugs, at least one endogenous small molecular weight compound that has been isolated from the crude synaptosomal fraction of bovine cerebral cortex also appears to modulate this receptor complex.

Mice exhibited a marked suppression of motor activity when placed into the same environment in which they had previously received electric foot shocks. Apomorphine-HCl (0.1 - 10 mg/kg) produced a dose-dependent reduction of the conditioned suppression of activity, but did not increase activity in non-shocked mice. Diazepam (0.2, 1, and 5 mg/kg), meprobamate (25 and 50 mg/kg), and chlorpromazine-HCl (2 and 5 mg/kg) did not reduce conditioned suppression. Thus, the conditioned suppression caused by a quick conditioning technique does not produce similar results to those using the conditioned emotional response involving suppression of operant lever-pressing behavior.

In water-deprived rats and mice, animals trained to the test situation spent more time in drinking than naive animals (first exposure to the test situation). The time spent in drinking, either during 5 min or during 10 min was recorded. As compared to controls, benzodiazepines, phenobarbital, meprobamate, and mecloqualone increased drinking time whether the experiments were run on naive or on experienced animals [5 or 10 (in mice) and 9 (in rats) exposures in the test situation]. All drugs were injected i.p. 30 min before testing. This release of the drinking behavior was more pronounced during the last 5 min than during the first 5 min of the 10 min test session. These results suggest that: 1. The inhibition of water intake of naive animals as compared to trained rats and mice, could be related to some emotional factors elicited by the first exposure to an unknown situation. 2. The increase in drinking time induced by the antianxiety drugs in a novel and in a familiar situation seems difficult to correlate only with the antianxiety action of these compounds. 3. Antianxiety drugs could interfere with the regulatory mechanism of thirst.

The effects of drugs on the potentials evoked by electrical stimulation on the sensorimotor area (SMA), nucleus reticularis tegmenti pontis (PTRN), nucleus reticularis lateralis (LRN), nucleus olivaris inferior (ION), or superficial radial nerve (SR) were investigated in cat cerebellar cortices. Pentobarbital-Na decreased the amplitude of the potentials evoked by all stimulations at every recording site. Pentobarbital-Na remarkably decreased the SMA- or PTRN-stimulation induced evoked potentials in the anterior lobe. Chlorpromazine decreased the amplitude of the potentials evoked by SMA stimulation on the anterior lobe and ipsilateral crus l, and the drug increased it on the posterior lobe and contralateral crus l. With precerebellar nuclei stimulations, chlorpromazine decreased the amplitude of the evoked potentials in cerebellar cortices, whereas SR stimulation-evoked potentials were remarkably increased in amplitude. Meprobamate increased the amplitude of the potentials evoked by precerebellar nuclei or SR stimulation at an early stage and then decreased it. Caffeine, picrotoxin, and strychnine remarkably increased the amplitude of the potentials in cerebellar cortices evoked by all stimulations. Strychnine in particular significantly increased the amplitude of the potentials evoked by SR stimulation. These results strongly indicate that CNS depressants and stimulants affect the cerebellar afferent pathways, probably in an indirect manner.

The [1-14C]2-deoxyglucose technique was employed for an evaluation of the regional pattern of alteration of brain metabolism induced by the anxiolytics phenobarbital (which is described in small doses as anxiolytic agent) and meprobamate. Their effects were compared with those produced by the anxiolytic benzodiazepine diazepam which we have described in a previous study. In low doses, both meprobamate (30 mg/kg i.v.) and phenobarbital (5 mg/kg i.v.) elicited a regional pattern of changes similar to those seen with diazepam. Thus, the local cerebral glucose utilization (LCGU) of the mammillary nuclei, the lateral and ventral thalamic nuclei, the anterior thalamic nuclei and the geniculate nuclei was significantly decreased. A doubling of the dose (meprobamate 60 mg/kg i.v.; phenobarbital 10 mg/kg i.v.), however, resulted in a decrement in LCGU in virtually every brain region examined. Further, at this higher dose, phenobarbital significantly increased LCGU in the interpeduncular nucleus. These data demonstrate that both meprobamate and phenobarbital, in moderate doses induce selective alterations in LCGU in particular brain regions with the pattern of changes similar to that induced by diazepam. The structures affected may be of general importance for the expression of the anxiolytic actions of each of those classes of minor tranquilizers in clinical use.

The rats of groups I, II, III and IV were treated orally with phenobarbital, meprobamate, codeine and vehicle, respectively, for total 21 days, and then drugs were withdrawn. All these rats were given again orally phenobarbital for 5 days starting from 70 days after the withdrawal. In comparison with groups III and IV, groups I and II showed larger weight gain during phenobarbital re-administration and longer-lasting weight loss and an larger increase in body temperature after the termination. These results suggested that the drug experience on sedative-hypnotics persisted over two months after the withdrawal and that did not cross to that of narcotics.

Five experiments were conducted to study the effects of alcohol and meprobamate, administered singly and in combination, at doses up to 1.20 g of alcohol per kg of body weight and up to 30 mg of meprobamate per kg. Most of the 158 men were of college age (range, 21-49). In all experiments it appeared to the subjects that both drugs were administered, alcohol as a 25% solution in orange juice and meprobamate as 10 tablets. One hour after the men took the meprobamate they had 1 hr to drink the beverage. Before and at 1/2 hr intervals after administration of the drugs blood samples were taken and behavioral response measured by means of a visual-motor coordination tracking task (Stressalyzer). An experimental session lasted 6 hr. In Experiment I (E-I) each of 12 men was tested on 2 days, after 0, 1.00 or 1.20 g of alcohol per kg and 0 or 25 mg of meprobamate per kg. In Experiment II (E-II) 56 men were tested (8 per group) after 0, 5, 10, 15, 20, 25 or 30 mg of meprobamate per kg and alcohol placebo. In Experiment III (E-III) 40 men were tested (8 per group) after 0, 0.25, 0.50, 0.75, or 1.00 g of alcohol per kg and meprobamate placebo. In Experiment IV (E-IV) 25 men (5 per group) received meprobamate 3 times a day (total daily dosage, 0, 7, 14, 21 or 28 mg per kg) for 12 days. On days 8 to 12 all subjects drank alcohol, as in E-III. In Experiment V (E-V) 25 subjects (5 per group) were tested on 5 days, drinking each day the same doses of alcohol as in E-III and all received the same doses of meprobamate as in E-IV.

Two amino-phenyl-pyridazine derivatives, SR 41378 and CM 40907, have been reported to antagonize seizures in mice, rats and Papio papio baboons with comparable potencies. Structurally, SR 41378 differs from CM 40907 by an additional chlorine in position 6 of the phenyl ring. In the present study the activity of these two compounds in the operant approach-avoidance conflict test in rats was examined and compared with that of diazepam, pentobarbital, meprobamate and valproate. SR 41378 increased punished responding, a measure of anticonflict activity (ED50 = 5.2 mg/kg), and decreased nonpunished responding, a measure of sedative activity, with a threshold active dose of 20 mg/kg i.p. The overall potency of SR 41378 was comparable to that of pentobarbital. CM 40907 (10-40 mg/kg i.p.) did not affect punished responding and decreased nonpunished responding at the dose of 40 mg/kg i.p. The duration of the anticonflict activity of SR 41378 increased with the dose and lasted over 4 h at the 20-mg/kg i.p. dose. At this dose, sedation lasted 1 h. An increase in anticonflict potency and tolerance to sedation were observed after a 5-day treatment with SR 41378 (20 mg/kg i.p.). The anticonflict and sedative activities of SR 41378 were not antagonized by Ro 15-1788 or CGS 8216. In vitro SR 41378 did not interact with benzodiazepine receptor sites. In conclusion, although CM 40907 and SR 41378 exhibit similar anticonvulsant activities, the present study reveals a major pharmacological difference between the two compounds because SR 41378 also possesses anticonflict properties.