Pharmacodynamics and pharmacokinetics of ethanol, diazepam and pentobarbital in young and aged rats

Sleeping time was measured in groups of old and young rats following the intraperitoneal injection of pentobarbital (39.5 mg.kg-1), diazepam (30 mg.kg-1) and ethanol (3 g.kg-1). Concentrations of pentobarbital, and unbound and total diazepam in serum, and ethanol in breath were quantified; as well as whole brain concentrations of diazepam and N-demethyldiazepam. Healthy old rats slept significantly longer than young rats after receiving diazepam and ethanol but not pentobarbital. There were no significant differences in serum or whole brain concentrations of diazepam or N-demethyldiazepam between healthy young and old rats. There were also no changes in the serum pentobarbital or breath ethanol concentrations between the young and old rats. Increases in pharmacologic effect that occur with aging may be caused by alterations in pharmacokinetic parameters or changes at the site of drug action. The cause of an increased pharmacodynamic effect depends upon the specific drug, possibly because these compounds affect the same receptorionophore complex at different sites.     

CNS depressant activities of roots of Coccos nucifera in mice

The ethanol extract of Coccos nucifera (EECN) was tested for possible pharmacological effects on experimental animals. EECN significantly potentiated the sleeping time of mice induced by standard hypnotics viz. pentobarbital sodium, diazepam, and meprobamate in a dose dependent manner. EECN 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. Pretreatment with EECN caused significant protection against pentylenetetrazole-induced convulsions. The behavioral studies on mice indicate CNS depressant activity of the ethanol extract of C. nucifera.     

CNS activities of ethanol extract of aerial parts of Hygrophila difformis in mice

The ethanol extract of aerial parts of Hygrophila difformis (EEHD) was tested for possible pharmacological effects on experimental animals. EEHD significantly potentiated the sleeping time of mice induced by standard hypnotics, viz. pentobarbital sodium, diazepam, and meprobamate in a dose dependent manner. EEHD 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. Pretreatment with EEHD caused significant protection against strychnine and leptazol-induced convulsions. The behavioral studies on mice indicate CNS depressant activity of the ethanol extract of H. difformis.     

Evaluation of the muscle relaxant properties of a novel beta-carboline, ZK 93423 in rats and cats.

The muscle relaxant action of ZK 93423 (6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate ethyl ester), a novel beta-carboline with agonistic properties at the benzodiazepine receptor, was examined by assessing its effect on the tonic electromyogram (EMG) activity of the gastrocnemiussoleus (GS) muscle of genetically spastic rats and on ventral root reflexes, presynaptic inhibition and fusimotor activity in the spinal cord of decerebrate cats. ZK 93423 (0.1-10.0 mg kg-1) depressed the tonic EMG activity in mutant rats in a dose-dependent manner. This effect was reversed by the benzodiazepine antagonist Ro 15-1788 (5.0 mg kg-1). Both ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) enhanced the presynaptic inhibition of the GS muscle and associated dorsal root potentials in decerebrate cats in an almost identical manner. The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) depressed the activity of both static and dynamic fusimotor neurones, as deduced from changes in the afferent responses of muscle spindle primary endings to low frequency (1 s-1) sinusoidal stretching. The depressant action of diazepam (0.3 mg kg-1) was weaker than that of ZK 93423 (0.5 mg kg-1). The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) failed to alter the magnitude of monosynaptic ventral root reflexes evoked by electrical stimulation of a flexor and an extensor nerve, whereas diazepam (0.3 mg kg-1) had a depressant effect on both types of monosynaptic reflexes, which was antagonized by Ro 15-1788 (5.0 mg kg-1). Neither ZK 93423 (0.5 mg kg-1) nor diazepam (0.3 mg kg-1) depressed polysynaptic ventral root reflexes evoked by electrical stimulation of a flexor and a cutaneous nerve. The present results demonstrate that ZK 93423 exerts a potent muscle relaxant action due to a specific interaction with benzodiazepine receptors. However, its profile of actions on spinal motor mechanisms is not identical to that of diazepam.     

Involvement of the serotonergic system in the prolongation of pentobarbital sleeping time produced by prostaglandin D2

In the present study, the depressant and sedative actions of prostaglandin D2 (PGD2) were investigated. Intravenous (IV) administration of PGD2 produced a significant decrease in the spontaneous locomotor activity of mice from 1 to 15 minutes following injection. Prostaglandin D2 was also able to potentiate pentobarbital sleeping time at doses of 0.4 and 4.0 mg/kg when administered intravenously. Distribution studies with 3H-PGD2 (6 microCi, 4 mg/kg) showed that only 0.04% of the tritium administered could be found in brain at 5 min after the injection, and that only 50% of this was parent 3H-PGD2. The role of the serotonergic neurotransmitter system in the depressant action of PGD2 was investigated with drugs which modulate this system. The ability of PGD2 to potentiate pentobarbital sleeping time was diminished by pretreatment with agents that reduce brain level or synthesis rate of serotonin. Such agents include para-chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor, 5,7-dihydroxytryptamine (5,7-DHT), a neurotoxin with selectivity for serotonergic neurons, and quipazine, a serotonergic autoreceptor stimulant. On the other hand, pretreatment with 5-hydroxytryptophan (5-HTP), the precursor of serotonin, further enhanced the potentiation of pentobarbital sleeping time by PGD2. These data suggest that the depressant actions of PGD2 are linked to the serotonergic neurotransmitter system.     

Discriminative stimulus properties of a new anxiolytic,DN-2327, in rats

In an operant learning lever-pressing procedure on an FR10 schedule of milk reinforcement, male Wistar rats were trained to discriminate between saline and 3 mg/kg IP DN-2327, a new anxiolytic which acts on benzodiazepine receptors, 3 mg/kg IP diazepam or 15 mg/kg IP pentylenetetrazol (PTZ). More than 80% appropriate lever responding was established after 27, 38 and 44 daily training sessions with DN-2327, diazepam and PTZ, respectively, as the training drug. Although rats trained with DN-2327 dose-dependently generalized to various doses of DN-2327 and diazepam, the cue of DN-2327 was more potent than that of diazepam: ED₅₀ values of DN-2327 and diazepam for stimulus generalization were 0.30 and 0.66 mg/kg, respectively. These animals partially generalized to pentobarbital (1–10 mg/kg) but did not generalize to buspirone (0.1–10 mg/kg). Rats trained with diazepam dose-dependently generalized to various doses of DN-2327, diazepam and pentobarbital with ED₅₀ values of 0.51, 0.47 and 4.5 mg/kg, respectively, but did not generalize to buspirone. In rats trained with PTZ, DN-2327 and diazepam antagonized the discriminative stimulus produced by 15 mg/kg PTZ in a dose-dependent manner with ED₅₀ values of 0.27 and 0.83 mg/kg, respectively, but buspirone neither antagonized nor was able to substitute for the PTZ-induced stimulus. The cue of DN-2327 was antagonized by flumazenil dose-dependently as was that of diazepam. Diazepam and pentobarbital reduced the total number of responses in all animals at 10 mg/kg, and buspirone did so at more than 3 mg/kg, while DN-2327 did not affect the total number of responses from 0.1 to 10 mg/kg. In conclusion, the cue of DN-2327 is similar to and more effective than that of diazepam; moreover, it is quite different from that of buspirone. In addition, the similarity of the interoceptive stimuli of DN-2327 and diazepam may suggest that they are not related to muscle relaxant and sedative properties, since the two drugs differ in this respect.     

缬草挥发油与水提物镇静催眠作用比较研究

目的：了解缬草镇静催眠的主要药效物质,为深入研究其有效成分提供物质基础。方法：通过缬草挥发油急性毒性实验,了解挥发油毒性的大小,确定药效实验剂量。采用镇静催眠的药效学实验,比较缬草挥发油与水提物协同戊巴比妥钠对小鼠的催眠作用。结果：小鼠灌胃缬草挥发油的LD50为278．99g·kg^-1（以生药计）,从而确定药效试验的给药剂量为高剂量组（85．71g·kg^-1）、中剂量组（57．14g·kg^-1）和低剂量组（28．57g·kg^-1）;缬草镇静催眠药效学实验表明,缬草挥发油可促进小鼠入睡效率,延长小鼠睡眠时间;水提物仅可延长小鼠的睡眠时间,与水提物相比,缬草挥发油能有效延长小鼠的睡眠时间。结论：缬草挥发油的镇静催眠效果明显优于其水溶性物质。     

Acute Effects of Oxazepam,Diazepam and Methylperone,alone and in Combination with Alcohol on Sedation,Coordination and Mood

Abstract Effects on critical flicker fusion frequency (CFFF), coordination and mood were studied after single oral doses of placebo, alcohol (0.5 ml ethanol/kg b. wt.), oxazepam (10, 20 and 40 mg), diazepam (5, 10, 20 and 40 mg) and methylperone (10, 25 and 50 mg), given either alone, or simultaneously with alcohol or with delayed alcohol administration. Methylperone was found to have a depressant effect similar to or greater (on a weight basis) than that of diazepam and oxazepam respectively. The correlation between sedative and antianxiety effect is discussed. The decrease in CFFF was parallelled by a decreased coordination ability. Alcohol alone had no effect on our parameters, but when given simultaneously with the drugs, it markedly increased the effect of diazepam, while the effect of oxazepam and methylperone were affected to a much lesser degree. The effect of the drugs on psychomotor skills and the interaction between alcohol and the drugs have important implications when treating out-patients. Methylperone as a potential anti-anxiety agent is discussed.     

Interactions between phencyclidine and central nervous system depressants evaluated in mice and rats

The effects of phencyclidine (PCP) alone and in combination with the CNS depressants, pentobarbital (PB) or ethanol (ETOH), were determined in mice using the inverted screen test and in rats using disruption of milk drinking behavior. The effects of PB and ETOH alone, and in combination, were also determined so that the PCP combinations could be compared to this clinically relevant interaction. These homergic drug interactions were analyzed using the dose-addition model by isobolographic analyses. Most drug combinations resulted in shifts to the left of the dose-effect curves relative to the dose-effect curves for the drugs alone; in no cases were shifts to the right (antagonism) observed. In general, the interactions between PCP and ETOH or PB were quantitatively less (infra-additive) than the interaction between the CNS depressants (dose-additive) when studied in mice. In the rat studies, the interactions between PCP and ETOH or PB were, overall, quantitatively greater (dose-additive or supra-additive) than the ETOH-PB interactions (infra-additive). Since even infra-additive interactions may result in substantially enhanced effects, these results suggest that coabuse of PCP with CNS depressant drugs could produce marked behavioral toxicity.     

Disinhibitory effects of buspirone and low doses of sulpiride and haloperidol in two experimental anxiety models in rats: Possible role of dopamine

Low doses of buspirone, haloperidol and sulpiride were compared with diazepam in two experimental models of anxiety in rats. In a conflict test, 0.6 and 1.2 mg/kg buspirone, 0.05 and 0.10 mg/kg haloperidol and 0.5 mg/kg sulpiride significantly increased punished responding. Buspirone 1.2 and 2.5 mg/kg significantly reduced the number of unpunished responses while haloperidol and sulpiride at the doses tested had no effect. Effects on punished responding were seen in a narrow dose range and were less pronounced with these drugs than with diazepam. Similar results were obtained with rats', activity in the two-compartment exploratory test. At doses causing no change in the locomotion of rats in photocell activity cages, buspirone (0.1 mg/kg), haloperidol (0.025–0.100 mg/kg) and sulpiride (0.5–1.0 mg/kg) significantly increased the number of crossings between the two compartments. Again, the peak effects were small when compared with the effect of diazepam and the active dose range was very narrow. Apomorphine 0.2 mg/kg SC significantly counteracted the effect of 0.1 mg buspirone and 1.0 mg/kg sulpiride in the two-compartment exploratory test with no effect on 2.5 mg/kg diazepam.The data show that buspirone, in a narrow dose range, shows disinhibitory effects in experimental models of anxiety. Similar effects are shown by low doses of haloperidol and sulpiride. It is suggested that buspirone and sulpiride produce these disinhibitory effects by blocking particular dopamine receptors in the brain, possibly those located in the nerve terminals, but it is likely that other mechanisms, particularly serotonin, are involved in the effects of buspirone in anxious states.     

Ethanol, but not the anxiolytic drugs buspirone and diazepam, produces a conditioned place preference in rats exposed to conditioned fear stress

The present study was designed to investigate the role of an anxiolytic effect in the development of a drug-associated place preference in rats exposed to conditioned fear stress, using the conditioned place-preference paradigm. The administration of a low dose of ethanol (300 mg/kg, IP) and the anxiolytic drugs, buspirone (1 and 2 mg/kg, IP) and diazepam (1.25 and 2.5 mg/kg, IP), did not produce a place preference in rats that were not exposed to conditioned fear stress. In rats that were exposed to conditioned fear stress, ethanol produced a significant place preference, while buspirone and diazepam failed to produce a place preference. In addition, ethanol, buspirone, and diazepam produced no place preference in rats treated with an anxiogenic dose of pentylenetetrazole (20 mg/kg, IP). A significant decrease in locomotor activity was observed in rats exposed to conditioned fear stress. Ethanol, but not buspirone and diazepam, significantly recovered or increased locomotor activity in rats exposed to conditioned fear stress. Further, the locomotor-stimulating effect of ethanol was markedly enhanced by repeated exposure to conditioned fear stress. These results suggest that the stimulating effect may be strongly related to the development of the rewarding effect of a low dose of ethanol under psychological stress, and that the conditioned place preference paradigm with conditioned fear stress may be useful for studying the rewarding mechanism of ethanol with regard to the interaction between ethanol and psychological stress.     

Preclinical abuse potential assessment of the anticonvulsant zonisamide

Zonisamide (Zonegran^®) is a broad‐spectrum antiepileptic agent that shares some pharmacological properties with other anticonvulsants, including phenytoin, carbamazepine, and valproic acid, but is differentiated from these agents by the ability to significantly block T‐type calcium channels. Zonisamide interacts with the γ‐amino‐butyric acid (GABA) receptor in an allosteric manner, and thus does not modulate GABA receptor effects. However, given the potential of drugs within the latter class for drug abuse in humans, an evaluation of zonisamide for abuse potential is an important component of its potential side‐effect profile. In the present study, zonisamide was tested in animal models of the subjective and reinforcing effects of central nervous system (CNS) depressant drugs, e.g., diazepam discrimination in rats and intravenous self‐administration in rhesus monkeys, respectively. In addition, zonisamide was evaluated for physical dependence liability in a chronic infusion model using rats. Zonisamide did not substitute for diazepam in rats trained to discriminate 2.5‐mg/kg diazepam from vehicle nor was it self‐administered by rhesus monkeys experienced in methohexital‐reinforced responding. Continuous infusion of zonisamide (400 or 600 mg/kg/day) did not prevent the loss of body weight associated with discontinued pentobarbital infusion. These doses of zonisamide did produce some incomplete attenuation of observable signs of pentobarbital withdrawal, likely due to direct sedative or depressant effects of these high doses. These results suggest that zonisamide would not produce diazepam‐like intoxication in humans nor would it likely be subject to abuse when made more widely available. Further, when administered chronically, zonisamide would not be expected to produce physical dependence of the CNS depressant type. Taken together, these results support the prediction that zonisamide would have low abuse liability. Drug Dev. Res. 54:66–74, 2001. © 2001 Wiley‐Liss, Inc.     

Effects of buspirone and diazepam, alone and in combination with alcohol, on skilled performance and evoked potentials

Effects of buspirone, 10 and 20 mg, and diazepam, 10 mg, on skilled performance and evoked responses, as well as their interactions with 0.8 g/kg of alcohol were investigated in 24 healthy men. Alcohol, 0.8 g/kg, caused the greatest performance impairment, followed closely by diazepam. Both doses of buspirone had lesser effects. Buspirone had primarily sedative effects which were short lasting, whereas diazepam impaired tracking and body balance in addition to being sedative. Both anxiolytics showed only slight additive interactions with the present dose of alcohol. A strong drug effect and a lesser but significant alcohol and a drug/alcohol interaction effect were seen on evoked potentials. Diazepam effects on evoked potentials were similar to alcohol, whereas buspirone in some instances appeared to reverse the alcohol effect. Pharmacokinetics of buspirone and diazepam were not significantly affected by concomitant administration of alcohol. The psychomotor side effect profile of a single anxiolytic dose of buspirone is preferable to a single 10-mg dose of diazepam.     

Potentiation of pyridoxine by depressants and anticonvulsants in the treatment of acute isoniazid intoxication in dogs

Treatments for acute isoniazid (INH) intoxication have included, singly and in various combinations, a great variety of drugs. As a consequence it is difficult to evaluate the efficacy of these antidotes, except for pyridoxine, the most commonly recommended one. In some cases of INH poisoning evaluation is further complicated because of concurrent alcohol ingestion. The objectives of this investigation were to determine whether ethanol enhances the toxic effects of acute INH overdose, as suggested by some clinical reports, and to evaluate the antidotal efficacy of phenobarbital, pentobarbital, phenytoin, ethanol, or diazepam when each is administered in combination with pyridoxine. Male dogs were either pretreated with iv ethanol and challenged 1 hr later with po INH, 50 or 75 mg/kg, or they were given INH, 75 mg/kg, and injected iv 30 min later with the test drugs, alone or in combination with pyridoxine. Ethanol pretreatment not only did not enhance the toxicity of INH but, in fact, it reduced the severity of convulsions, although it did not change the mortality rate. In the antidotal study, none of the five CNS depressants or anticonvulsants protected against clonic-tonic seizures or death. Pyridoxine, however, reduced the severity of the seizures and prevented death, although it did not completely block convulsions. The combination antidotal treatments (pyridoxine plus each of the CNS drugs) were the most effective; they prevented both convulsions and lethality. It is suggested that pyridoxine is the basic antidote for treatment of acute INH poisoning, and that the addition of an anticonvulsant or a CNS depressant to the therapy enhances effectiveness.     

Telemetry as a tool to measure sedative effects of a valerian root extract and its single constituents in mice

Valeriana officinalis L. is a popular herbal treatment for mild sleep disorders. Clinical and non-clinical studies found contradictory results for valerian extracts and single constituents regarding the influence on sleep parameters. It was the aim of this study to investigate the sedative effects of a valerian root extract. Therefore, locomotor activity and core body temperature were recorded in male mice using radiotelemetry. A 70 % ethanolic extract prepared from the roots of V. officinalis (s. l.) and some of its single constituents, valerenic acid, linarin, and apigenin, were tested for effects on locomotion and body temperature over 180 minutes after oral administration. The extract was tested in a dose range of 250-1000 mg/kg, and only a dose of 1000 mg/kg valerian extract showed a mild short-term sedative effect with reduced locomotor activity between 66-78 min minutes after administration. Paradoxically, an increased activity was observed after 150 minutes after gavage. A dose of 1 mg/kg valerenic acid produced an intermittent stimulation of activity. However, a mild short-term sedative effect was found for linarin at 12 mg/kg and apigenin at 1.5 mg/kg. Considering the cumulative locomotor activity over the observation period of 180 min, it is concluded that neither the extract nor one of the compounds had considerable sedative effects. More precisely, the observed short-term changes in activity pattern indicate that valerian extract as well as the flavonoids linarin and apigenin are rather effective to reduce sleep latency than to act as a sleep-maintaining agent.     

Evaluation of CNS Depressant Activity of Different Plant parts of Nyctanthes arbortristis Linn

The present study was carried out with the water-soluble portion of the ethanol extracts of flowers, barks, seeds and leaves of Nyctanthes arbortristis Linn. to confirm their CNS depressant activity. The ethanol extracts of the plant parts were obtained by soxhlet extraction. After performing the gross behavioral study, the CNS depressant activity was evaluated by observing the prolongation of sleeping time induced by pentobarbital sodium in mice. Attempts have been made to explore the possible mechanism behind this activity by determining their effect on brain monoamine neurotransmitters like dopamine and serotonin. The gross behavioral study showed that ethanol extracts of the leaves, flowers and seeds possess significant CNS depressant activity. The leaves, flowers, seeds and barks (600 mg/kg) showed significant and dose-dependent prolongation of onset and duration of sleep and so found to cause decrease dopamine and increase serotonin level. From which it can be concluded that the CNS depressant activity of the ethanol extracts of seeds, leaves and flowers may be due to the decrease in dopamine and increase in serotonin level.     

Corticosterone increases severity of acute withdrawal from ethanol,pentobarbital, and diazepam in mice

It has been suggested that withdrawal from several subclasses of central nervous system (CNS) depressants involves common underlying mechanisms. For example, mice genetically selected for severe ethanol withdrawal convulsions (Withdrawal Seizure Prone or WSP) have also been found to express severe withdrawal following treatment with barbiturates and benzodiazepines. Corticosteroids appear to modulate severity of withdrawal from CNS depressants. Therefore, it was hypothesized that corticosterone would enhance withdrawal convulsions following acute ethanol, pentobarbital, and diazepam in WSP mice. Corticosterone (20 mg/kg) administered following each of these drugs significantly increased severity of handling-induced convulsions during withdrawal. Corticosterone did not affect pre-withdrawal convulsion scores or handling-induced convulsions of drug-naive mice. These results suggest that withdrawal convulsions following acute ethanol, pentobarbital, and diazepam are sensitive to modulation by corticosterone and they support the hypothesis that stress may increase drug withdrawal severity.Supported by grant # DA05496, #AA06243, and by the Department of Veterans Affairs.     

Interaction studies in mice of SCH 29851, a potential non-sedating antihistamine, with commonly used therapeutic agents

SCH 29851 was studied for its ability to interact with selected drugs used in man. The non-sedating antihistamine terfenadine and the sedating antihistamine diphenhydramine were also studied for comparison. SCH 29851 at 80 mg/kg po in mice, a dose about 50 times its ED50 for blocking histamine-induced paw edema in the same species, potentiated the anticonvulsant effects of diazepam. At the high dose of 320 mg/kg po, about 80 times its ED50 for antihistamine effects, SCH 29851 potentiated the ability of high doses of ethanol and hexobarbital to induce loss of righting reflexes (LRR). However, no potentiation was seen when SCH 29851 was studied with lower doses of ethanol or phenobarbital that had anticonvulsant effects but did not cause LRR. At this high dose of 320 mg/kg po, SCH 29851 also did not interact with the antihypertensive drugs propranolol and alpha-methyldopa, the anti-ulcer drug cimetidine, the nasal decongestant pseudoephedrine, or the CNS stimulant d-amphetamine. A nearly identical profile of interactions was seen with terfenadine, including potentiation of diazepam at 50 times its antihistamine ED50, potentiation of ethanol- and barbiturate-induced LRR at 80 times its antihistamine ED50, and lack of interaction effects at 320 mg/kg po with each of the other tested drugs. The demonstration in this study of the significant interactions between diphenhydramine and many of the tested drugs is consistent with the clinical experience in man that this drug does have sedating properties and significant interactions with drugs like ethanol and diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacological properties of Y-23684, a benzodiazepine receptor partial agonist.

1. The pharmacological properties of a benzodiazepine receptor (BZR) partial agonist, Y-23684 were investigated in comparison with those of diazepam, a conventional BZR full agonist. 2. Y-23684 and diazepam showed high and selective affinity for the BZR with Ki values of 41 and 5.8 nM, respectively. 3. In contrast to diazepam, variability was noted in the anticonvulsive potency of Y-23684 depending on convulsants (bicuculline, pentylenetetrazol and maximal electrical shock). Y-23684 produced the most potent protective effect against bicuculline in rats and mice with ED50S of 1.3 and 1.2 mg kg-1, respectively. 4. In rat conflict models (Geller-Seifter and water-lick tests), Y-23684 produced an antipunishment action at doses 2-4 times lower than diazepam. In contrast to diazepam, Y-23684 did not affect unpunished responding up to 50 mg kg-1 in the Geller-Seifter test. 5. In other rat models of anxiety (social interaction and elevated plus-maze tests), Y-23684 was as efficacious as and ten fold more potent than diazepam. In a mouse model of anxiety (exploration (light/dark box) test), Y-23684 was as efficacious and two fold less potent as diazepam. In these paradigms, Y-23684 showed a selective anxiolytic profile over a wide dose-range without loss of efficacy and sedative action. 6. The impairment of motor coordination (rotarod) and potentiation of CNS depressants (ethanol and hexobarbitone) by Y-23684 was much weaker than that of diazepam. 7. These results suggest that Y-23684 would be a potent and selective anxiolytic agent in man with less side-effects than conventional BZ-anxiolytics.     

A Comparative Study of the Effects of Sparteine,Lupanine and Lupin Extract on the Central Nervous System of the Mouse

Lupin is toxic because of its alkaloid content, sparteine and lupanine in particular. Although the pharmacological properties of sparteine are well known those of lupanine have not been much studied. This paper reports procedures for extraction, purification and crystallization of lupanine, and methods for the preparation of an extract for injection of Lupinus mutabilis Sweet, and for the determination of the acute toxicity and maximum non-lethal dose (DL0) of lupanine, sparteine and lupin extract in the mouse. The three substances were tested on the central nervous system (CNS) for locomotor activity, for interaction with specific drugs used for treatment of the CNS (the stimulant drugs amphetamine and pentetrazol and the depressant drugs pentobarbital and chlorpromazine) and for analgesic activity. The results indicate that lupanine and lupin extract are less toxic than sparteine and that at the doses studied the three products have a weak sedative effect on the CNS.