Electroencephalographic study with buspirone, a novel nonbenzodiazepine anxiolytic, and its major metabolite, 1-(2-pyrimidinyl)piperazine (1-PP), in rabbits

The electroencephalographic (EEG) effects of buspirone and its major metabolite, 1-(2-pyrimidinyl)piperazine (1-PP), were investigated in rabbits with chronic electrode implants, and the effects were compared with those of diazepam. Intravenous administration of buspirone at 0.1 to 1.0 mg/kg evoked an increase in the arousal EEG pattern period (low amplitude fast waves) in the cortical EEG and synchronization of the hippocampal theta waves with decreased voltages, whereas both 1-PP (0.5 to 2.0 mg/kg, i.v.) and diazepam (1.0 and 2.0 mg/kg) evoked an increase in the drowsy EEG pattern periods: high voltage slow waves and spindle bursts in the cortical EEG and desynchronization of the hippocampal theta waves. Buspirone at higher doses caused behavioral excitation in rabbits, whereas both 1-PP and diazepam produced sedation. Buspirone did not affect EEG arousal responses to both auditory stimulation (2,000 Hz, monotone) and electrical stimulation (100 Hz, 0.1 msec, 3-6 V) of the midbrain reticular formation or the posterior hypothalamus. However, 1-PP tended to inhibit the EEG arousal response to auditory stimulation but not brain stimulation, and diazepam markedly suppressed the responses induced by both stimulations. The recruiting response induced by centromedian thalamic stimulation at a low frequency (7 Hz, 0.1 msec, 4-8 V) was not affected by buspirone, 1-PP and diazepam. Neither buspirone nor 1-PP had an effect on the photic driving response to a flash light (2 Hz) in the occipital cortex of the rabbit, whereas the response was suppressed by diazepam. Both buspirone and 1-PP enhanced the duration of after discharges induced by electrical stimulation (50 Hz, 0.5 msec, 4-15 V) of the dorsal hippocampus, whereas diazepam markedly inhibited the afterdischarges. These results suggest that the EEG effect of buspirone is quite different to those of 1-PP and diazepam in qualitative aspects. It is also suggested that buspirone, unlike diazepam, is an effective anxiolytic drug without a sedative effect.     

Effects of DN-2327, a new anxiolytic,diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze

In the present study, the effects of a new anxiolytic, DN-2327, were compared to those of diazepam and buspirone in rats in the elevated plus-maze test. Two indices of anxiety were obtained in this test: the number of entries into the open arms expressed as a percentage of the total number of arm entries and the percentage of time spent on the open arms. Both a typical anxiolytic, diazepam, at 2.5, 5 and 10 mg/kg, PO and a new anxiolytic, DN-2327, at 2.5 and 5 mg/kg, PO dose-dependently increased the two indices: the percentage of time spent on the open arms and the percentage of open-arm entries. On the other hand, pentylenetetrazol (PTZ) at 10 and 20 mg/kg, IP decreased the two indices dose dependently as did yohimbine at 1.5 and 3 mg/kg, IP. DN-2327 at 2.5 and 5 mg/kg, PO and diazepam at 5 and 10 mg/kg, PO dose dependently and significantly increased the two indices that were suppressed following administration of PTZ at 10 mg/kg, IP. The effects of both DN-2327, 5 mg/kg, PO, and diazepam, 10 mg/kg, PO, on the two indices were significantly antagonized by the benzodiazepine (BZD) receptor antagonist flumazenil, 20 mg/kg, IP. Buspirone (2.5–20 mg/kg, PO) did not affect either of the two responses but dose dependently decreased the number of rearings, although in the Vogel conflict test, the anti-conflict activity of buspirone was equipotent to that of diazepam and DN-2327 at the minimum effective dose (10 mg/kg, PO) of each drug. In conclusion, the present experiment revealed that the anxiolytic effect of DN-2327 in this test was clear, whereas buspirone showed no apparent effect.     

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.     

Acute and subacute effects of diazepam on psychomotor skills: interaction with alcohol.

Effects of diazepam and alcohol on psychomotor skills were measured in two trials. In the first one, 200 healthy students volunteered for a double-blind single-dose study. Three doses of diazepam (5, 10 and 20 mg) and alcohol (0.5, 0.8 and 1.2 g/kg) were used alone and combined to construct dose-response graphs. All doses of alcohol impaired divided attention while co-ordinative skills were impaired by the 1.2 g/kg dose. Diazepam alone did not impair reactive or co-ordinative skills whereas the combinations of diazepam and alcohol did so. To further elucidate the subactue effects, a double-blind randomized study was conducted administering 2 and 10 mg of diazepam t.i.d. for two weeks to 18 healthy volunteers. The psychomotor tests were performed on the 7th and 14th days of drug administration, and 0.5 g/kg of alcohol was given on either day. Diazepam 2 mg, alone or with alcohol, did not differ from placebo. 10 mg of diazepam slightly increased reaction times but not reaction mistakes, and impaired both co-ordination and attention. Alcohol did not enhance diazepam effects. We suggest that a development of tolerance to diazepam may compensate the deleterious interaction of the agents found in acute studies.     

Conditioned taste aversion and place preference with buspirone and gepirone

The effects of the nonbenzodiazepine anxiolytics buspirone and gepirone were compared to diazepam at 1, 3, and 10 mg/kg using the conditioned taste aversion (CTA) paradigm. Buspirone and gepirone produced stronger CTA than diazepam (3 and 10 mg/kg) across repeated conditioning trials, indicating that these nonbenzodiazepine anxiolytics may have stronger aversive properties than diazepam. The effects of buspirone and gepirone (1 and 3 mg/kg) were also assessed using the conditioned place preference (CPP) paradigm. Both buspirone (1 and 3 mg/kg) and gepirone (3 mg/kg only) produced CPP, indicating that these drugs may have rewarding properties, and that buspirone is more potent than gepirone in producing CPP. These findings demonstrate that buspirone and gepirone have affective properties similar to abused drugs, and may therefore have abuse potential. It was also demonstrated that buspirone (3 mg/kg), but not gepirone (3 mg/kg), increased dopamine (DA) synthesis in the nucleus accumbens, a mesolimbic brain area thought to be involved in drug reward.     

Hyponeophagia and arousal in rats: Effects of diazepam, 5-methoxy-N,N-dimethyltryptamine,d-amphetamine and food deprivation

A modified hyponeophagia test is described as an animal model of anxiety. The effects of 0, 0.3, 1.0, 3.0 and 10 mg/kg diazepam, given both acutely and for 7 days pretest, were assessed in rats. Acutely, diazepam reduced hyponeophagia over the dose range 0.3–3.0 mg/kg but 10.0 mg/kg produced sedation and large variability. Chronically, the dose-response relationships were monotonic and the maximal effect was increased, suggesting that differential tolerance occurs to the sedative, but not to the anxiolytic, effects of this drug. Increased food deprivation did not mimic benzodiazepine effects on hyponeophagia, and actually prolonged eating latency in rats treated with 5-methoxy-N,N-dimethyltryptamine (2.5 mg/kg), which does not support an interpretation of diazepam effects in terms of appetitive actions. An arousal hypothesis of hyponeophagia was proposed and supported by the antagonism of the sedative effects of 10.0 mg/kg diazepam by d-amphetamine (0.5 mg/kg). Although both male and female rats were used throughout, sex differences were few in these studies.     

Buspirone and lorazepam abuse liability in humans: behavioral effects, subjective effects and choice

This study compared behavioral and subjective effects of two anxiolytics, the benzodiazepine lorazepam and the azaspirodecanedione buspirone, in healthy male volunteers with histories of sedative drug abuse. Placebo, lorazepam (1, 2, 4, 8mg/70kg) and buspirone (15, 30, 60, 120mg/70kg) were administered p.o. in a mixed sequence in a double-blind, cross-over design. Lorazepam, but not buspirone, decreased psychomotor/cognitive performance. Both drugs produced similar increases in ratings of drug strength, however the onset and offset times for lorazepam were later than for buspirone. Lorazepam increased ratings of liking in contrast to buspirone which produced negative mood-related subjective effects (e.g. increases in ratings of disliking, bad/unpleasant effects, and tension-anxiety). Lorazepam was categorized by subjects as producing effects similar to barbiturates or benzodiazepines in contrast to buspirone which was not. When subjects were given a choice between self-administering an intermediate dose of lorazepam (4mg/70kg) or buspirone (60mg/70kg), which produced similar ratings of drug strength, eight out of nine subjects chose lorazepam. This study provides the clearest human experimental evidence to date that the abuse liability of buspirone is lower than that of a prototypic benzodiazepine, even at supratherapeutic doses.     

Acute and Subacute Effects of Diazepam on Psychomotor Skills: Interaction with Alcohol

Abstract Effects of diazepam and alcohol on psychomotor skills were measured in two trials. In the first one, 200 healthy students volunteered for a double-blind single-dose study. Three doses of diazepam (5, 10 and 20 mg) and alcohol (0.5, 0.8 and 1.2 g/kg) were used alone and combined to construct dose-response graphs. All doses of alcohol impaired divided attention while co-ordinative skills were impaired by the 1.2 g/kg dose. Diazepam alone did not impair reactive or co-ordinative skills whereas the combinations of diazepam and alcohol did so. To further elucidate the subacute effects, a double-blind randomized study was conducted administering 2 and 10 mg of diazepam t.i.d. for two weeks to 18 healthy volunteers. The psychomotor tests were performed on the 7th and 14th days of drug administration, and 0.5 g/kg of alcohol was given on either day. Diazepam 2 mg, alone or with alcohol, did not differ from placebo. 10 mg of diazepam slightly increased reaction times but not reaction mistakes, and impaired both co-ordination and attention. Alcohol did not enhance diazepam effects. We suggest that a development of tolerance to diazepam may compensate the deleterious interaction of the agents found in acute studies.     

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.     

Electroencephalographic study with SC-48274, a novel nonbenzodiazepine anxiolytic in conscious rabbits]

The electroencephalographic (EEG) effects of SC-48274 were investigated in conscious rabbits and compared with those of buspirone and diazepam. SC-48274 (20-30 mg/kg, i.v.) evoked an increase in drowsy EEG pattern period. Diazepam (2-3 mg/kg, i.v.) also increased the drowsy EEG pattern, while buspirone (0.5 mg/kg, i.v.) increased the arousal EEG pattern period. Neither SC-48274 nor buspirone affected the EEG arousal response to both auditory stimulation and electrical stimulation of the midbrain reticular formation of the posterior hypothalamus, while diazepam markedly suppressed the responses to both stimulations. The recruiting response to centromedian thalamic stimulation was not significantly affected by SC-48274 and buspirone, and it was slightly enhanced by diazepam. Neither SC-48274 nor buspirone had any effect on the photic driving response to flash light in the occipital cortex, while the response was markedly suppressed by diazepam. The duration of afterdischarges induced by electrical stimulation of the dorsal hippocampus was slightly inhibited by SC-48274 and markedly inhibited by diazepam, while buspirone enhanced the duration. These results suggest that the EEG effect of SC-48274 is quite different to those of buspirone and diazepam with respect to the qualitative aspects. We also suggest that SC-48274, unlike diazepam, is an effective anxiolytic drug with weak sedation.     

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.     

Discriminative stimulus effects of alprazolam and diazepam: generalization to benzodiazepines, antidepressants and buspirone

Rats in one group were trained to discriminate alprazolam (1.0mg/kg, i.p.) and in another group diazepam (3.0mg/kg, i.p.) from saline in a two-lever drug discrimination procedure. Food presentation occurred after 10 consecutive responses on the lever associated either with the training drug or with saline. Alprazolam, diazepam, lorazepam and chlor diazepoxide increased responding on the drug-associated lever in a comparable dose-related manner in both groups of rats: the relative order of potency was lorazepam >/= alprazolam > diazepam >/= chlordiazepoxide. Flumazenil (10.0mg/kg, i.p.) attenuated the effects of the training drugs. A range of doses of buspirone and four drugs having antidepressant properties (amitriptyline, fluoxetine, cericlamine, imipramine) then were studied in both groups of rats. All five drugs caused approximately 40% increases (group mean) in drug-appropriate responding in alprazolam-trained rats whereas only amitriptyline partially substituted for diazepam. The results indicate that alprazolam has interoceptive stimulus effects that overlap with the stimulus effects of diazepam, yet the effects of alprazolam may not be identical to those of diazepam because the antidepressant drugs and buspirone substituted partially for alprazolam but generally not for diazepam.     

Effects of buspirone, diazepam, and zolpidem on open field behavior, and brain [3H]muscimol binding after buspirone pretreatment

The effects of 5-HT(1A) receptor agonist buspirone, a nonselective (diazepam), and a selective (zolpidem) GABA(A) receptor agonist were compared in the open field test of neophobia. Unhabituated rats were pretreated with the drugs once, prior to a first exposure to the open field, and their behavior was recorded both during this test and during a second trial 24 h later. It has been hypothesized that the decrease in exploratory activity observed during the second test session may be considered an adaptive reaction to the first day aversive experience (neophobia). If so, a selective modulation of 5-HT and GABA systems activity during the test could bring about significant changes in animal behavior on the retest. Buspirone at the lowest dose of 0.3 mg/kg revealed anxiolytic-like properties on the first day, whereas the action of diazepam and zolpidem was modulated by the dose-related sedative effect. At the dose of 2.4 mg/kg buspirone elicited delayed in time anxiolytic-like action, i.e., produced the antithigmotactic effect during the retrial 24 h later. Diazepam and zolpidem failed to exhibit similar profile of action. Autoradiography of [3H]muscimol binding after pretreatment of rats with buspirone showed a significant increase in the selective radioligand binding within the frontal cortex and a similar, near-significant tendency in the dentate gyrus of the hippocampus. The behavioral data validate buspirone as important drug for the treatment of anxiety disorders, devoid of disruptive influence on motor and cognitive processes. The open field test, as modified by us, appeared sensitive in distinguishing the behavioral profiles of action of different anxiolytic compounds, including 5-HT(1A) receptor agonist. The present results support the assumption that reduced turnover of 5-HT due to stimulation of 5-HT(1A) autoreceptors, may bring about changes in GABA(A) receptor system activity, in some brain structures, leading to the anxiolytic effect.     

The psychopharmacological effects of premazepam, diazepam and placebo in healthy human subjects.

Pharmacological studies of premazepam in animals predicted antianxiety activity without sedation and, in combination with diazepam, a reduction in the sedative effects of the latter. The effects of single doses of premazepam (25 and 50 mg), diazepam (10 mg), premazepam (25 mg) plus diazepam (10 mg), and a placebo on subjective feelings, psychological tests and the EEG were studied in a double-blind cross-over study in 10 healthy subjects. In a repeated dose study in eight subjects, the effects on subjective feelings, psychological tests and the EEG of premazepam (5 and 10 mg twice-daily), diazepam (5mg twice-daily) and a placebo were compared. Premazepam had a different EEG profile from diazepam, producing more slow and less fast wave activity. In the single dose study its effects were similar to diazepam for sedative action and most of the psychological tests, with a tendency towards greater psychomotor impairment. In the repeated dose study, however, premazepam caused less sedation and also tended to produce less psychomotor impairment. The combination dose of premazepam (25 mg) plus diazepam (10 mg) in the single dose study indicated an additive effect rather than an antagonistic one.     

Effects of diphenylhydantoin and diazepam on hippocampal evoked responses

Diphenylhydantoin and diazepam were compared with regard to their effects on responses to single stimuli, and on post-tetanic potentiation of evoked potentials within the hippocampus of anaesthetized rats. Interhippocampal afferents to pyramidal cells were stimulated electrically, while extracellular field potentials were recorded at successive depths within the contralateral hippocampus. Recording electrodes penetrated perpendicularly from a surface point homotopic to the site of stimulation. The anticonvulsants (40 mg/kg diphenylhydantoin, 5 mg/kg diazepam), 30 min after intravenous infusion, depressed post-tetanic potentiation in the stratum radiatum. At these doses, responses to single stimuli were essentially unaltered. Doses nearer the toxic range (80 mg/kg diphenylhydantoin, 10 mg/kgdiazepam) also reduced post-tetanic potentiation in the stratum radiatum, but increased (up to 150%) post-tetanic potentiation recorded from granule cells in the area dentata. The results indicate that diphenylhydantoin and diazepam have: (1) selective actions on hippocampal post-tetanic potentiation which are site and dose dependent; (2) qualitatively similar end-effects on post-tetanic potentials in two hippocampal subregions; (3) minimal effects on responses to single stimuli at doses which depress or enhance hippocampal post-tetanic potentiation.     

Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure

The discriminative stimulus effects of buspirone and diazepam were examined in 12 healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 15 mg/70 kg buspirone, and 10 mg/70 kg diazepam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made two hours after drug administration. Ten out of 12 subjects acquired the three-response discrimination. When lower doses of buspirone (3.75 and 7.5 mg/70 kg) and diazepam (2.5 and 5.0 mg/70 kg) were tested in a subsequent generalization testing phase, both buspirone and diazepam produced dose-related increases in appropriate drug identifications, without significant cross-generalization. Analyses of standardized and unstructured self report questionnaires revealed that buspirone and diazepam produced different profiles of effects, and that buspirone was associated with a number of “negative” subject-rated effects including tension, nausea, and dizziness. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for buspirone relative to diazepam which is consistent with its distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure. Received: 7 July 1997/Final version: 18 December 1997     

Effects of buspirone and gepirone on IV cocaine self-administration in rhesus monkeys

Buspirone and gepirone were evaluated as potential pharmacotherapies for cocaine abuse by studying the effects of acute and repeated treatment on IV cocaine self-administration in rhesus monkeys. Chlorpromazine was also evaluated as a positive control. Effects of IV drug pretreatments were tested during daily 60-min sessions with lever-pressing reinforced under a fixed-ratio 10 schedule of 0.02 or 0.05 mg/kg cocaine infusions. Acute pretreatment with buspirone (0.1 and 0.3 mg/kg, IV) increased rates of cocaine self-administration without disrupting food pellet consumption. Some doses of buspirone also produced changes in rates of cocaine self-administration without altering the within-session pattern of responding. In contrast, acute doses of gepirone had little effect on rates of cocaine self-administration, while disruptions in food consumption and changes in the within-session pattern of cocaine self-administration were obtained at the highest dose of gepirone tested (1.0 mg/kg). When either buspirone (0.1 and 0.3 mg/kg, IV) or gepirone (0.1 mg/kg, IV) were administered daily for 10 days, consistent effects on cocaine self-administration were not observed. Thus, the effects of acute buspirone administration on cocaine-maintained behavior were similar to the effects produced by chlorpromazine and other dopaminergic antagonists, whereas, gepirone was ineffective. These results provide some support for further evaluation of buspirone as a potential pharmacotherapy for cocaine abuse, although its lack of efficacy with repeated treatment is not encouraging. The negative results with gepirone provide less rationale for continued investigations with this drug, possibly because of its lesser involvement than buspirone with dopaminergic neurotransmission.     

Preference for diazepam,but not buspirone,in moderate drinkers

The purpose of the present study was to determine the preference for buspirone, an anxiolytic predicted to have minimal abuse potential, in comparison with diazepam in moderate drinkers. Preference for diazepam and buspirone was assessed in 55 moderate drinkers using a seven-session procedure consisting of four sampling sessions followed by three choice sessions. On each sampling session subjects ingested five capsules, one every 30 min. Color-coded capsules contained placebo on two sessions and drug on two sessions. Each drug capsule contained diazepam (4 mg) for 30 subjects and buspirone (5 mg) for 25 subjects. On choice sessions subjects chose whichever of the two color-coded capsules, i.e., drug or placebo, they wished to take. After ingesting one capsule, every 30 min they had the option of ingesting another capsule of the same color and content, for a maximum of seven capsules over the session (maximum of 28 mg diazepam or 35 mg buspirone). In the diazepam group 70% of subjects chose diazepam over placebo on at least two of the three choice sessions, whereas in the buspirone group only 24% of subjects chose buspirone over placebo on at least two sessions. Both diazepam and buspirone increased measures of sedation. Only diazepam increased ratings of liking and impaired performance, whereas only buspirone decreased ratings of feeling Friendly. These results replicate previous findings indicating that diazepam has reinforcing effects in moderate drinkers. Further, these results demonstrate the pharmacological specificity of this effect by showing that buspirone did not function as a reinforcer under these same conditions.     

3-(Methoxycarbonyl)-amino-beta-carboline reduces both the sedative and anticonvulsant effects of diazepam

The intrinsic effects of the benzodiazepine receptor ligand beta-CMC (3-(methoxycarbonyl)-amino-beta-carboline) and its interaction with the anticonvulsant and sedative effects of diazepam were assessed. beta-CMC (100 mg/kg i.p.) significantly elevated seizure threshold to bicuculline. beta-CMC (10 mg/kg) failed to alter the anticonvulsant action of diazepam (5 mg/kg i.p.), but significantly attenuated diazepam's sedative effect. A higher dose of beta-CMC (40 mg/kg) did attenuate diazepam's anticonvulsant action. The data suggest that beta-CMC is a partial agonist at benzodiazepine receptors.     

Isobolographic analysis of the sedative interaction between six central nervous system depressant drugs and Valeriana edulis hydroalcoholic extract in mice

It has been declared frequently that valerian may potentiate the effect of other central nervous system (CNS) depressant drugs, however there has been a lack of experimental data. We have evaluated the profile of the interactions between the ethanol extract of Valeriana edulis spp procera and six CNS depressant drugs using an exploratory model to test the sedative effect in mice. All the compounds tested showed a dose-dependent sedative effect with the following ED50 values: valerian 181.62, diazepam 1.21, ethanol 1938, pentobarbital 11.86, buspirone 1.04, haloperidol 0.41 and diphenhydramine 17.06 mg kg-1. An isobolographic analysis was used to evaluate the sedative interaction of the intraperitoneal co-administration of 1:1 fixed-ratio combination of equi-effective doses of valerian extract with each CNS depressant drug. The ED50 theoretical (Zadd) and experimental (Zexp) for each combination were: valerian+diazepam,Zadd=91.41 mg kg-1, Zexp=81.64 mg kg-1; valerian+ethanol, Zadd=1060.22 mg kg-1, Zexp=687.89 mg kg-1; valerian+pentobarbital, Zadd=96.74 mg kg-1, Zexp=151.83 mg kg-1; valerian+buspirone, Zadd=91.33 mg kg-1, Zexp=112.73 mg kg-1; valerian+haloperidol, Zadd=91.01 mg kg-1, Zexp=91.52 mg kg-1; valerian+diphenhydramine, Zadd=99.34 mg kg-1, Zexp=123.52 mg kg-1. Neither synergistic nor attenuate effects were found in any of the combinations evaluated. We concluded that the valerian extract did not potentiate the sedative effect of commonly prescribed CNS depressant drugs as was expected. The additive effect found through the isobolographic analysis suggested that the sedative effect of V. edulis resulted from the activation of common mechanisms of haloperidol, diazepam, buspirone, pentobarbital, diphenhydramine and ethanol.