摘要:

AbstractIn benzodiazepine‐receptor binding assays using membrane preparations from rat brain cortex, the inhibitor affinity constants, K1, of clobazam and diazepam in displacing3H‐flunitrazepam binding are 170.0 and 7.0 nM, respectively. Thus, the in vitro activity of clobazam in the receptor assay does not seem to correlate with its in vivo potency. With both drugs, identical Hill coefficients (0.94) near unity have been obtained, indicating an equal affinity to possibly existing receptor subtypes under usual experimental conditions. When membrane suspensions in either sodium phosphate buffer or TRIS‐HCl buffer are preincubated at 60°C for 60 min, inactivation of one or two binding components (BZ1and BZ2, respectively) occurs. After preincubation in TRIS‐HCl, a third subtype (BZ3) of binding sites remains. Clobazam reveals a high affinity to subtype BZ3, similar to that of diazepam, but is much less active in displacing3H‐flunitrazepam from subtypes BZ1and BZ2, whereas diazepam also shows a high affinity to BZ1. The possible relevance of these findings is discussed, and an involvement of subtype BZ3in mediating anxiolytic drug effects is

ISSN:0272-4391    

DOI:10.1002/ddr.430010713

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe aim of the study was to investigate the effects of the 1,4‐benzodiazepine diazepam and the 1,5‐benzodiazepine clobazam on the inhibition of the isotonically recorded, electrically induced twitch contractions of the guinea pig and rat vas deferens preparations induced γ‐aminobutyric acid (GAB) (GABABreceptors) and adenosine (purine receptors). Both benzodiazepines (10−6− 10−5M) potentiated GABA, but clobazam was more potent. In contrast, diazepam (10−6− 3 × 10−5M) was more potent than clobazam in potentiating adenosine. Several other 1,4‐benzodiazepines were tested. These exhibited a wide range of potencies: the rank order for potentiating GABA differed from the potency order for potentiating adenosine. It is concluded that benzodiazepines, by an unknown mechanism, potentiate the effects of GABABreceptor stimulation. The mechanism is probably independent of the inhibition of adenosine uptake, which is responsible for potentiating pur

ISSN:0272-4391    

DOI:10.1002/ddr.430010714

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe relationship between the changes in gamma‐aminobutyric (GABA)‐ergic transmission elicited by the benzodiazepines and the anxiolytic activity and psychomotor deficits they induce was investigated. This was done by administering several anxiolytic and nonanxiolytic compounds to unstressed rats as well as rats exposed to the “open field” apparatus and measuring the resulting changes in GABA‐turnover in five brain regions. The anxiolytics were administered both acutely and chronically and at doses which induced psychomotor deficits as well as at doses which did not. It was found that “open field” exposure (an anxiety paradigm) increased GABA‐turnover in most of the brain areas studied, while anxiolytics tended to reduce GABA‐turnover in most regions even after chronic administration for 5 days. In contrast, nonanxiolytic compounds tended to increase GABA‐turnover, but to a lesser extent than “open field” exposure. In the cerebellum, unlike most of the brain areas studied, GABA‐turnover was reduced only when anxiolytics were given at doses which substantially decreased open field ambulation. On the basis of these data it is concluded that the GABA‐ergic system may mediate both the anxiolytic activity of the benzodiazepines and some of the psychomotor deficits they induce. It is postulated that the lack of psychomotor deficits elicited by clobazam may be attributable to the relatively high doses required to alter GABA‐turnover in the cerebellum as opposed to the brain area(s)

ISSN:0272-4391    

DOI:10.1002/ddr.430010715

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe pharmacodynamics and pharmacokinetics of the benzodiazepines are discussed and differences which may be important in the clinical situation are stressed. Clobazam, one of a new generation of benzodiazepines, is discussed in relation to the 1,4‐benzodiazepine

ISSN:0272-4391    

DOI:10.1002/ddr.430010716

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractMale rats were trained to emit responses on one lever after they were injected with pentylenetetrazol and a different lever when injected with saline in order to obtain food reinforcement. It was shown that the pentylenetetrazol action, which served as a cue for appropriate response selection, was predictive of anxiogenic activity. This cue was blocked by anxiolytic drugs in a dose‐dependent manner but not by anticonvulsant or depressant drugs. This procedure was shown to reliably predict elicitation of anxiogenicity or its blockad

ISSN:0272-4391    

DOI:10.1002/ddr.430010717

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractIn mice tested for 60 min in photometer‐activity boxes, an increased locomotor activity (+50% to +100%) was observed after administration of cocaine (4 mg/kg i.p.). Such hyperactivity was markedly enhanced by all benzodiazepines studied (flurazepam excepted), at doses which did not modify spontaneous motility: chlordiazepoxide (1 mg/kg), diazepam (1 to 2 mg/kg), clobazam (1 mg/kg), oxazepam (0.25 mg/kg), nitrazepam (0.03 to 0.25 mg/kg), flunitrazepam (0.015 mg/kg), clonazepam (0.004 mg/kg) and lorazepam (0.004 mg/kg). These doses are very low, e.g., 8 to 20 times lower than those required to antagonize the locomotor stimulation caused by cocaine. The increase of cocaine‐induced hypermotility elicited by nitrazepam (0.125 mg/kg i.p.) was reduced or suppressed by impairing gamma‐aminobutyric acid (GABA)‐ergic transmission with picrotoxin (0.25 mg/kg) or by blocking α or β adrenergic receptors with prazosin (1 mg/kg i.p.) or propranolol (4 mg/kg i.p.), respectively. At these doses neither picrotoxin, prazosin, nor propranolol modified the spontaneous locomotor activity or the hyperactivity induced by cocaine alone. These results suggest that benzodiazepines may exert their facilitatory activity on cocaine‐induced hyperactivity by interfering with some central catecholaminergic processes either directly or through the involvement of a GABA

ISSN:0272-4391    

DOI:10.1002/ddr.430010718

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractClobazam, a 1,5‐benzodiazepine, and diazepam, a 1,4‐benzodiazepine, were tested for their influence on motor activity and exploratory behavior in mice in an automatized hole‐board apparatus with two light beams (“Planche á trous”) and in a nonautomatized motility‐exploration (MOTEX) device, designed by Weischer 1976. Clobazam at oral doses of 5 to 80 mg/kg caused a marked increase in locomotion (79% to 122%) under MOTEX conditions, whereas results with the hole‐board device were inconsistent and misleading: Enhanced locomotion was represented as reduced motor activity in terms of light‐beam crossings. Exploratory behavior was reduced by clobazam in both MOTEX and Planche á trous at ED50 values of 33 and 67 mg/kg orally (p.o.), respectively. Diazepam at oral doses of 1 to 10 mg/kg slightly but not significantly increased locomotion in MOTEX and reduced motor activity in the hold‐board test (ED50 = 3.8 mg/kg). Exploratory behavior was inhibited under both conditions at ED50 values of 3.2 and 6.7 mg/kg p.o., respectively. The inability of a two light‐beam system to properly examine locomotor activity (particularly when peripheral areas of the apparatus are favored by the animals) is considered the reason for misleading results obtained with clobazam in the hold‐board test. The marked increase in locomotion induced by clobazam in a nonautomatized apparatus (MOTEX) is discussed in terms of disinhibitory effects in connection with the fact that clobazam does not induce amn

ISSN:0272-4391    

DOI:10.1002/ddr.430010719

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe aim of the study was to investigate antagonism of the rigidity produced by morphine in rats as a potential method for examining the muscle relaxant properties of benzodiazepines. The force required to displace the hind limbs by 1 cm was measured with an apparatus that was developed for measuring drug‐induced changes in the limb muscle tone of conscious, lightly restrained rats. Neither diazepam nor clobazam alone, in doses up to 3 mg/kg Intraperitoneal (IP), had any effects on limb muscle tone. Morphine (7.5 mg/kg) caused a rapid‐onset, sustained rigidity, which was partly reversed by diazepam at doses (0.2–0.5 mg/kg) that did not greatly potentiate morphine‐induced respiratory depression. In contrast, clobazam (0.2–0.5 mg/kg) had no effect on morphine rigidity. Several other 1,4‐benzodiazepines were tested in low doses. Both temazepam and lorazepam partly reversed morphine‐induced rigidity, whereas chlordiazepoxide, flurazepam, and clonazepam had no effect. It is concluded that antagonism of morphine rigidity might provide a sensitive method for comparing muscle relaxant properties of be

ISSN:0272-4391    

DOI:10.1002/ddr.430010720

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractEffects of the 1, 4‐benzodiazepines, nordiazepam (1.0–3.0 mg/kg) and temazepam (1.0–20.0 mg/kg), and of the 1,5‐benzodiazepine, clobazam (1.0–20.0 mg/kg), were studied on spatial delayed alternation and delayed matching‐to‐sample behaviour in the monkey (Macaca mulatta). Nordiazepam and temazepam impaired correctness of response on both tasks though at different dose levels (nordiazepam10.0 mg/kg). Clobazam (3.0 mg/kg), but not its metabolite desmethylclobazam (3.0–15.0 mg/kg), impaired correctness of response on delayed matching‐to‐sample, though clobazam up to 20.0 mg/kg was without effect on spatial delayed alternatin. Increased response time may be related, at least in part, to complexity of response, but a differential effect between tasks on correctness of response is likely

ISSN:0272-4391    

DOI:10.1002/ddr.430010721

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY

摘要:

AbstractThe growing utility of performance tests in the evaluation of psychoactive compounds is noted. Studies of drug effect in cerebrally impaired alcoholics demonstrated many difficulties with available tests. Assumptions about lateralisation of function have been examined with a novel visual/verbal memory test that indicates the importance of interhemispheric association. An apparatus has been developed to test inter‐ and intrahemisphere organisation. Naive subjects showed a range of thresholds corresponding to the amount of pathways involved, but on retest all thresholds fell and approximated. Single doses of diazepam and clobazam seemed to produce the greatest reduction, but numbers are too small for significance. The importance of cognitive factors, the theoretical implications, and the possible relevance for psychopharmacology are examine

ISSN:0272-4391    

DOI:10.1002/ddr.430010722

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1982

数据来源: WILEY