Pharmacology of Benzodiazepines: Laboratory and Clinical Correlations

Zbinden, G.; Randall, Lowell O.

doi:10.1016/s1054-3589(08)60658-4

Cited by 254 publications

(69 citation statements)

References 95 publications

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“…It was quite clear, however, when plotting dose-response curves for death (Figure 2c (Young et al, 1974). Although relatively high doses of diazepam (16 mg/kg orally) have been reported to inhibit strychnine convulsions in mice (see Zbinden & Randall, 1967), Costa et al (1975) The affinity of strychnine for its binding site in vitro is three orders of magnitude greater than that of glycine (Young & Snyder, 1973), and under the experimental conditions used (rat crude synaptic membrane fractions, 2 nM strychnine, 4°C) glycine and diazepam were of comparable potency in reducing strychnine binding, half maximum inhibition occurring with concentrations of 25 gM and 26 gM respectively (Young et al, 1974). Thus if diazepam mimics the postsynaptic action of glycine (or strychnine) and interferes with strychnine binding the present investigation might have been expected to have revealed a modification in the effectiveness of strychnine as a glycine antagonist and as a convulsant.…”

Section: Spinal Interneuronesmentioning

confidence: 98%

Benzodiazepines and Central Glycine Receptors

Curtis

Game

Lodge

1976

British J Pharmacology

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In cats, anaesthetized with pentobarbitone, intravenous diazepam (minimum dose 3.0 mg/kg) enhanced dorsal root potentials but did not significantly diminish the reduction by electrophoretic strychnine of the inhibitory action of electrophoretic glycine on dorsal horn interneurones. In mice, intraperitoneal diazepam (2.5 mg/kg) had no appreciable effect on the potency of strychnine as a convulsant, although providing some protection against bicuculline. These observations, together with the failure of chlordiazepoxide to either inhibit the firing of spinal interneurones or reduce antagonism between strychnine and glycine when administered locally, provide no support for the interaction between benzodiazepines and mammalian central glycine receptors which has been proposed on the basis of in vitro studies of strychnine binding.

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Section: Spinal Interneuronesmentioning

confidence: 98%

Benzodiazepines and Central Glycine Receptors

Curtis

Game

Lodge

1976

British J Pharmacology

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“…They preferentially explore the enclosed arms of an elevated maze when presented with a choice between enclosed and open arms, and they will spend more time in the dark side of a shuttle box in which one side is dark, and one side is brightly illuminated (Crawley and Goodwin, 1980). These behaviors are altered by administration of drugs that humans report are anxiolytic (eg diazepam; Barrett and DiMascio, 1966;McDowall et al, 1966;Zbinden and Randall, 1967) or anxiogenic (eg FG 7142;Dorow, 1987), and so these behaviors have been widely used in assays to evaluate the anxiety-modulating effects of drugs and other manipulations. Anxiolytic drugs increase, and anxiogenic drugs decrease exploration of the open arms of the elevated plus maze (Handley and Mithani, 1984;Pellow and File, 1986), the central region of an open field (Hughes, 1972;Stefanski et al, 1992;Plaznik et al, 1994;Simon et al, 1994), and the lighted compartment of a dark-light shuttle box (Crawley and Goodwin, 1980;Costall et al, 1989;Onaivi and Martin, 1989;Chaouloff et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Nociceptin/Orphanin FQ Increases Anxiety-Related Behavior and Circulating Levels of Corticosterone During Neophobic Tests of Anxiety

Fernandez

Misilmeri

Felger

et al. 2003

Neuropsychopharmacol

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Intracranial administration of nociceptin/orphanin FQ (N/OFQ) increases circulating concentrations of adrenocorticotrophic hormone and corticosterone in unstressed rats, and elevates the responsiveness of these hormones during mild stress. Furthermore, N/OFQ and its cognate receptor are both abundant in a variety of limbic nuclei, and stress exposure decreases neuronal N/OFQ content in forebrain neurons. In light of these and other findings, we examined the potential involvement of N/OFQ in regulation of anxiety-related behaviors in rats. In the open field, elevated plus maze, and dark-light neophobic tests, intracerebroventricular N/OFQ (1.0 pmole-1.0 nmole) increased the expression of anxiety-related behaviors. Specifically, N/OFQ increased the latency to enter, decreased the number of entries into, and decreased the time spent in the exposed or brightly lit environments of all three tests. N/OFQ also enhanced thigmotactic responses in the open field test. The effects of diazepam and of the benzodiazepine inverse agonist FG 7142 were also assessed in independent groups of rats. In all three tests, the behavioral effects of N/OFQ resembled the anxiogenic actions of FG 7142, and contrasted with the anxiolytic actions of diazepam. N/OFQ administration also increased circulating concentrations of corticosterone during anxiety testing, in comparison with the concentrations in vehicle-treated controls. We conclude that N/OFQ administration is anxiogenic, and elevates responsiveness of the hypothalamic pituitary-adrenal axis during neophobic tests of anxiety. This supports the possibility that N/OFQ neurotransmission participates in processing of emotionally-salient and stressful stimuli, and suggests that normal functioning of the N/OFQ system may be important in physiological and psychological well-being.

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“…It was also reported that doses of benzodiazepine which did not affect the alpha motor system depressed gamma rigidity (19). Many investigators have postulated that the mechanism of nitrazepam or diazepam producing skeletal muscle relaxation is due to an inhibitory action on the brain stem reticular formation, most likely on the reticular facilitatory system (13,20,21).…”

Section: Discussionmentioning

confidence: 99%

EFFECTS OF NEW s-TRIAZOLOBENZODIAZEPINE (D-40TA) AND OTHER CENTRAL MUSCLE RELAXANTS ON SPINAL AND SUPRASPINAL REFLEXES IN CATS

Chiba

Nagawa

1973

Jpn.J.Pharmacol

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Abstract-The inhibitory effect of benzodiazepine-type agents such as 8-chloro-6-phenyl-4H-s-triazolo [4, 3a] [1, 4] benzodiazepine (D-40TA), diazepam and nitrazepam on the spinal and supraspinal polysynaptic reflexes was compared with that of mephenesin, methocarbamol, chlorzoxazone and chlormezanone in cats. Benzodiazepines did not depress the spinal and supraspinal polysynaptic reflexes or reflex potentials in the spinal and the gallamine-immobilized cats. In these respects, chlormezanone resembled benzodiazepines.On the other hand, mephenesin, methocarbamol and chlorzoxazone blocked these reflexes in all kinds of preparations such as the anesthetized, the spinal, the decerebrate and the gallamine-immobilized preparations. D-40TA depressed gamma rigidity at the dose below that necessary to depress alpha rigidity. Moreover, it inhibited more profoundly the tonic stretch reflex than the phasic one. Spontaneous and evoked discharges of the muscle spindle in the decerebrate cat were significantly depressed by D-40TA, while those of spinal cat were unaffected. These results suggest that skeletal muscle relaxation by benzodiazepines including D-40TA is attributed to the primary depression of the brain stem reticular system and in turn the ascending inhibitory action via the gamma system on the spinal and supraspinal polysynaptic neurons. It should be stressed that the integrity of the connection between the brain stem and gamma system in the spinal cord and its related muscles is also required for eliciting the depression of supraspinal polysynaptic reflex by these agents. Mephenesin-type agents presumably inhibit directly the interneurons at the spinal and supraspinal levels. Later, the benzodiazepine agents have been found to possess tranquilizing and muscle relaxant properties. The depression of polysynaptic spinal reflexes by diazepam, one of these benzodiazepines, has been proposed to be due to the action principally on the brain stem reticular formation, on the basis of the finding that spinal polysynaptic depression in decerebrate cats is nullified by spinal transection (3).Our current study on the benzodiazepines led to the discovery of a new type of compound, 8-chloro-6-phenyl-4H-s-triazolo [4, 3a] [1, 4]-benzodiazepine (D-40TA) which was highly active in tranquilizing, sedative-hypnotic and muscle relaxant effects in experimental animals (4). In our neuropharmacological study on this agent, the depression of

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Pharmacology of Benzodiazepines: Laboratory and Clinical Correlations

Cited by 254 publications

References 95 publications

Benzodiazepines and Central Glycine Receptors

Benzodiazepines and Central Glycine Receptors

Nociceptin/Orphanin FQ Increases Anxiety-Related Behavior and Circulating Levels of Corticosterone During Neophobic Tests of Anxiety

EFFECTS OF NEW s-TRIAZOLOBENZODIAZEPINE (D-40TA) AND OTHER CENTRAL MUSCLE RELAXANTS ON SPINAL AND SUPRASPINAL REFLEXES IN CATS

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