Chronic Administration Of Diazepam Research Articles

A neuroendocrine approach to benzodiazepine tolerance and dependence.

British Journal of Clinical PharmacologyVolume 11, Issue 5 p. 526-528 Free Access A neuroendocrine approach to benzodiazepine tolerance and dependence. H Petursson, H PeturssonSearch for more papers by this authorE Shur, E ShurSearch for more papers by this authorS Checkley, S CheckleySearch for more papers by this authorA Slade, A SladeSearch for more papers by this authorMH Lader, MH LaderSearch for more papers by this author H Petursson, H PeturssonSearch for more papers by this authorE Shur, E ShurSearch for more papers by this authorS Checkley, S CheckleySearch for more papers by this authorA Slade, A SladeSearch for more papers by this authorMH Lader, MH LaderSearch for more papers by this author First published: May 1981 https://doi.org/10.1111/j.1365-2125.1981.tb01164.xCitations: 7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References FIORETTI, P., MELIS, G.B., PAOLETTI, A.M., PARODO, G., CAMINITI, F., CORSINI, G.U. & MARTINI, L. (1978). γ-amino-β-hydroxy butyric acid stimulates prolactin and growth hormone release in normal women. J. clin. Endocrinol. Metab., 47, 1336– 1340. FRUENSGAARD, K. (1976). Withdrawal psychosis: A study of 30 consecutive cases. Acta psychiat. Scand., 53, 105– 118. GREENBLATT, D.J. & SHADER, R.I. (1979). Dependence, tolerance, and addiction to benzodiazepines: clinical and pharmacokinetic considerations. Drug Metab. Rev., 8, 13– 28. GREENBLATT, D.J., WOO, E., ALLEN, M.D., ORSULAK, P.J. & SHADER, R.I. (1978). Rapid recovery from massive diazepam overdose. J. Am. med. Ass., 240, 1872– 1874. HALLSTROM, C. & LADER, M.H. (1981). Benzodiazepine withdrawal phenomena. Int. pharmac. (in press). HOLLISTER, L., MOTZENBECKER, F. & DEGAN, R. (1961). Withdrawal reactions from chlordiazepoxide (Librium). Psychopharmacology, 2, 63– 68. KOULU, M., LAMMINTAUSTA, R. & DAHLSTRÖM, S. (1979). Stimulatory effect of acute Baclofen administration on human growth hormone secretion. J. clin. Endocrinol. Metab., 48, 1038– 1039. LADER, M.H., BAKER, W.J. & CURRY, S. (1980). Physiological and psychological effects of chlorazepate in man. Br. J. clin. Pharmac., 9, 83– 90. MÖHLER, H., OKADA, T. & ENNA, S.J. (1978). Benzodiazepine and neurotransmitter receptor binding in rat brain after chronic administration of diazepam or phenobarbital. Brain Res., 156, 391– 395. PRESKORN, S.H. & DENNER, L.J. (1977). Benzodiazepines and withdrawal psychosis. J. Am. med. Ass., 237, 36– 38. SYVÄLAHTI, E.K.G. & KANTO, J.H. (1975). Serum growth hormone, serum immunoreactive insulin and blood glucose response to oral and intravenous diazepam in man. Int. J. clin. Pharmac., 12, 74– 82. TAKAHARA, J., YUNOKI, S., YAKUSHIJI, W., YAMAUCHI, J., YAMANE, Y. & OFUJI, T. (1977). Stimulatory effects of γ-hydroxy-butyric acid on growth hormone and prolactin release in humans. J. clin. Endocrinol. Metab., 44, 1014– 1017. TAMMINGA, C.E., EOPHYTIDES, A., CHASE, T.N. & FROHMAN, L.A. (1978). Stimulation of prolactin and growth hormone secretion by muscimol a γ-amino-butyric acid agonist. J. clin. Endocrinol. Metab., 47, 1348– 1351. VELLUCCI, S.V. & FILE, S.E. (1979). Chlordiazepoxide loses its anxiolytic action with long-term treatment. Psychopharmacology, 62, 61– 65. Citing Literature Volume11, Issue5May 1981Pages 526-528 ReferencesRelatedInformation

P-188) - Alterations in trie central nervous system induced by chronic administration of diazepam during an early postnatal period in rats

P-188) - Alterations in trie central nervous system induced by chronic administration of diazepam during an early postnatal period in rats

Disposition of intravenous diazepam in young men and women.

The disposition of a single intravenous dose of diazepam (10 mg) was studied in 11 young, healthy subjects (6 males and 5 females on oral contraceptives). Plasma samples were obtained over 28 days and diazepam and N-desmethyldiazepam plasma concentrations and diazepam free fractions were determined. The salivary excretion of diazepam and N-desmethyldiazepam was studied over 72 h. A series of psychomotor performance tests were administered over the first 8 h. Interindividual variation in mean diazepam disposition over time is not principally related to variation in plasma protein binding; 93% of the variation in clearance is accounted for by variation in intrinsic clearance. Interindividual variation in diazepam disposition is modest but the plasma clearance of diazepam in women on oral contraceptives (median 14.0 ml/min) is significantly (p=0.004) less than in men (median 23.4 ml/min) and the area under the curve (AUC) of diazepam is highly correlated with the AUC of the principal active metabolite (r=0.90, p<0.001). The AUC of N-desmethyldiazepam (median 9.2 µg·h/ml) in women is greater (p=0.06) than in men (median 7.5 µg·h/ml). On chronic administration of diazepam, therefore, women taking oral contraceptives will have greater plasma concentrations per unit dose of both diazepam and N-desmethyldiazepam than men. The clearance of diazepam in control groups of 11 young men (median 23.8 ml/min) and 10 young women not taking oral contraceptives (median 26.8 ml/min) is not significantly different. Plasma and salivary concentratrions of diazepam are correlated (p<0.001) but the predictive value of this correlation is limited (r=0.70) since the ratio of salivary to plasma concentrations varies significantly over the day. The use of calculated free diazepam plasma concentrations does not improve the correlation (r=0.68) but the slope of this regression (1.00) is that predicted by theory.

Effects of chronic treatment of rats with diazepam on GABAergic system

1. 1. The high affinity binding of GABA to frozen crude cerebellar synaptic membranes was determined in rats. Only one type of receptor site was found ( K D : 52.10 ± 13.3 nM; B max: 1.81 ± 0.23 pmol/mg protein). 2. 2. Chronic administration of Diazepam did not modify either K D or B max of GABA binding to frozen crude membranes. 3. 3. An inhibitory activity of GABA binding to purified synaptic membranes was found in supernatant buffer from crude cerebellar synaptic membranes. 4. 4. The treatment with Diazepam increased the inhibitory activity of supernatant fraction. 5. 5. Glutamic Acid Decarboxylase activity levels in frontal cerebral cortex homogenates were not modified either by the treatment or by in vitro adidition of Diazepam. 6. 6. K m values of the enzyme for glutamate in homogenates from frontal cerebral cortex was not modified by the treatment.

The integrity of the social hierarchy in mice following administration of psychotropic drugs.

1 Mice in small groups develop a despotic type of social hierarchy, a feature of which is to resist alteration through the medium of psychotropic drugs. This makes a rapid pharmacologically induced change in the social hierarchy impossible. 2 Patrolling the territory and a certain level of social interaction are both critical factors in maintaining the phenomenon of inertia in the social hierarchy. Psychotropic drugs (diazepam, droperidol and mescaline) altered both these factors to a varying degree and also displayed a differing ability to maintain the inertia of the social hierarchy. 3 A drug-induced alteration in the level of aggression in a subordinate mouse in a group of three does not cause an alteration in its social position. 4 Chronic administration of diazepam, droperidol or mescaline, all of which alter the level of aggression in different ways, can result in an inversion of the social hierarchy where a competitive rival is present in the group of mice. The rate of inversion of the social hierarchy depends on the type of pre-existing social hierarchy. 5 It is suggested that the ability of psychotropic drugs to maintain the inertia of the hierarchy be used as an index of their effect upon certain types of species-specific behaviour; in particular aggression.

Effect of acute and chronic anticonvulsant administration on endogenous γ-hydroxybutyrate in rat brain

The effect of acute and chronic administration of ethosuximide, trimethadione, sodium valproate, clonazepam, phenobarbital, and diazepam on brain concentrations of γ-hydroxybutyrate (GHB) was determined by gas-liquid chromatography. The dose and time to sacrifice for each drug was determined by testing for effectiveness against GHB-induced absence seizures in the rat using an automated frequency analysis for quantitation of the electrocorticogram. Acute administration of ethosuximide, trimethadione, and sodium valproate, produced an increase in whole brain GHB. Ethosuximide, trimethadione, and phenobarbital given chronically produced a decrease in whole brain GHB. All changes took place in subcortex and cerebellum. Acute ethosuximide treatment produced a greater increase in GHB concentration at higher doses. The acute changes with the drugs coincided with the onset of anticonvulsant effect, but were short-lived and, in the case of ethosuximide and trimethadione, followed by a significant depression in GHB concentrations. The anti-petit mal action of these anticon-vulsants may be related to their effect on GHB in brain.

The effect of diazepam upon the development of hypertension in the spontaneously hypertensive rat.

Summary: The long term antihypertensive effects of the chronic administration of diazepam (D) beginning in the newborn period to spontaneously hypertensive rat (SHR) is the subject of this study. The following treatment groups were investigated: SHR-D = SHR treated with diazepam; SHR-V = SHR treated with diazepam vehicle; WKY-D = Wistar Kyoto control rat (WKY) treated with diazepam; WKY-V = WKY treated with vehicle. Treatment was begun on the 1st day of life. Injections of the following agents were made during hindquarter perfusion: norephinephrine bitartrate, epinephrine hydrochloride, angiotensin-II, barium chloride, and acetylcholine. SHR-V had persistent, progressive hypertension. The blood pressure of SHR-D rose slowly, but did attain levels higher than pressures of either WKY groups. In response to diazepam, the vascular resistance of SHR-D was reduced in comparison to SHR-V. SHR showed significantly greater vascular responses to catecholamines as compared to WKY. These enhanced vascular responses were reduced, but not abolished, by diazepam. When diazepam was administered to adult SHR with established hypertension, the blood pressure was not reduced. No decrease in vascular reactivity was found. In conclusion, treatment from birth with diazepam exerts a profound effect upon the development of high blood pressure and elevated vascular resistance in SHR. Only the young prehypertensive animals treated chronically were responsive to diazepam. The major effect of diazepam may be mediated via generalized depression of vascular smooth muscle responsiveness.Speculation: Early pharmacologic intervention in young animals, genetically predisposed to severe hypertension, blunts the expression of the disease. This suggests that prehypertensive animals have alterations that can be pharmacologically modified. Vascular smooth muscle may be the common pathway of action for these agents.

Increased specific binding of [ 3H]diazepam in rat brain following chronic diazepam administration

Male rats (175 g) were given 30 mg of diazepam in their food daily for 35 days. The animals became drowsy and ataxic from this high dose of drug. After the 35-day dosing, the rats were killed daily, and specific binding of [ 3H]diazepam and [ 3H]flunitrazepam was determined in synaptosomal preparations from these and corresponding control rats. On days 3, 4, 6, and 7 after the treatment period the specific binding of [ 3H]diazepam was double that of the control binding and specific binding of [ 3H]-flunitrazepam was 1.67 times that of control. The data indicate that very high doses of diazepam, given for long periods, cause increased specific binding of radiolabeled ligand to brain subfractions. The possible mechanisms and implications are discussed. When lower doses or shorter dosage regimens are used, increased binding is not observed.

Benzodiasepine and neurotransmitter receptor binding in rat brain after chronic administration of diazepam or phenobarbital

Benzodiasepine and neurotransmitter receptor binding in rat brain after chronic administration of diazepam or phenobarbital

Modification of ovine fetal respiratory-like activity by chronic diazepam administration

Chronic maternal administration of diazepam resulted in a modification of fetal respiratory-like activity (FRLA) in the sheep. An over-all increase in this activity occurred. This increase was probably due to a rebound effect following periods of acute suppression with each administration of diazepam. Loss of central control in the regulation of FRLA was implied. A complete reversal of a circadian rhythm of FRLA was observed in animals receiving diazepam. These changes have implications with respect to the antenatal monitoring of the fetus and sequelae in the newborn infant.

Functional changes in cerebral 5-hydroxytryptamine metabolism in the mouse induced by anticonvulsant drugs.

1 Acute administration of clonazepam, diazepam, and diphenylhydantoin to mice elevated cerebral 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA); chronic administration had less effect. 2 Acute administration of clonazepam and diazepam but not diphenylhydantoin raised cerebral trytophan levels; chronic administration of clonazepam caused a smaller elevation of cerebral tryptophan but chronic administration of diazepam still caused a large rise in cerebral tryptophan. 3 Neither clonazepam nor diazepam caused induction of drug metabolizing enzymes on chronic administration but diphenylhydantoin had a marked effect. 4 These data suggest that the altered 5-HT metabolism caused by these compounds is unrelated to a common action on tryptophan levels, and that the reduced effect of clonazepam and diazepam on chronic administration cannot be attributed to increased metabolism of these compounds. 5 Clonazepam induced abnormal head movements in mice in a dose-dependent manner. Pretreatment of animals with tranylcypromine increased the intensity of movement, although pargyline was without effect. Similar effects were observed with diazepam and diphenylhydantoin, suggesting that the increase in cerebral 5-HT caused by these compounds is of functional significance in stimulating 5-HT receptors.

Additional studies on the importance of glycine and GABA in mediating the actions of benzodiazepines

Tolerance to the anti-strychnine and anti-bicuculline properties of diazepam developed after chronic administration of diazepam. No tolerance developed to the anti-pentylenetetrazole activity of diazepam. These latter results suggest that anti-pentylenetetrazole activity may reflect the anxiolytic potential of benzodiazepines. Since bicuculline and strychnine block GABA and glycine receptors, respectively, the present results suggest that the GABA-ergic and glycine-ergic properties of the benzodiazepines develop tolerance and for this reason are unrelated to the anxiolytic actions of benzodiazepines.

A quantitative electroencephalographic comparison of some benzodiazepines in the primate

Eleven benzodiazepines were tested for their effects on the spontaneous EEG in the monkey, Macaca nemestrina. Dose-response studies made it possible to separate these compounds into 3 distinct groups. While all the benzodiazepines produced α-slowing and an increase in low frequency components at comparatively high doses, they differed in their capability to induce spindle-like activity in the frontal and to a lesser extent in the parietal, cortices. Some of the compounds, including diazepam, chlordiazepoxide, and nitrazepam at certain doses, produced a selective enhancement of spindle-like activity which completely dominated the frontal EEG. Others including prazepam did not produce a significant appearance of spindles. Some were intermediate in their characteristics. Spindle-like activity could be differentiated from barbiturate spindles and they behaved qualitetively like control β-activity. Chronic diazepam administration produced different effects from acute administration. Dominant frequencies re-stabilized across the cortex at a frequency significantly higher than control-α. After 11 days of behaviorally effective chronic administration, an additional 12 recovery days elapsed before control activity was re-established.