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PubMed1995

Diazepam induces tolerance in the isolated skin of Pleurodema thaul.

The effects of the long-term administration of diazepam on the potential difference and short-circuit current of the isolated skin of the toad Pleurodema thaul (P. thaul) were investigated. Diazepam applied in a concentration range of 4.6 x 10(-6) to 5.2 x 10(-5) M decreased both electrical parameters. This response was unaffected by flumazenil indicating that the action of diazepam is not induced through benzodiazepine receptors. Induction of tolerance to diazepam on its observed effects on potential difference and short-circuit current was obtained by the administration of a single dose of the drug in a slow release preparation. Skins tolerant to diazepam were also tolerant to the acute effects of verapamil on both electric parameters. Tolerance to diazepam effects was partly reversed by increasing Ca2+ concentration in the inner bathing solution. The results are consistent with a Ca2+ channel blocking effect of diazepam in the P. thaul skin.

Animals↗
PubMed1995

Diazepam potentiates the positive inotropic effect of isoprenaline in rat ventricle strips: role of cyclic AMP.

The responses of the electrically driven right ventricle strip of the rat heart to isoprenaline and other cyclic AMP-related inotropic agents were recorded in the absence and in the presence of diazepam. Isoprenaline, in concentrations ranging from 10 nM to 1 microM, significantly increased, in a concentration-dependent manner, the contractile force in this preparation. Diazepam (10 microM) produced a leftward shift in the isoprenaline concentration-response curve and significantly reduced its EC50. Higher concentrations of diazepam (100 microM) produced no further shift, but reduced the maximum of the concentration-response curve of isoprenaline. Forskolin (0.5-10 microM), which directly stimulates adenyl cyclase, also produced a concentration-dependent increase in cardiac contractility. Diazepam (10 microM) displaced to the left the concentration-response curve for forskolin and reduced its EC50. The cyclic AMP analogous dibutyryl cyclic AMP (0.1-1 mM) produced concentration-dependent positive inotropic effects which were not significantly modified in the presence of diazepam (10 microM). Diazepam (10 microM) significantly enhanced the cyclic AMP production induced by isoprenaline (0.1 microM) and forskolin (10 microM) by about 136% and 35% respectively. These results indicate that diazepam potentiates the positive inotropic effect induced by beta-adrenoceptor agonists, probably by increasing cyclic AMP production induced by these agents.

Adenylyl Cyclases↗
PubMed1980

The effect of diazepam administration during pregnancy or labor on the heart rate variability of the newborn infant.

Maternal diazepam medication during labor reduces beat-to-beat variability of the fetal heart rate. In this study, the prolongation of the effect was examined in the newborn. The mother received diazepam: (A) during labor as a tranquilizer, (B) daily in low doses at the end of pregnancy, or (C) in high doses i.v. for (pre-)eclampsia. A control group had no analgesic or sedative during pregnancy or labor. The electrocardiogram (ECG) was recorded daily from each newborn during the first 6 days after birth. After preprocessing of the ECG, the median R-R interval, the long-term irregularity index (LTI index) and the interval difference index (ID index) were calculated. A cubic spline interpolation method was applied to compare the various groups with respect to these heart rate parameters. The median R-R interval showed no particular differences in trend for all groups. The LTI index was decreased in the first days after birth in the chronic diazepam (B), and in the diazepam infusion groups (C), but statistical significance was not reached. The ID index was significantly decreased in the first 1-2 days in the newborns of the acute and chronic diazepam group. In the diazepam infusion group, an even longer lasting effect was observed. Maternal diazepam medication affects the beat-to-beat variability in the newborn. The duration of the effect is dependent on dosage and route of administration.

Diazepam↗
PubMed1983

The neuropharmacology of various diazepam antagonists.

Recently, compounds which bind avidly to benzodiazepine binding sites have been shown to possess diazepam antagonist properties. For example, the benzodiazepine RO 15-1788 and the pyrazoloquinoline CGS 8216 can antagonize the anxiolytic, sedative, muscle relaxant and anticonvulsant properties of diazepam. The beta-carbolines have also been shown to antagonize several actions of diazepam. Other compounds including physostigmine, naloxone, bicuculline, picrotoxin, caffeine and theophylline, lack appreciable affinity for benzodiazepine binding sites but do antagonize at least some of the behavioral actions of diazepam. Their antagonist properties are probably the result of opposing pharmacological actions rather than direct receptor antagonism. Clinically, a potent safe diazepam antagonist could be used to reverse effects of diazepam overdose and to speed recovery of diazepam-treated patients after various out-patient procedures.

Animals↗
PubMed1988

A comparison of the effects of buspirone and diazepam on plasma corticosterone levels in rat.

The effect of the anxiolytic agents, buspirone and diazepam, on the hypothalamic-pituitary-adrenal axis (HPAA), indicated by changes in the concentration of corticosterone (CS) in plasma, were studied 1/2, 1, 2, 4, 6, 8 and 24 hr after administration of the drug (i.p.). Samples of plasma were collected in the mid-morning (0930-1130 hr) when activity in the hypothalamic-pituitary-adrenal axis in the rat and control levels of corticosterone were low and were repeated in the afternoon (1400-1600 hr) when activity in the hypothalamic-pituitary-arenal axis and levels of corticosterone were higher. At small doses (1 mg/kg) buspirone had a greater facilitating effect on the hypothalamic-pituitary-adrenal axis than did diazepam. In addition, buspirone had a greater maximum facilitatory effect (477%) on levels of corticosterone than diazepam (345%). However, buspirone (ED50 = 8.6 mumol/kg) and diazepam (ED50 = 8.7 mumol/kg) were equipotent. Administration of 1 mg/kg of buspirone in the morning increased the combined 1/2 and 1 hr circulating levels of corticosterone 75% above control levels. Diazepam, at 1 mg/kg, did not produce any significant changes in levels of corticosterone. Large doses (10 mg/kg) of buspirone increased morning levels of corticosterone by 328% and diazepam increased levels of corticosterone by 265%. During the afternoon small doses of buspirone or diazepam did not significantly alter levels of corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The ontogeny of benzodiazepine receptors in selected regions of the rat brain: effect of perinatal exposure to diazepam.

The postnatal development of the binding of [3H]flunitrazepam to benzodiazepine receptors has been studied in the frontal cortex, cerebellum, striatum, hypothalamus and hippocampus of the rat after prenatal, perinatal and postnatal exposure to diazepam. The dams were injected subcutaneously with single daily doses of 1 mg/kg of diazepam from day 7-20 of gestation or from day 15 of gestation day 6 after birth. Offspring of untreated dams were injected in the same way from postnatal day 7-20. The developmental profiles of the binding of [3H]flunitrazepam obtained in both control and diazepam-treated groups of animals were very similar. This supported the idea of a sequential development of benzodiazepine receptors in relation to the different rates of maturation of certain structures of the brain. Prenatal administration of diazepam resulted in an increase of the binding of [3H]flunitrazepam in the frontal cortex by 20% at postnatal day 90 and in a decrease of binding in the hippocampus by 14% at postnatal day 60 and an increase of binding by 18% at postnatal day 90. Perinatal exposure to diazepam did not affect the binding of [3H]flunitrazepam in the hippocampus in young adult offspring. Postnatal application of diazepam resulted in a transiently decreased binding of [3H]flunitrazepam in the cerebellum by 20% at postnatal day 28. The results obtained point to the necessity for a prolonged evaluation of events after exposure to diazepam in early stages of development of the brain.

Animals↗
PubMed1992

Diazepam facilitates acceptance of alien lambs by postparturient ewes.

The aim of this study was to determine the effect of diazepam on the behavior of parturient ewes towards alien lambs. There is evidence that benzodiazepines cause behavioral changes during the lactation period in rats. In two independent experiments, it was found that the ewes acceptance of alien lambs significantly increased following a single injection of the benzodiazepine, diazepam, given either 1 or 12 h after parturition. In a third experiment, in which the alien lamb was not permitted to suckle during a period of 2 h after the injection, the diazepam treatment did not provoke significant differences in maternal behavior of the ewes, although in the ewes treated with diazepam, suckling clearly tended to increase. At the dose employed (20 mg), administered 1 h after birth, diazepam caused no signs of sedation as assessed in an open-field test carried out 3 h after parturition. This doesn't eliminate the possibility of diazepam having a sedative effect in the period of 2 h immediately after its administration and before the test and, in this way, facilitating suckling which could be responsible for the maternal behavior observed after this period. As diazepam gives rise to an enhanced GABAergic activity in the brain, these observations suggest that a GABAergic mechanism could also play a role in the process whereby ewes form a selective bond with their own offspring.

Aggression↗
PubMed1983

Diazepam dose preference in humans.

Diazepam dose preference was studied in 10 human subjects in a hospital setting. Subjects were allowed to select between a standard compound (diazepam or pentobarbital) and one of several doses of diazepam (2-40 mg/capsule) on an ad lib basis. When 5 or 10 mg/capsule diazepam was the standard, no clear cut diazepam dose preference was found. When 30 or 50 mg/capsule pentobarbital was the standard, clear cut diazepam dose preference in some subjects was found. The shape of the dose preference function differed among subjects. Within subjects, diazepam dose preference differed within the self-administration day, with some subjects preferring one dose in the morning and a different dose later in the day.

Adult↗
PubMed1984

Stimulus control by diazepam of behavior maintained under fixed-ratio stimulus-shock termination schedules in rats.

The stimulus control of behavior by diazepam (1.0 mg/kg) was investigated where responding was maintained under fixed-ratio (FR) schedules of stimulus-shock termination in rats. The size of the FR requirement was either 1, 5, 10, or 20 responses. At each FR requirement, dose-effect curves were determined for diazepam, flurazepam, pentobarbital and cyproheptadine. Diazepam-like discriminative stimuli were produced by flurazepam and pentobarbital but not by cyproheptadine. The magnitude of the FR requirement had no significant effect on the dose-effect curves for percentage of responses emitted on the diazepam-appropriate choice lever for any of the four drugs. On the other hand, the effects of these drugs on rates of responding depended on the magnitude of the FR requirement. None of the drugs altered response rates under the FR1 schedule. Diazepam tended to increase response rates under the FR5 schedule, but had no effect or decreased rates under the FR10 and FR20 schedules. Flurazepam and pentobarbital predominantly decreased rates at FR requirements of 5, 10 or 20 responses. Cyproheptadine had no significant effect on response rates at any schedule parameter. Together with previous reports, the present results indicate that the discriminative effects of diazepam are similar under schedules employing noxious (this study) or non-noxious (other reports) consequences, even though the effects on response rates of diazepam-like drugs differ depending on the schedule of reinforcement and consequent event maintaining the behavior.

Animals↗
PubMed1987

The effects of diazepam on brain 5-HT and 5-HIAA in stressed and unstressed rats.

Diazepam, administered to rats at a high dose (25 mg/kg PO) has been shown to have no effect on the plasma corticosterone response to the stress of an elevated open platform. It did however, reduce the plasma corticosterone in rats repeatedly exposed to the apparatus. Diazepam-withdrawal from stress-habituated rats increased plasma corticosterone (p less than 0.01) whereas withdrawal of diazepam from unstressed rats had no effect on plasma corticosterone. It is concluded that this effect of diazepam-withdrawal may reflect the development of dependence upon the drug. Significant effects were not observed following the administration of a lower non-selective dose (5 mg/kg PO) of diazepam and, therefore, it is not clear whether dependence to its sedative, rather than the anxiolytic properties have been measured. Acute diazepam (25 mg/kg) increased (p less than 0.05) hippocampal 5-hydroxyindoleacetic acid; its withdrawal from unstressed rats after 40 days reduced (p less than 0.01) hypothalamic 5-hydroxytryptamine. There was no evidence that the effects of diazepam or its withdrawal on plasma corticosterone in stressed rats were associated directly with changes in brain 5-hydroxyindoles.

Altitude↗
PubMed1989

Behavioral interactions between nicotine and diazepam.

Graded doses of nicotine (0.01-1.0 mg/kg) were administered alone and together with three doses of diazepam (0.3, 1.0 and 3.0 mg/kg) to rats responding on a fixed-interval 2-min schedule of liquid food reinforcement. Nicotine (0.03-1.0 mg/kg) increased overall rate, but diazepam had little effect. Both nicotine and the two highest doses of diazepam attenuated the change in response rate through the interval. When combined with nicotine the lowest dose of diazepam increased overall rates above those produced by nicotine alone. However, it appeared to diminish the effects of nicotine on the within-interval pattern of responding. These changes appeared to be due to an elevation in the high rates at the end of the interval. In contrast, the highest diazepam dose increased overall response rates when combined with low doses of nicotine, but decreased the high rates observed after larger nicotine doses. This dose of diazepam combined in an additive manner with nicotine to reduce the degree of response rate change within the interval. The interaction between nicotine and diazepam depends on the aspect of behavior under investigation and the particular doses of the two drugs.

Animals↗
PubMed1992

Diazepam impairs retention of spatial information without affecting retrieval or cue learning.

We further investigated the effect of diazepam on the processing of spatial information in a water maze task. Diazepam significantly impaired the retention of spatial information in a group of rats trained to locate a hidden platform. In a free swim trial carried out after training, diazepam-treated rats showed no bias to the target quadrant. There was no effect of diazepam on retrieval of spatial information in well-trained rats, and diazepam was devoid of any effect on cue learning in the water maze. However, diazepam blocked latent place learning during cue training in the water maze. Our results indicate that the GABA-BZD receptor modulates spatial information processing and that diazepam specifically impairs the retention of spatial information without affecting retrieval or cue learning.

Animals↗
PubMed1992

Interaction of GABA and serotonin in the anxiolytic action of diazepam and serotonergic anxiolytics.

The general purpose of the present study was to analyze the possible interactions between the GABA-benzodiazepine and the serotonergic (5-HT) systems in the anxiolytic action of diazepam and the 5-HT1A agonists, ipsapirone, indorenate, and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The effect of the benzodiazepine receptor antagonist, flumazenil (10.0 mg/kg), on the anxiolytic action of ipsapirone (5.0 mg/kg), indorenate (5.0 mg/kg), and 8-OH-DPAT (0.125 mg/kg) was examined on the avoidance exploratory behavior paradigm in mice. The effect of the 5-HT1 blockers, methiotepin (0.31 mg/kg), pindolol (3.1 mg/kg), and alprenolol (5.0 mg/kg), on the anxiolytic action of diazepam (0.5 mg/kg) was also studied. In the last part of this work, the putative potentiation between diazepam (0.25 mg/kg) and each of the serotonergic anxiolytics was investigated. The antianxiety effect of diazepam, ipsapirone, indorenate, and 8-OH-DPAT was prevented by flumazenil. The serotonergic/beta-blocker, alprenolol, partially antagonized the diazepam effect. Finally, a potentiation of suboptimal doses of diazepam and ipsapirone, but not with indorenate or 8-OH-DPAT, was observed. The findings suggest an interaction between both systems on the anxiolytic action of diazepam and the 5-HT1A agonists.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Antagonism of isoniazid-induced convulsions by abecarnil in mice tolerant to diazepam.

The ability of the benzodiazepine receptor full agonist diazepam, the selective agonist abecarnil, and the partial agonist imidazenil to antagonize convulsions induced by isoniazid (200 mg/kg, S.C.) was studied in mice chronically treated with diazepam (3 mg/kg, i.p., three times daily) or abecarnil (0.1 or 1 mg/kg, i.p., three times daily or 6 mg/kg, S.C., daily). Diazepam induced tolerance to its own anticonvulsant effect. In contrast, chronic treatment with abecarnil failed to induce tolerance to its own anticonvulsant activity. Animals treated with abecarnil at 0.1 mg/kg developed cross-tolerance to imidazenil, whereas those treated with 1 mg/kg became less sensitive to diazepam. Mice chronically treated with abecarnil at 6 mg/kg showed almost complete tolerance to diazepam. Abecarnil was able to antagonize the convulsions elicited by isoniazid in diazepam-tolerant mice. These data indicate that chronic administration of abecarnil, unlike that of classical benzodiazepines, does not induce tolerance to its anticonvulsant effect, and that abecarnil overcomes tolerance induced by long-term treatment with the full agonist diazepam.

Animals↗
PubMed1994

Effect of chronic maternal diazepam treatment on the development of stress-induced antinociception in young rats.

The use and abuse of benzodiazepines is widespread and we have begun to address whether maternal exposure to these drugs influences the development of opioid systems. We have studied the effect of maternal diazepam treatment on stress-induced antinociception in the neonatal offspring. Diazepam (1 or 10 mg/kg) was administered twice daily to mothers from conception. Pre- and postweanling rat pups were assessed for opioid-mediated stress-induced antinociception by 3-min swimming and measuring nociception using the tail immersion test. In preweanling rats there was stress-induced antinociception in both vehicle- and diazepam-treated animals but in diazepam-treated groups (1 and 10 mg/kg) this was insensitive to reversal by the opioid antagonist naloxone, suggesting that nonopioid systems are operating this response. In postweanling rats a similar insensitivity to naloxone was observed in 1 mg/kg diazepam-treated groups; with 10 mg/kg diazepam there was no significant antinociception. The results suggest that maternal diazepam treatment interferes with the development of stress-mediated responses and that part of this toxicity is due to actions on opioid systems in the CNS.

Animals↗
PubMed1994

Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam.

In a previous study, rats treated chronically with flurazepam were tolerant to the anticonvulsant action of some benzodiazepines (BZs), but not others (34). To determine if this differential crosstolerance was unique to flurazepam, rats were treated chronically with diazepam or midazolam, and tested for tolerance to the anticonvulsant actions of diazepam, midazolam, clonazepam, and clobazam. Regional benzodiazepine receptor binding in brain was also studied. In contrast to previous findings with flurazepam, 1 week treatment with diazepam or with midazolam did not cause tolerance. Rats treated with diazepam for 3 weeks were tolerant to diazepam, clonazepam, clobazam, and midazolam. In contrast, rats treated 3 weeks with midazolam were tolerant to diazepam and midazolam, but not clobazam or clonazepam. Neither diazepam nor midazolam treatment for 3 weeks altered BZ binding in cerebral cortex, cerebellum, or hippocampus. The effects of chronic BZ treatment depended not only on the BZ given chronically, but also on the BZ used to evaluate these effects, suggesting drug-specific interactions of different BZs with their receptors.

Animals↗
PubMed1994

Rapid tolerance to the depressive effects of diazepam on guinea pig motor control using divided doses.

The effects of acute and chronic IP injections of diazepam on the guinea pig righting reflex latency (RRL) were measured using an automated measurement system known as a "tolerometer." Single IP injections of 2.0, 6.0, 18.0, and 20.0 mg/kg diazepam significantly increased the RRL compared to no injection (naive animals), diazepam vehicle injections, or 1.0 mg/kg diazepam injections. The effects of chronic IP injection schedules on the RRL were compared: 18 or 20 mg/kg in a single, once daily injection for 5 days; 6 mg/kg in a single, once daily injection for 5 days; and 6 mg/kg, three times a day, for 5 days. Neither 20, 18, nor 6 mg/kg/day for 5 days resulted in significant tolerance to the depressive effects of diazepam on the righting reflex. By contrast, when 6 mg/kg was administered three times a day for 5 days, tolerance developed by the third day of treatment. There were no differences between the three groups in the amount of exposure to the measurement apparatus or the testing situation. These results support the view that species like guinea pig and rat that metabolise diazepam rapidly, develop tolerance more quickly if diazepam is administered in divided doses or by continuous release; this may be because the duration of the occupation of CNS benzodiazepine recognition sites is a critical factor in the development of tolerance.

Animals↗
PubMed1986

Effect of chronic exposure to methylxanthines on diazepam cerebral binding in female rats and their offsprings.

Caffeine, theophylline or saline were injected daily into female rats during the gestation and lactation periods. Crude synaptosomal membranes were isolated from the brains of offsprings at various stages of development and their ability to specifically bind [3H]diazepam was tested. An other approach consisted of injecting [3H]diazepam into offsprings and cerebral specifically bound diazepam was measured. It was shown that methylxanthines were able to inhibit [3H]diazepam binding by reducing total number of binding sites in the brain of 5- and 15-day-old rats born from treated mothers, with a total recovery of control values at 25 days of age. Moreover, in vivo percentage of cerebral bound diazepam dramatically fell when rats were exposed to methylxanthines in utero and through the mother's milk. Since caffeine and theophylline displace diazepam binding not necessarily in a competitive manner, it is suggested that they could interfere with diazepam as adenosine antagonists.

Animals↗