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PubMed1982

Pharmacodynamic and pharmacokinetic properties of diazepam in horses.

The cardiopulmonary, behavioral, and pharmacokinetic properties of diazepam were determined in horses. Heart rate, cardiac output, mean pulmonary artery, aortic and right atrial blood pressures, respiratory rate, and arterial pH and blood gas values did not change after IV diazepam (0.05, 0.1, 0.2, 0.4 mg/kg) administration. Increasing doses of diazepam resulted in signs of muscle weakness including fixed stance, muscle fasciculations of the head, neck, and thorax muscles, ataxia, and then recumbency. Dosages of diazepam exceeding 0.2 mg/kg produced mild sedation. Behavioral changes persisted for up to 2 hours with a dosage of 0.4 mg/kg. Plasma concentration-time data in horses given brief (5 min) infusions of diazepam were described by a triexponential equation. Total body clearances of diazepam were between 6.94 and 9.56 ml/min/kg, and the half-life values between 2.52 and 21.6 hours. The volume of distribution at steady state was 1.56 to 2.94 L/kg. N-Desmethyldiazepam was identified by gas chromatography-mass spectrometry following glucuronide hydrolysis of urine. Oxazepam, N-methyloxazepam, and N-desmethyldiazepam, but not diazepam, were detected after glucuronide hydrolysis of urine collected from 1 horse which was given 140 mg of IV diazepam. Only N-desmethyldiazepam was detected in hydrolyzed urine samples collected from other horses given 80 mg of diazepam.

Animals↗

PubMed1981

Pharmacokinetics of diazepam in the dog.

After i.v. administration of 2 mg/kg diazepam to dogs, concentrations of unmetabolized drug showed a triexponential decline with an average elimination half-life t0.5(beta) of 3.2 hr. Desmethyldiazepam appeared rapidly in plasma and exceeded diazepam concentrations by far. Elimination half-lives of this metabolite averaged 3.6 hr. Oxazepam reached maximal plasma concentrations in the range of 100 ng/ml after about 2 hr which then declined with a half-life of 5.7 hr. When the sum of the concentrations of diazepam and its active metabolites was plotted against time, the curve could be fitted by an open 2-compartment model, so that one of the apparent 3 compartments in the distribution of diazepam must be assumed to represent first pass demethylation to desmethyldiazepam. After oral administration of the same dose, desmethyldiazepam concentrations exceeded those of diazepam from the first blood sample taken. The share of unmetabolized diazepam in the total area under curve was only 1-3% after oral administration, but 7-21% after i.v. administration. Oral bioavailability was in the range of 74-100%. By continued oral administration of 1 or 2 mg/kg diazepam t.i.d. it was possible to maintain steady state plasma concentrations of 1000-2000 ng/ml desmethyldiazepam and maximal diazepam concentrations of 100-800 ng/ml. Oxazepam did not exceed a concentration of 100-200 ng/ml and small concentrations of 3-hydroxydiazepam could also be detected in these experiments. There was no indication of enzyme induction by this dose regimen. Both diazepam and desmethyldiazepam rapidly passed the blood/CSF barrier and reached steady state concentrations is CSF corresponding to the part not bound to serum proteins.

Administration, Oral↗

PubMed1980

Availability of diazepam from plastic containers.

The effect of plastic intravenous containers and volume-control administration sets on diazepam availability was studied. Solutions of diazepam in dextrose 5% in water and in 0.9% sodium chloride were prepared in plastic burette chambers and polyvinyl chloride (PVC) bags. Diazepam concentration was measured spectrophotometrically for (1) samples taken from the burette chamber and from the end of the administration set, (2) samples prepared in glass beakers and then infused through plastic administration sets with 0.5-micron filters, (3) samples prepared in PVC bags, and (4) sections of the PVC bags and volume-control sets in which diazepam solutions were prepared and infused. Two hours after admixture, diazepam concentration was significantly reduced in the burette chamber (p less than 0.05). Diazepam concentration was reduced by about 55% after infusion through administration sets (p less than 0.0005) and after two hours of storage in PVC bags. About 24% of the diazepam concentration was recovered from the volume-control set (none was detected in the filter) and 49-56% was recovered from the PVC bags. Admixture of diazepam solutions in plastic containers and administration through plastic administration sets will significantly reduce their diazepam concentrations.

Diazepam↗

PubMed1994

Metabolic and subjective responses to oral diazepam and midazolam.

Diazepam premedication decreases the overall metabolic rate and oxygen consumption. Whether its properties are shared by midazolam is not known. In this study, eight healthy male volunteers were given oral diazepam (10 mg), midazolam (15 mg) and placebo in a random double-blind cross-over fashion. Metabolic responses were measured using an indirect calorimetry device. Subjective responses were measured using a visual analogue scale. Plasma concentrations of diazepam, midazolam and desmethyldiazepam were analysed and correlated to changes in metabolic and subjective responses. When compared to placebo, both diazepam and midazolam significantly decreased oxygen consumption (P < 0.01 in pairwise comparisons) and energy expenditure (P < 0.01 in pairwise comparisons). While there was a significant correlation between the plasma concentrations of diazepam and the changes in metabolic parameters, no such correlation was found with midazolam. Both diazepam and midazolam were subjectively more sedative than placebo (P < 0.05). There was no significant difference between the sedative effects of diazepam and midazolam, but diazepam was subjectively better tolerated than midazolam. These results indicate that both diazepam and midazolam, in addition to their CNS effects, significantly decrease the overall metabolic rate and oxygen consumption in healthy volunteers.

Administration, Oral↗

PubMed1996

Modifications of gamma-aminobutyric acidA receptor subunit expression in rat neocortex during tolerance to diazepam.

We evaluated whether tolerance to the antagonism of bicuculine-induced seizures by diazepam is associated with changes (i) in the content of mRNAs encoding for gamma-aminobutyric acidA (GABAA) receptor subunits, (ii) in the expression density of these subunits, and (iii) in the 1,4-benzodiazepine binding site characteristics in discrete neocortical structures. We found that in diazepam-tolerant rats, the content of the mRNA encoding for the alpha 1 subunit of the GABAA receptor decreased in the frontoparietal motor (FrPaM) cortex and in the hippocampus (42% and 20%, respectively) but not in the frontoparietal somatosensory (FrPaSS) cortex, striatum, olfactory bulb, and cerebellum. In the FrPaM cortex, gamma 2S and gamma 2L subunit mRNA contents were also decreased (48% and 30%, respectively), whereas that of alpha 5 was increased (30%). In the FrPaM and FrPaSS cortices as well as in cerebellum of diazepam-tolerant rats, the content of alpha 2, alpha 3, alpha 6, beta 2, and delta subunit mRNA was unchanged, as was the content of alpha 2, alpha 5, gamma 1, and gamma 2S subunit mRNA in the hippocampus. Furthermore, the reduction in alpha 1 subunit mRNA content in the FrPaM cortex and the anticonvulsant tolerance to diazepam returned to control values 72 hr after termination of the protracted diazepam treatment. Rats receiving a treatment with imidazenil in doses equipotent and with a schedule identical to that of diazepam failed to exhibit tolerance to the anticonvulsant action of this drug or cross-tolerance to diazepam. In these rats, the content of mRNA encoding for alpha 1, alpha 2, alpha 3, alpha 5, alpha 6, gamma 1, gamma 2S, gamma 2L, and delta GABAA receptor subunits failed to change in the FrPaM and FrPaSS cortices, in the hippocampus, and in the other brain areas that were studied in diazepam-tolerant rats. Although the density and affinity of [3H]flumazenil and [3H]imidazenil binding failed to change in the FrPaM and FrPaSS cortices of diazepam-tolerant rats, the expression density of alpha 1 subunit immunogold labeling decreased by 37%, whereas that of alpha 5, gamma 2L/S, and beta 2/3 increased by 158%, 50%, and 47%, respectively, in the FrPaM cortex, and the density of the alpha 5 subunit selectively increased (209%) in the FrPaSS cortex. In contrast, the immunogold labeling density of the alpha 1, alpha 5, gamma 2L/S, and beta 2/3 subunits failed to change in either the FrPaM or FrPaSS cortex of rats receiving protracted imidazenil treatment.

Animals↗

PubMed1996

Inhibitory effects of diazepam in rat vas deferens: role of calcium.

Diazepam and Ro5-4864 effects on noradrenaline-induced rat vas deferens contractions were studied. We investigated whether central or peripheral type benzodiazepine receptors were involved, by studying the effects of the selective central or peripheral benzodiazepine receptor antagonists, flumazenil (Ro 151788) or PK 11195 respectively. Diazepam interactions with GABA, adenosine, theophylline, and hypercalcic medium (3.5 mM) were studied. Also, we investigate diazepam effect on KCl depolarized vas deferens. Results showed that diazepam (10(-4) to 1.7 x 10 (-4) M) and Ro 5-4864 (10(-5) to 5.5 x 10(-5) M) inhibited NA-induced vas deferens contractions and that neither flumazenil nor PK 11195 antagonized diazepam or Ro 5-4864 inhibitory effects respectively. GABA, adenosine and theophylline did not modify neither NA vas deferens response nor diazepam inhibitory action. Diazepam effect was significantly reduced in and 3.5 mM calcium medium and KCl vas deferens response was inhibited by diazepam 1.3 x 10(-5) and 1.3 x 10(-4) M. It is concluded that in rat vas deferens diazepam effect seems to be related with calcium mobilization.

Adenosine↗

PubMed2001

Effects of diazepam on neutrophil (PMN) free amino acid profiles and immune functions in vitro. Metabolical and immunological consequences of L-alanyl-L-glutamine supplementation.

The objective of this study was to determine the effects of diazepam, L-alanyl-L-glutamine (ala-gln) or diazepam combined with ala-gln on polymorphonuclear leukocyte (PMN) free amino acid profiles. In a parallel study the effects on PMN immune functions were also documented for the first time. The incubation of whole blood with diazepam led to significant changes in PMN free glutamine, aspartate, glutamate, ornithine, arginine, citrulline, taurine and methionine as well as branched chain and neutral amino acid concentrations. Ala-gln caused significant increases in PMN glutamine and alanine and asparagine, aspartate, glutamate, ornithine, arginine, serine and glycine profiles. Regarding PMN immune functions, diazepam significantly decreased superoxide anion (O(2)(-)) and hydrogen peroxide production (H(2)O(2)) and myeloperoxidase activity (MPO) while ala-gln significantly increased PMN immune functions. Ala-gln supplemented to diazepam largely reversed the changes in PMN amino acid profiles and PMN immune functions brought about by diazepam. Overall, diazepam or ala-gln lead to significant changes in PMN free amino acids. Important PMN immune functions also seem to be affected. In regards to the results, there is significant relevance to the pharmacological regimens which enhance the supply of diazepam or ala-gln in whole blood suggesting that considerable changes in PMN "labile free amino acid pool" occur. These regimens often follow beneficial nutritional therapy or maleficent pharmacological stress and may be one of the determinants in cell nutrition which influence PMN function. It is partially through its effect on PMN labile free amino acid pool that ala-gln supplemented to diazepam may maintain PMN immune functions in vitro.

Journal Article↗

PubMed1997

Effect of dextran 70 blood substitute on diazepam binding by human serum albumin.

Diazepam binding studies with dextran 70 and human serum albumin (HSA) were carried out using centrifugation and a membrane ultrafiltration technique to separate the drug protein complex and the free microsolute. The molecular filtration method was found to be precise and reproducible with very little variations. The binding of diazepam to dextran was significant but considerably smaller when compared with the extensive binding of diazepam to HSA. The results of these studies demonstrate that diazepam binding of HSA is altered in the presence of dextran. Diazepam binds to dextran resulting in displacement of diazepam from albumin binding sites. The contributing effect of dextran to overall diazepam binding increased as the dextran concentration increased and the HSA concentration decreased. However, the net result of HSA dilution with dextran 70 was still an increase in the percent free diazepam. Various concentrations of dextran 70 significantly displaced HSA bound diazepam in all the mixtures studied.

Journal Article↗

PubMed1999

Increased precursor availability did not increase food intake and 5-HT turnover rate in the hypothalamus of diazepam injected rats.

In view of a possible role of serotonin (5-hydroxytryptamine; 5- HT) in regulation of appetite and anxiety, the effects of 1, 3 and 5 mg/kg doses of diazepam on brain serotonin precursor and effects of single and repeated diazepam (1 mg/kg 2* daily for 4 days) administration on hypothalamic 5-HT, 5-hydroxyindoleacetic acid (5-HIAA and 5-HIAA/5-HT ratio are investigated in rats. Daily diazepam treatment decreased food intakes. Diazepam injected rats exhibited a dose-dependent increase of tryptophan in the hypothalamus. Administration of diazepam (1 mg/kg) to 4 day saline injected rats on the 5th day increased 5-HT and decreased 5-HIAA levels in the hypothalamus. 5-HIAA/5-HT level also decreased. 4-day diazepam injected rats injected with saline on the 5th day also exhibited similar changes of 5-HT. 5-HIAA and 5-HIAA/5-HT ratio. Administration of diazepam to 4 day diazepam injected rats again decreased 5-HIAA concentrations but did not increase 5-HT levels in the hypothalami of rats. Possible mechanism involved in the anorectic effects of diazepam-induced changes of hypothalamic 5-HT turnover rate is discussed.

Journal Article↗

PubMed1991

Antiarrhythmic and proarrhythmic properties of diazepam demonstrated by electrophysiological study in humans.

We evaluated the electrophysiological parameters before and after the intravenous infusion of diazepam (0.2 mg/kg) in 20 cardiac patients to investigate the drug's antiarrhythmic effect. Diazepam did not significantly change the arterial pressure. After the intravenous infusion of diazepam, the sinus cycle length significantly shortened from 847 +/- 132 to 747 +/- 155 ms (p less than 0.01). No significant change in the maximal sinus node recovery time was noted. The AH interval at the atrial pacing length of 600 ms shortened significantly from 140 +/- 40 to 127 +/- 39 ms (p less than 0.05). However, there was no significant change after the administration of diazepam in the longest atrial pacing rate associated with Wenckebach conduction in the atrioventricular (AV) node, effective and functional refractory periods of the AV node, HV interval, and QRS width during ventricular pacing at the cycle length of 600 ms. The atrial and ventricular effective refractory periods remained unchanged after the administration of diazepam. Six of the eight patients who showed dual AV nodal refractory period curves in the control study did not demonstrate them after diazepam administration by increasing the atrial or AV node effective refractory period. Thus, diazepam showed significant electrophysiological effects of the heart including shortening of the sinus cycle length, improvement in AV node conduction, and no significant effect on the His-Purkinje or intraventricular conduction and refractoriness of the atrium, AV node and ventricle. On the other hand, diazepam may influence the inducibility of supraventricular reentrant tachycardia incorporating the AV node.

Adult↗

PubMedDate not supplied

Prolonged accumulation of diazepam in obesity.

Six obese (mean weight 92 kg) and five normal (60 kg) subjects received 2 mg diazepam nightly for 30 nights. Determination of diazepam and desmethyldiazepam plasma concentrations during the dosing period and for a withdrawal period indicated that accumulation half-life for both diazepam (7.8 days in obese vs. 3.1 days in normal subjects, P less than 0.05) and desmethyldiazepam (30.3 vs. 7.2 days, P less than 0.05) was markedly prolonged in obese subjects. However, mean steady-state plasma concentrations of diazepam (68 vs. 67 ng/ml) and desmethyldiazepam (156 vs. 91 ng/ml) did not significantly differ between groups. To determine the basis for this delay in accumulation in obese subjects, single-dose pharmacokinetics of diazepam and desmethyldiazepam were determined. Diazepam elimination half-life was greatly prolonged in the obese subjects (82 vs. 32 hours, P less than 0.005), with no change in total metabolic clearance (32 vs. 26 ml/min). Instead, a large increase in volume of distribution (228 vs. 70 liters, P less than 0.01) was the reason for prolongation of the elimination half-life. Similarly for desmethyldiazepam, elimination half-life was prolonged in obese subjects (130 vs. 56 hours, P less than 0.01), without a change in total metabolic clearance (13.7 vs. 19.2 ml/min), due to increased volume of distribution (151 vs. 73 liters, P less than 0.01). During chronic dosing with diazepam, obese patients may experience a much slower onset of maximal drug effect compared to normal-weight patients because of the greatly delayed accumulation of diazepam and desmethyldiazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Absolute bioavailability and effect of food and antacid on diazepam absorption from a slow-release preparation.

A series of healthy volunteers received a single 7.5-mg intravenous dose of diazepam on one occasion and a single 15-mg oral dose of slow-release diazepam (DZ-SR) on another occasion. Diazepam concentrations were measured by gas chromatography in multiple plasma samples drawn during seven days after each dose. Absorption of diazepam from DZ-SR was slow, with mean +/- S.E. peak concentrations attained at 3.8 +/- 0.5 hours after dosage. Absolute bioavailability of DZ-SR averaged 0.98 +/- 0.06. In two other studies, diazepam absorption from DZ-SR was evaluated when coadministered with a standard breakfast or with an antacid preparation (Maalox). Neither food nor antacid altered the rate of diazepam absorption and did not impair the completeness of absorption. Higher peak total plasma diazepam concentrations occurred in the postprandial as opposed to the fasting state, but this was an artifact of reduced protein binding (increased free fraction) due to fasting. Thus, diazepam absorption from DZ-SR is slow and essentially complete.

Adolescent↗

PubMed2001

Intramuscular diazepam pharmacokinetics in soman-exposed guinea pigs.

Intramuscular (i.m.) diazepam is included by the US military as an anticonvulsant in the standard therapeutic regimen for organophosphorus nerve agent intoxication. In this study we investigated the pharmacokinetics of diazepam after i.m. administration while monitoring pharmacodynamic (electroencephalogram, EEG) data in soman-exposed guinea pigs. Prior to experiments the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered pyridostigmine (0.026 mg x kg(-1) i.m.) 30 min prior to soman (56 microg x kg(-1), 2 x LD50; subcutaneously, s.c.), which was followed in 1 min by atropine sulfate (2 mg x kg(-1) i.m.) and pralidoxime chloride (25 mg x kg(-1) i.m.). All animals receiving this regimen developed seizure activity. Diazepam (10 mg x kg(-1) i.m.) was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure terminated or not terminated at 30 min after diazepam. Serial blood samples were obtained from each animal. Diazepam (10 mg x kg(-1) i.m.) terminated seizure activity in 52% of the animals within 30 min. The pharmacokinetics were characterized by a one-compartment model with first-order absorption and elimination. The maximum plasma concentrations (Cmax) were 991 and 839 ng x ml(-1) for seizure terminated and not terminated, respectively. Mean plasma concentrations of diazepam were significantly different (P < 0.05) for seizure terminated vs not terminated groups at 30 min. The plasma Cmax in seizure-terminated animals in this study is similar to the minimum range of plasma diazepam (200-800 ng x ml(-1)) reported to suppress seizure activity in humans. It has been reported in an earlier study that the minimum effective i.m. dose (0.1 mg x kg(-1)) required to prevent soman-induced convulsions in Rhesus monkeys produces a mean Cmax of 50 ng x ml(-1) for diazepam. The data from our current study suggest that a higher dose (and corresponding Cmax) is necessary to terminate ongoing seizure activity.

Adsorption↗

PubMed1980

Poloxamer 188 as vehicle for injectable diazepam.

The significant occurrence of thrombophlebitis in patients administered diazepam intravenously was described recently. This side effect has been attributed to the crystallization of diazepam and its subsequent precipitation upon contact with blood or intravenous fluids. The current study was designed to reveal whether the solubilizing capability of poloxamer 188 reduces the incidence of thrombotic and inflammatory effects of diazepam in rabbits. The incidence of early (3-hr) ear vein necrosis was 72% in the diazepam-treated ears, while the incidence of necrosis in the ears that received poloxamer 188 as a vehicle for diazepam was 25%. The occurrence of thrombosis and loss of vessel integrity also was higher in diazepam-treated ears than in those treated with diazepam plus poloxamer 188. Solubilization of diazepam with poloxamer 188 may decrease the incidence of the tested side effects.

Animals↗

PubMed1991

Pharmacokinetics of diazepam intramuscularly administered to rhesus monkeys.

The purpose of this study was to define the pharmacokinetics of diazepam in monkeys following an im injection of 100 micrograms/kg (the minimum effective dose that prevents nerve agent-induced convulsions in pyridostigmine-pretreated, atropine- and 2-PAM-treated monkeys) in order to predict what im dose in humans is needed to prevent nerve agent-induced convulsions. Six rhesus monkeys were administered diazepam in the hind limb. Blood (3 mL) was collected via an indwelling saphenous catheter immediately prior to and 5, 10, 15, 25, 40, 60, 90, 120, 180, and 240 min after diazepam dosing. A contract laboratory, blind to the labeling code, analyzed diazepam serum concentrations by electron-capture gas chromatography and the percentage of unbound diazepam by equilibrium dialysis. The concentration-time data for total (unbound and bound) diazepam individually determined for each animal was best described by a one-compartment open model with first-order absorption and elimination. The average maximum serum concentration (50 ng/mL) was reached in 29 min. The volume of distribution and systemic clearance, assuming 100% bioavailability, were 1.5 L/kg and 19.4 mL/min/kg, respectively. The percentage of diazepam unbound to serum proteins was 4.6% and, therefore, the maximum concentration of free diazepam was 2.3 ng/mL. These results, when compared with human pharmacokinetic studies, allow a means of extrapolating effective monkey anticonvulsant doses to humans on a pharmacokinetic basis.

Animals↗

PubMed1983

Involvement of GABA in palate morphogenesis and its relation to diazepam teratogenesis in two mouse strains.

Previous studies have indicated that serotonin and acetylcholine stimulate palate shelf reorientation. The present studies were undertaken to determine whether gamma-aminobutyric acid (GABA) functions as an inhibitory neurotransmitter in the palate and whether diazepam mimics GABA to inhibit shelf reorientation and cause cleft palate. First, it was shown that 10(-4) M GABA inhibits palate shelf reorientation in day 14.5 AJ embryos cultured for 2 hours. Anterior palate reorientation stimulated by 10(-5) M serotonin was decreased by GABA; 10(-5) M picrotoxin (GABA antagonist) stimulated anterior shelf reorientation and reversed the effect of GABA. Diazepam (10(-4) M) partially inhibited palate shelf reorientation and that stimulated by 10(-5) M serotonin. Diazepam (400 mg/kg) was administered to AJ mice at day 13.5 of gestation and embryos were cultured at day 14.5. The inhibition produced by diazepam was significantly reduced by 10(-5) M picrotoxin. The teratogenic effect of diazepam was compared with AJ and Swiss-Webster Vancouver (SWV) inbred strains. Diazepam produced greater clefting in SWV mice (57% net) than in the AJ (18% net) when compared to their water- and food-starved controls. The greater sensitivity of the SWV strain than the AJ strain to diazepam, as well as to GABA, was also observed in embryo culture. GABA (10(-5) M) markedly inhibited posterior palate reorientation and reversed the stimulation produced by bethanechol in SWV mice. The inhibitory effects of GABA on the posterior palate were partially reversed by picrotoxin. Furthermore, diazepam inhibited palate reorientation either when administered to the pregnant dam or added in embryo culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Retrograde memory enhancement by diazepam: its relation to anterograde amnesia, and some clinical implications.

The effect of diazepam on retention of an inhibitory avoidance task was investigated in mice. In Experiment 1, animals were trained in this task, and tested for retention 24 h later. The mice received, 20 min after training, an IP injection of either diazepam (2 mg/kg) or saline; half of the mice in each treatment group were exposed, 40 min after avoidance training (and 20 min after the injections) to a Y maze. Exposure to the Y maze disrupted retention of the avoidance task in the saline-treated animals, and enhanced it in the diazepam-treated mice. Retention of habituation to the Y maze was impaired in the diazepam group. The effect can be explained by an interaction of the drug with the Y maze, by which exposure to the Y maze became facilitatory, instead of deleterious, to retention of the avoidance task. This may or may not be related to anterograde amnesia for the Y maze; and may be related to effects of diazepam seen in clinical practice. In Experiment 2, diazepam was given prior to, instead of after, inhibitory avoidance training; it caused anterograde amnesia for this task, which was not reversed by pre-test diazepam, and was therefore not due to state dependency. In conclusion, the effect of diazepam on inhibitory avoidance learning depends on the time at which the drug is given. A pretraining injection causes amnesia, whereas a post-training injection, while ineffective per se, may facilitate retention of the task when it is followed by exposure to a habituation procedure.

Amnesia↗

PubMed1996

Effects of diazepam on conflict behaviour and on plasma corticosterone levels in male and female rats.

The anxiolytic properties of diazepam and its effects on plasma corticosterone levels were compared in male and female, water deprived rats exposed to the punished (0.8 mA) drinking procedure. The effects of diazepam on unpunished licking, tested under familiar or unfamiliar conditions, and on the lick latency were also studied and a comparison between the two sexes was made. Both punished and unpunished drinking were less in females than in males. In both sexes, a clear anticonflict effect, i.e. a much greater effect on punished than on unpunished drinking, was obtained with 2 and 4 mg/kg, but not with 1 mg/kg, of diazepam i.p. Plasma corticosterone levels were higher in water deprived females than in males. Following the punished and unpunished drinking procedure, plasma corticosterone levels were found to have decreased more in female than in male rats, especially after administration of 1 mg/kg of diazepam. Diazepam had similar anticonflict effects in rats of both sexes but had a greater suppressive effect on the plasma corticosterone levels in female rats. There was no correlation between the anxiolytic effects of diazepam and its effect on the plasma corticosterone levels. When testing was done under unfamiliar conditions, the latency to licking was greater in female than in male rats and diazepam (1, 2 and 4 mg/kg) increased this latency in both sexes. The results suggest sex differences in the neuroendocrine, but not in the anxiolytic, effects of diazepam.

Analysis of Variance↗