Showing papers on "Barbiturate published in 1981"

GABA‐Benzodiazepine‐Barbiturate Receptor Interactions

Abstract: The major inhibitory neurotransmitter in mammalian brain, y-aminobutyric acid (GABA), exerts its effects through increased postsynaptic membrane permeability to chloride ions (McBurney and Barker, 1978; Nistri et a]., 1980). The GABA receptor and associated chloride ion channel appear to be part of a protein complex containing receptor sites for GABA, benzodiazepines, and picrotoxininl barbiturates, as well as the chloride ionophore (Fig. 1). The three types of drug receptor sites studied by radioactive ligand binding have been thoroughly characterized to show their relevance to in vivo actions of the drugs that bind to the receptor sites in v i m . Various lines of evidence support the hypothesis that modulation of the postsynaptic response to GABA is involved in many of the actions of both the benzodiazepines (Haefely et a]., 1979; Costa and Guidotti, 1979) and the barbiturates and related central nervous system depressants (Nicoll et al., 1975; Haefely et a]., 1979; Macdonald and Barker, 1979). This article reviews the recent evidence for in v i m interactions between the three categories of drug receptors; the evidence supports the model for a complex as depicted in Fig. 1 and thus the relevance of GABA to the actions of the other drugs.

Pentobarbital: dual actions to increase brain benzodiazepine receptor affinity.

Abstract: The binding of [3H]diazepam to benzodiazepine receptors was studied in extensively washed membranes of rat cerebral cortex in the presence of the depressant barbiturate, pentobarbital. Pentobarbital, like the endogenous neurotransmitter gamma-aminobutyric acid (GABA), increased the basal binding and also potentiated the GABA-enhanced binding of [3H]diazepam to benzodiazepine receptors by increasing the apparent affinity of [3H]diazepam for the benzodiazepine receptor. The concentrations of pentobarbital necessary to elicit these effects in vitro are the same as those observed after treatment with pharmacologically relevant doses, suggesting that a common neurochemical association may exist between these types of compounds.

Self-injection of barbiturates and benzodiazepines in baboons

Abstract: Self-injection of three barbiturates, six benzodiazepines, and chlorpromazine was examined in baboons. Intravenous injections of drug were dependent upon completion of 160 lever presses (a 160-response fixed-ratio schedule). A 3-h time-out period followed each injection, permitting a maximum of eight injections per day. Prior to testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. Amobarbital, pentobarbital, and secobarbital maintained the highest levels of self-injection, which were similar to those maintained by cocaine. Clonazepam, clorazepate, diazepam, flurazepam, medazepam, and midazolam maintained relatively modest levels of self-injection, while chlorpromazine maintained only low levels, which were in the range of vehicle control. Of the six benzodiazepines, midazolam produced the highest levels of self-injection. At the highest self-injected doses, the barbiturates produced anesthesia in contrast to the benzodiazepines, which produced only sedation. None of the drugs affected food intake except for chlorpromazine, which produced dose-related decreases. The differences among the drug classes (i.e., barbiturate, benzodiazepine, phenothiazine) with respect to the maintenance of self-injection correspond well with the results of previous animal and human drug self-administration studies.

Perturbation of benzodiazepine receptor binding by pyrazolopyridines involves picrotoxinin/barbiturate receptor sites

Abstract: The two pyrazolopyridines, etazolate (SQ20009) and cartazolate (SQ65396), enhance the binding of [3H]diazepam to benzodiazepine receptor sites in rat brain. This enhancement is due to a change in affinity without a change in maximal binding. Pentobarbital also enhances [3H]diazepam binding by lowering the K(D). Pentobarbital gives a maximal enhancement of benzodiazepine binding slightly greater than that induced by etazolate, but maximal concentrations of etazolate cannot increase further the maximal enhancement by pentobarbital. By contrast, the enhancement of benzodiazepine binding by γ-aminobutyric acid (GABA) is fully additive with the effect of either etazolate or pentobarbital. The enhancement by γ-aminobutyric acid is blocked specifically by the two γ-aminobutyric acid mimetic compounds, imidazole acetic acid and 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol (THIP), compounds which do not inhibit the enhancement of diazepam binding by pentobarbital or etazolate. The effects of etazolate and pentobarbital, but not those of GABA, can be blocked competitively by 1 to 10 μM picrotoxinin. Etazolate and cartazolate, like pentobarbital competitively inhibit α-[3H]dihydropicrotoxinin binding with potencies correlating well with their stimulatory properties on benzodiazepine binding. These results suggest that pyrazolopyridines, like pentobarbital, stimulate [3H]diazepam binding through a picrotoxinin-sensitive site which is distinct from the γ-aminobutyric acid receptor site. These in vitro interactions between the etazolate and benzodiazepine receptor sites can be modulated also by the GABA antagonist, bicuculline, consistent with the existence of a complex containing three receptors (GABA, benzodiazepines, and etazolate/barbiturates/picrotoxinin). Bicuculline reverses completely the effects of etazolate and GABA on benzodiazepine binding but reverses only partially the enhancement by pentobarbital. This difference between the effects of pentobarbital and etazolate, as well as differences in their maximal enhancing effects mentioned above, suggests that pentobarbital may have an action similar to etazolate on some bicuculline-sensitive benzodiazepine binding sites, but, in addition, pentobarbital can enhance some other benzodiazepine sites in a manner which is neither mimicked by etazolate nor blocked by bicuculline. (Less)

Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique

Abstract: Although intravenous phenobarbital loading is effective in barbiturate withdrawal, controlled infusions of a drug are inconvenient. To develop a practical and more widely applicable method, oral loading doses of phenobarbital were given to 21 barbiturate addicts, whose estimated mean daily intake of barbiturates was 1 gm (range 0.5 to 4 gm). Twelve had a past or present history of barbiturate withdrawal seizures. Phenobarbital was given orally at a rate of 120 mg/hr until a predetermined clinical end point of phenobarbital effect was achieved. This end point was the presence of at least three of the following: nystagmus, drowsiness, ataxia, dysarthria, or emotional lability. The total phenobarbital loading dose (mean +/- SD) was 23.4 +/- 7.1 mg/kg, median phenobarbital concentration after loading was 35.9 mg/l (range 13.2 to 71.6 mg/l), and median half-life (t 1/2) of phenobarbital was 90 hr (range 38 to 240 hr). One patient with t 1/2 = 38 hr was given supplemental doses of phenobarbital. None developed seizures or other evidence of barbiturate withdrawal.

Pharmacological responses to pentobarbital in different strains of mice.

Abstract: This study was designed to assess the strain differences in pentobarbital toxicity, narcosis, the development of tolerance and physical dependence, the half-life of pentobarbital and the activities of hepatic microsomal electron transfer chain in DBA/2J, C57BL/6J and ICR mice. The comparisons of responses to acute pentobarbital-induced narcosis with two different doses revealed that DBA was most sensitive among these strains. When continuous administration of pentobarbital by pentobarbital pellet implantation is concerned, four criteria were used to assess strain differences: 1) determination of the duration of the loss of righting reflex during pentobarbital pellet implantation; 2) cumulative mortality after pentobarbital pellet implantation; 3) degree of tolerance development after 3 days of s.c. implantation of a 75-mg pentobarbital pellet by the relative decrease in the pentobarbital sleeping time; and 4) assessment of hyperexcitability by pentylenetetrazol- and audiogenic-induced seizures after pellet removal. The order of susceptibility to continuous pentobarbital pellet implantation was found to be as follows: DBA/2J > C57BL/6J > ICR. The biochemical data also revealed that the half-life of pentobarbital in DBA/2J mice was significantly longer than that of C57BL/6J or ICR mice in both brain and serum. Further studies also showed that DBA/2J mice have lower hepatic cytochrome P-450 and cytochrome b5 levels and NADPH dehydrogenase and NADPH-cytochrome c reductase activities as compared with the other strains of mice. However, these parameters were markedly induced in DBA/2J mice after the development of tolerance to pentobarbital. It appears that the differences in genetic variation could be of importance for further studies in gaining insight of the mechanism of barbiturate tolerance and dependence.

Barbiturates and Lung Cancer In Humans

Abstract: In a hypothesis-generating study looking for possible carcinogenic effects of drugs in humans, each of three barbiturates (pentobarbital sodium, phenobarbital, and secobarbital sodium) showed a statistically significant association with the subsequent development of lung cancer, with relative risks ranging from 1.5 to 2.8. Further analysis showed that the association was not explained by the increased prescription of barbiturate drugs shortly before the diagnosis of lung cancer or by an association of barbiturate use with cigarette smoking. Much of the data did not support a causal relationship. Neither a relation of lung cancer to duration or intensity of use not one between barbiturate use and a specific histologic type could be demonstrated.

Effect of pentobarbital on the reactivity of isolated human cerebral arteries

Abstract: ✓ The authors have analyzed the effect of pentobarbital (10−5M to 10−3M) on the contractile activity of isolated human cerebral arteries. Pentobarbital was found to inhibit both the spontaneous mechanical activity and the basal tone of these vessels. Relaxation induced by this drug was dose-dependent, and was more marked when the arterial tone was previously increased with noradrenalin, potassium chloride, or 5-hydroxytryptamine. In addition, pentobarbital inhibits, in a dose-dependent manner, the contractions elicited by these vasoconstrictor agents. The present findings indicate that barbiturates decrease cerebrovascular reactivity, and disagree with the hypothesis that these drugs reduce raised intracranial pressure by means of exerting a direct constrictive effect on the cerebral arteries.

Comparison of ethanol and barbiturate physical dependence.

Abstract: The physical dependence and tolerance characteristics of barbiturates and ethanol were compared. One group of cats was given anesthetic doses of pentobarbital chronically to produce severe physical dependence ("high dose" group). Two other groups of animals were given barbital or ethanol at "chronically equivalent" doses which produced gross ataxia without anesthesia ("low dose" groups). The doses required to produce the preset level of central nervous system depression progressively increased in all three groups during the chronic administration. Functional tolerance estimated by measuring the drug concentration in the blood at the peak of the drug response was demonstrated in all three groups. Drug administration was terminated after various durations and withdrawal was rated. Severity of withdrawal was assessed by monitoring spontaneous convulsions and by rating motor, autonomic and behavioral signs. These ratings were used to compute peak intensity of withdrawal. The number of convulsions, incidence of lethality during withdrawal and peak withdrawal intensity ratings were considerably higher in the ethanol groups than in the low dose barbiturate groups. Similarly, the number of convulsions, incidence of lethality during withdrawal and peak intensity ratings were consistently higher in the high dose barbiturate groups than in the low dose barbiturate groups. The results indicate that ethanol produced more severe withdrawal than barbiturate when the level of chronic intoxication was comparable in the two groups. Also, the level of central nervous system depression during administration was an important factor influencing intensity of barbiturate withdrawal.

Barbiturate dependence and drug preference

Abstract: Rats exposed to a daily 3-hr session of intermittent food delivery ingested physical-dependent levels of a 1 mg/ml sodium phenobarbital solution. This chronic, voluntary, high level of session phenobarbital intake had no effect on 21-hr home cage barbiturate preference. Substitution of water for phenobarbital during the session after 7.5 weeks precipitated various spontaneous withdrawal signs in some of the animals by the 24th hr of drug withdrawal but no change was found in home-cage barbiturate preference at any time. Physical dependence alone does not seem to play a crucial role in the maintenance of drug intake behavior.

Sedative-hypnotic tolerance testing and withdrawal comparing diazepam to barbiturates.

Abstract: A study was conducted to assess the feasibility of substituting diazepam for pentobarbital and phenobarbital in sedative-hypnotic tolerance testing and withdrawal of tolerant patients Nineteen patients potentially dependent on sedative-hypnotics were tolerance tested with either diazepam or pentobarbital and, if tolerant, were withdrawn with diazepam or phenobarbital, respectively Seventy-eight subjects previously described in the literature with drug dependencies similar to the diazepam and barbiturate groups provided a basis for comparing the diazepam group to untreated patients to determine whether diazepam was able to prevent abstinence symptoms Withdrawal was successfully completed in all patients The expected and observed incidence of seizures, delirium, and minor withdrawal for the barbiturate group and seizures and delirium for the diazepam group did not differ significantly, although a large type II error compromised these conclusions A significant difference was seen between the observed and expected incidence of minor withdrawal symptoms in the diazepam-withdrawn patients

Membrane Stability Changes of Subcellular Organelles After Barbiturate Treatment

Abstract: In the early seventies another effect of barbiturates came into discussion. NILSON, 1971 (21) and MICHENFELDER et al., 1973 (19) found barbiturate anesthesia to have a protective effect during brain ischemia and hypoxia. In the years to come there were many reports on the beneficial effects of barbiturates on local (13, 14, 27) and global brain ischemia (2, 3, 26, 30). All authors reported clear improvements and less neurological deficits when the animals were treated with barbiturates during brain ischemia. MARSHALL et al. (16, 17, 18) were able to decrease ICP of severely brain injured patients by means of barbiturate therapy and, thus, to improve outcome and reduce mortality rate.

Acute and chronic effects of pentobarbital on 5-hydroxytryptamine in mouse brain

Abstract: 1. 1. The influence of acute and chronic administration of pentobarbital on the brain 5-hydroxytryptamine systems was investigated in mice. 2. 2. Treatment of the animals with sodium pentobarbital, 75 mg/kg, i.p., resulted in an increase of 5-hydroxytryptamine and a decrease of 5-hydroxyindoleacetic acid levels. 3. 3. Acute pentobarbital treatment also caused the reduction of 5-hydroxytryptamine turnover without an equivalent decrease in 5-hydroxytryptamine synthesis. However, the 5-hydroxytryptamine synthesis was significantly decreased in animals which have developed tolerance to pentobarbital. 4. 4. The pretreatment of animals with p-chlorophenylalanine attenuated the development of tolerance to pentobarbital without altering the response of the animal to acute administration pentobarbital. 5. 5. On the other hand, no significant change was observed in 5-hydroxytryptamine systems in pentobarbital-withdrawal groups. 6. 6. These results strongly suggest that functional states of brain serotonergic systems may be involved in barbiturate action.

Effects of chronic delta 9-tetrahydrocannabinol administration on schedule-controlled behavior of pigeons: cross-tolerance to pentobarbital and barbital.

Abstract: Pigeons responding under a variable-interval (VI) 75-s schedule of food presentation were used to study cross-tolerance from Δ9-tetrahyrocannabinol (Δ9-THC) to pentobarbital and barbital. After initial dose-effect functions for pentobarbital and barbital were determined, the birds received Δ9-THC injections for 6 weeks. This chronic administration regimen resulted in a greater than 100-fold tolerance to Δ9-THC. Redetermination of the pentobarbital and barbital dose-effect functions during the chronic Δ9-THC regimen revealed statistically significant shifts to the right for the pentobarbital (0.191 log unit) and barbital (0.078 log unit) dose-effect curves. All six birds showed tolerance to pentobarbital, while four of the six showed tolerance to barbital. Blood barbital levels before and after chronic Δ9-THC administration did not differ significantly. Tolerance to Δ9-THC was more prolonged and of much greater magnitude than the cross-tolerance to pentobarbital or barbital. The results demonstrate that cross-tolerance can develop from Δ9-THC to a barbiturate that normally undergoes little metabolism.