Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to investigate physical dependence upon diazepam systematically in two inbred strains of rats, Lewis (LEW) and Fischer 344 (F344). Rats were chronically fed food containing diazepam on an escalating drug dosage schedule, from 1 and 2 to 12 mg/g of food, over a period of 30 days. During treatment, the growth curve in LEW and F344 rats was suppressed compared with the respective controls. Motor incoordination was evaluated by a rotarod performance test. The ranking of the motor incoordination during the final concentration of diazepam was as follows: F344 greater than LEW. After substitution of normal food for the diazepam-admixed food, various signs of diazepam withdrawal occurred 16-120 h later. These signs included vocalization, irritability, muscle rigidity, ear-twitching, Straub's tail, piloerection, fascicular twitch, tremor, convulsion, and death. The incidences of vocalization, ear-twitching, piloerection, and tremor in F344 were significantly higher than those in LEW rats. Furthermore, two of six F344 rats showed spontaneous convulsions and one rat died of convulsions. Overall withdrawal scores were significantly greater in F344 (16.0) than in LEW (6.3) rats. These results suggest that diazepam withdrawal severity is strongly influenced by genetic factors, and F344 rats are highly susceptible to dependence upon benzodiazepines.
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PMID:Genetic differences in the development of physical dependence upon diazepam in Lewis and Fischer 344 inbred rat strains. 143 78

1. Tolerance to and physical dependence on alprazolam were induced in mice by administering two doses of a slow release preparation. 2. Physical dependence was evaluated by the abstinence syndrome induced by flumazenil. Tolerance was studied by measuring the motor incoordination induced by a test dose of alprazolam. 3. The intensity of tolerance was decreased by the administration of L-phenylisopropyl adenosine (L-PIA), cyclopentyl adenosine (CPA), cyclohexyl adenosine (CHA), N-ethylcarboxamide adenosine (NECA), 8-phenyltheophylline (8-PTP) and theophylline (TP). 4. The intensity of the abstinence syndrome induced by flumazenil was attenuated by L-PIA, CPA NECA, TP and 8-PTP. 5. The results suggest that benzodiazepines may exert, at least in part, their effects by involving adenosine in the central nervous system.
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PMID:Adenosine analogs attenuate tolerance-dependence on alprazolam. 193 96

The establishment of, and sex differences in, physical dependence on methaqualone (MQ) in rats were studied by the drug-admixed food (DAF) method. Female and male rats were treated with MQ-admixed food on the same schedule of gradually increasing doses (0.5 and 1 to 6 mg of methaqualone/g of food). Only female rats showed hypothermia from MQ at 1 and 2 mg/g and motor incoordination from MQ at 4 and 6 mg/g of food. Moreover, after MQ withdrawal, severe withdrawal signs, including convulsions and death, were observed in female rats, but not in male rats. We also instituted a different schedule of graded increases in dose (1 and 2 to 10 and 12 mg/g of food) to develop physical dependence on MQ in male rats. Under this schedule male rats exhibited a hypothermia and severe motor incoordination from MQ 6 and 8 mg/g of food condition. After MQ withdrawal, various severe signs of MQ withdrawal occurred, including tremor, convulsions and death. These results demonstrate that severe physical dependence on MQ in both sexes can be established using the DAF method, and that there are marked sex differences in the physical dependence on MQ.
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PMID:Sex differences in physical dependence on methaqualone in the rat. 317 79

The effects of flunarizine and diltiazem both on development of physical dependence on barbital and on barbital withdrawal signs in rats were examined using the drug-admixed food (DAF) method. Rats were chronically treated with barbital or barbital in combination with flunarizine (fixed at 1.5 mg/g of food) or diltiazem (fixed at 0.75 mg/g of food)-admixed food on the schedule of gradually increasing doses of barbital. Motor incoordination during the treatment was potentiated by coadministration of flunarizine, but not by coadministration of diltiazem. After the termination of drug treatment, the body weight loss and withdrawal scores were significantly suppressed in the group coadministered flunarizine, but not in that coadministered diltiazem. There were no significant differences in plasma barbital levels after the withdrawal between groups. In the substitution test, flunarizine (20 and 40 mg/kg, IP) significantly suppressed the body weight loss and withdrawal scores after the withdrawal, but diltiazem (20 mg/kg, IP) did not. These results indicated that flunarizine suppressed both the development of physical dependence on barbital and barbital withdrawal signs, mainly according to the suppression of convulsions, but not diltiazem, which is known to poorly penetrate into the brain. Therefore, the present findings suggest that central calcium channels may be involved in both the development of physical dependence on barbital and the appearance of barbital withdrawal signs.
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PMID:Effects of flunarizine and diltiazem on physical dependence on barbital in rats. 839 34

The current study examined behavioral effects and possible development of physical dependence after once-daily doses of zolpidem (0, 1.0, 3.2, 10.0, 32.0 mg/kg intragastrically [i.g.]) in three baboons. Each dose was administered for 17 days and then the dose was increased; the 32.0 mg/kg dose was administered for 27 days. Baboons had access to food pellets for 20 hr/day beginning 15 min after dosing. Each day, baboons were presented with a fine motor task. Observation sessions were conducted 1 hr after dosing on days 1, 10, 12 and 14 of each dose condition and after termination of drug dosing. On days 10 and 14 of each dose condition, vehicle and flumazenil (5 mg/kg i.m.) were administered, respectively. Zolpidem increased the number of pellets obtained by two of three baboons. Vomit and/or retch and grimace (signs believed to be indicative of abdominal discomfort) were observed in one or two baboons during all zolpidem dose conditions (1.0-32.0 mg/kg). Time to complete the fine motor task increased dose-dependently in all three baboons, and incoordination was observed during the task in two baboons at 10.0 and 32.0 mg/kg. Analysis of blood plasma showed that measurable levels of zolpidem were present 24 hr after dosing in all drug conditions. The signs of flumazenil-precipitated withdrawal were summarized on a 9-point scale. Scores ranged from 1 to 5 in the 1.0 mg/kg condition, from 2 to 5 in the 3.2 and 10.0 mg/kg conditions and from 4 to 6 in the 32.0 mg/kg condition. Signs that were considered intermediate in severity were observed. Specifically, tremor, jerk and/or rigidly braced posture was observed in one baboon at 1.0 mg/kg, two baboons at the next two doses and all three baboons at 32.0 mg/kg. Vomit and/or retch also occurred in two baboons at dose conditions above 1.0 mg/kg. Discontinuation of zolpidem dosing after 78 to 79 days resulted in mild withdrawal signs (e.g., number of pellets obtained were lower and number of 1-min intervals increased in which eyes were closed, or in which lying down, head lower than torso posture and/or withdrawn posture were observed) on the first day in two baboons. The peak withdrawal scores were 4 or 5 on days 5 to 10; two baboons vomited and/or retched and all three baboons showed tremor, jerk and/or rigidly braced posture. Thus, zolpidem produced physical dependence under once-daily dosing conditions, and the severity of the withdrawal syndrome can be characterized as intermediate.
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PMID:Zolpidem physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons. 953 93

Inhalable solvents possess significant abuse liability and produce many of the neurobehavioral effects typically associated with central nervous system-depressant agents, including motor incoordination, anxiolysis, and the elicitation of signs of physical dependence on withdrawal. We tested the hypothesis that the commonly abused solvents toluene, 1,1,1-trichloroethane (TCE), and trichloroethylene (TCY) affect ligand-gated ion channel activity, as do other classes of central nervous system-depressive agents. TCE and toluene, like ethanol, reversibly enhanced gamma-aminobutyric acid (GABA)(A) receptor-mediated synaptic currents in rat hippocampal slices. All three inhalants significantly and reversibly enhanced neurotransmitter-activated currents at alpha1beta1 GABA(A) and alpha1 glycine receptors expressed in Xenopus oocytes. We previously identified specific amino acids of glycine and GABA(A) receptor subunits mediating alcohol and volatile anesthetic enhancement of receptor function. Toluene, TCE, and TCY were tested on several glycine receptor mutants, some of which were insensitive to ethanol and/or enflurane. Toluene and TCY enhancement of glycine receptor function was seen in all these mutants. However, the potentiating effects of TCE were abolished in three mutants and enhanced in two, a pattern more akin to that seen with enflurane than ethanol. These data suggest that inhaled drugs of abuse affect ligand-gated ion channels, and that the molecular sites of action of these compounds may overlap with those of ethanol and the volatile anesthetics.
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PMID:Glycine and gamma-aminobutyric acid(A) receptor function is enhanced by inhaled drugs of abuse. 1082 91