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 (+)-amphetamine circling rate of rats with unilateral 6-OHDA lesions in the striatum was recorded. Morphine tablets were implanted subcutaneously for chronic treatment. In the morphine-dependent animal the circling rate to amphetamine given 4 days after morphine was first implanted was depressed but after withdrawal with naloxone a day later the rate increased, returning to normal after 21 days. Barbiturate physical dependence was induced by adding increasing amounts of barbitone to the drinking water of lesioned rats over four weeks after which the amphetamine circling response was depressed and remained so after the barbituate was withdrawn. Ethanol tolerance was induced by adding ethanol to the drinking water of lesioned rats for four weeks. Neither the induction of tolerance over this period nor ethanol withdrawal had any effect on the circling response to amphetamine. The change in the response of striatal dopamine neurons to amphetamine that occurs after chronic morphine treatment, cannot be produced by chronic treatment with either barbitone or ethanol. The neurochemical bases of barbiturate and ethanol tolerance are different from morphine tolerance.
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PMID:Effect of tolerance to morphine, ethanol and barbiturate on amphetamine circling in rats with a striatal dopamine lesion. 2 10

We have previously demonstrated the antagonizing effect of aspartic acid on some effects of morphine and on the development of physical dependence on, and tolerance to, morphine. In the present study, we have withdrawal from morphine or administration of a morphine antagonist. For this purpose sixty five white rats were given morphine and aspartic acid separately and in combination in a 5% saccharose solution instead of drinking water for 30 days. Some of the dependent rats were then withdrawn and others were injected with levallorphan. Flying, jumping, wet-dog shaking, body weight loss and motor activity were estimated and free amino acid levels in the brain were determined. Aspartic acid was found to prevent or antagonize the behavioural signs and the changes in the free amino acid levels in the brain. The results are discussed in the light of the previous data.
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PMID:The antagonizing effect of aspartic acid on morphine withdrawal and levallorphan-precipitated abstinence syndrome signs and on associated changes in brain levels of free amino acids in the rat. 10 53

The microsomal cytochromes P-450 and b5 and the enzymes of the hepatic microsomal electron transport system (HMETS) including NADPH-cytochrome c reductase and NADPH oxidase activities were monitored in male ICR mice (25-30 g) over a six-day period following the repeated oral administration of 7, 14 and 28 mg/kg per day of l-alpha-acetylmethadol hydrochloride (LAAM) or an equivalent volume of water. Cytochrome P-450 and the microsomal enzyme activity of NADPH oxidase were maximally elevated (three- to four-fold above control values) by the third day of LAAM administration (28 mg/kg per day). These elevations not only correlated on a dose and a temporal basis with previously reported microsomal activities including LAAM N-demethylase, but also with the reported development of cellular tolerance and physical dependence following an identical regimen of LAAM. In addition, NADPH-cytochrome c reductase and cytochrome b5 increased in activity and content, respectively, after the repeated administration of this narcotic. However, the enzyme activity was first significantly elevated after only a single dose of LAAM. Thereafter, it showed a pattern of induction similar to that of NADPH oxidase. In contrast, cytochrome b5 was only elevated after the last repeated dose. The significance of these findings is discussed in some detail relative to the generation of the two analgesically active metabolites of LAAM.
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PMID:Additional metabolic correlates of 1-alpha-acetylmethadol (LAAM)-induced cellular tolerance and physical dependence: the role of the hepatic microsomal electron transport system. 11 96

Experimental evaluation of Wikler's interoceptive conditioning hypothesis of relapse to opioid use in ex-addicts requires a preliminary study of the degree of physical dependence produced by two methods of drug administration. Wistar rats were made physically dependent on morphine by single daily intravenous injections or by a continuous i.v. infusion. Rats received the same total daily dose regardless of administration schedule. The initial daily morphine dose was 20 mg/kg, and was increased every fourth day by 20 mg/kg, until a dose of 200 mg/kg per day was reached. The rats were maintained at the highest dose level for 18 days, at which time morphine was discontinued. Body weight and water intake were the primary variables measured during addiction, maintenance, and abstinence phases of the study. Equivalent and parallel changes in mean weight and water intake in injection and infusion rats indicate equivalent degrees of physical dependence were developed. This finding allows separation of the contribution of conditioning factors and of protracted abstinence in facilitating opioid self-administration in formerly-dependent organisms.
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PMID:Interoceptive conditioning through repeated suppression of morphine-abstinence. I. Basis for conditioning: once-daily vs. continuous intravenous morphine infusion. 26 13

Male Golden Hamsters drank large amounts of ethanol with food and water freely available, when ethanol was presented in water at concentrations of 10-40% (w/v). Although the hamsters consumed an average of 13.8 g/kg/day of ethanol for 3 months, no withdrawal signs were observed during 4 days without ethanol, nor were withdrawal signs observed during withdrawal after 4 more months of ethanol consumption. Although the Golden Hamster consumes large amounts of ethanol without the need for food or water deprivation, the Golden Hamsters may have limited usefulness as a model of physical dependence.
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PMID:Failure of signs of physical dependence to develop in hamsters after prolonged consumption of large doses of ethanol. 56 65

A single administration of ifenprodil at the doses of 100, 200 and 400 mg/kg (p.o.), and 50 and 100 mg/kg (i.m.) produced a moderate CNS depression in rats, such as, sedation, ptosis, systemic muscle relaxation and decrease in motor activity. These symptoms appeared dose-dependently and persisted for about 4 hours following administration. In a direct physical dependence test, 5 groups of rats were fed the ifenprodil-admixed food together with drinking water ad libitum for 24 hours daily for 53 approximately 103 days (mean ifenprodil intake, 43--240 mg/kg/day), on the gradedly increased dosage schedule with a dosage level of 0.5 vs. 1 mg/g food to 4 mg/g food. In the natural withdrawal following administration, no significant withdrawal signs were observed in any group. In a substitution test either for phenobarbital or morphine, no suppression of withdrawal signs during the period of cross-administration of ifenprodil and no maintenance of dependence were observed. In a physical dependence-producing test, the rats fed ifenprodil never manifested withdrawal signs such as diarrhea, "wet shakes", sudden loss of body weight as in the levallorphan precipitation test. Ifenprodil apparently has no physical dependence liability.
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PMID:[Physical dependence liability test of ifenprodil in rats (author's transl)]. 56 49

A new drug delivery system to induce physical dependence to morphine in rats is described. The device consists of a silicone polymer containing a water soluble "carrier" material, sodium alginate, which swells on contact with moisture to release the drug. The silicone or silastic pellets formulated to contain morphine sulfate are very easily prepared and the advantages over existing methods to induce physical dependence to morphine are discussed. In addition, a comparison of the percent of drug released and withdrawal intensities in rats was made with a silastic-morphine sulfate pellet, silastic-morphine base pellet and a microcrystalline cellulose-morphine base pellet.
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PMID:Preparation and evaluation of a sustained morphine delivery system in rats. 56 64

Following the repeated oral administration of l-alpha-acetylmethadol (LAAM) employing a dose (28 mg/kg per day) shown to induce its own metabolism by three- to four-fold, mice exhibited a rapid development of cellular tolerance and physical dependence which correlated on a temporal basis with this self-induction of LAAM metabolism. Evidence of cellular tolerance included significant elevations in the LAAM oral LD50, LAAM ICV (intracerebroventricular) LD50, LAAM oral AD50 and the LAAM ICV AD50 following repeated administration of this narcotic. Since the ICV parameters and the morphine AD50 were elevated over water control values, cellular tolerance appeared to play an important role in explaining the elevations noted for the oral parameters because the former were not influenced by changes in the rate of LAAM metabolism. Moreover, SKF-525A, a microsomal enzyme inhibitor, had little effect on the LAAM oral LD50 and the LAAM oral AD50, further indicating a minor role for dispositional tolerance. It is concluded that the induction noted for repeated oral LAAM administration most likely is responsible for generating more potent metabolites which in turn act to produce the cellular tolerance and physical dependence in these mice through constant exposure of the CNS.
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PMID:Development of cellular tolerance to lethality and analgesia concurrent with physical dependence following repeated oral administration of LAAM. 57 49

Rats maintained physically dependent upon morphine by scheduled access to drinking water containing morphine were trained to discriminate between s.c. injections of saline and 0.1 mg/kg of naltrexone in a discrete trial avoidance procedure in which a response on one of two choice levers would prevent or terminate the delivery of mild electric shocks to the floor of the test chember. Stimulus control of behavior by naltrexone in the morphine-dependent rat (defined as the reliable completion of at least 18 trials of a 20-trial session on the appropriate choice lever) had many of the features previously described for the stimulus control of behavior by morphine in the nondependent rat: long-term stability and reproducibility, orderly dose- and time-effect relationships and pharmacologic specificity. Stimulus control by naltrexone was blocked in a dose-related manner by morphine, an effect completely surmounted by a 10-fold increase in the dose of naltrexone suggesting a competitive antagonism. The naltrexone-induced discriminative stimuli appeared to be related to precipitated morphine withdrawal phenomena: following the abrupt withdrawal of morphine the amount and time course of naltrexone-appropriate responding were directly related to the degree of physical dependence; loss of body weight, a reliable index of morphine withdrawal in the rat, paralleled changes in naltrexone-appropriate responding; the maximum level of naltrexone-appropriate responding produced by a total of eight narcotic antagonists with agonist activity of differing prominence was a function of the extent of separation of the agonist and antagonist components of action of the drugs. Control of behavior by stimuli associated with morphine withdrawal may afford a specific animal model for studying factors relevant to the perpetuation of chronic drug use by human addicts.
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PMID:Discriminative stimulus effects of naltrexone in the morphine-dependent rat. 57 45

Oral barbital treatments consisting of average daily doses of 200 mg/kg with durations of 15-50 weeks have been used to induce functional tolerance and physical dependence. Tolerance is usually studied with a hexobarbital threshold while increased excitation has been studied by various means, such as induction of convulsions with pilocarpine or choline. After barbital treatments for 30 weeks brain weights are reduced by approximately 10 per cent. This reduction is not due to changes in body weight or water content of the brain. The decrease is still found 30 days after the end of the barbital treatment. Supersensitivity to pilocarpine and reduced acetylcholine content in the brain are some earlier published indications that cholinergic mechanisms are involved in abstinence. Further studies have shown that atropine (8 mg/kg given intraperitoneally on the third day of abstinence) can reduce the tolerance to hexobarbital. An atropine treatment (4 mg/kg per day for 2 weeks) given late in the period of abstinence following a barbital treatment can induce a tolerance to hexobarbital. A prerequisite for this tolerance is the earlier barbital treatment. A steric selectivity in the action of hexobarbital is indicated by the interaction between atropine (8 mg/kg) and the isomers of hexobarbital. In normal rats only the potent isomer of hexobarbital is influenced by atropine. If the convulsive effect of choline is utilized in a threshold test, an increased sensitivity indicating increased excitation is found on day 10-11 of the period of abstinence when other signs of excitation are returning to normal. When these signs are maximal, on day 3, no increased sensitivity to choline is found. Choline seems to act on a selective mechanism which is revealed only late in the abstinence period. Hexobarbital thresholds performed on two phases of the blood ethanol concentration curve were used to study the interaction between ethanol and hexobarbital during abstinence following a barbital treatment. Immediately after the end of the barbital treatment, a general tolerance was present. A week later, ethanol eliminated the tolerance to hexobarbital. On day 15 of abstinence, no tolerance to hexobarbital was found, but there was a tolerance to ethanol on the increasing portion of the blood ethanol concentration curve. Thus, it is unlikely that physical dependence and functional tolerance constitute a single phenomenon in abstinence after barbital treatments. Cholinergic mechanisms seem to be involved in the presumably adaptive changes that can be recorded.
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PMID:Some aspects of the changes induced by chronic barbital treatments in the male rat. 57 87


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