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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of three dosage schedules on the expression of a withdrawal syndrome indicative of physical dependence on pentobarbital was determined in male Sprague-Dawley rats. Rats were prepared with an intraperitoneal cannula and were continuously infused with either saline (control) or pentobarbital sodium, using an escalating drug dosage schedule, for either 5 (PB-5), 13 (PB-13) or 20 (PB-20) days. Final doses reached were 500 mg/kg/day (PB-5) and 1000 mg/kg/day (PB-13). PB-20 rats reached 1000 mg/kg/day on day 13 and were maintained at this dose for an additional 7 days. Body weight, water consumption and assessment of CNS depression were obtained daily. Following the last day of pentobarbital infusion all rats were infused with saline for a 72-hour drug-free period. Water consumption, body weight and assessment of overt behavioral signs indicative of a drug withdrawal syndrome were obtained at specific times during the drug-free period. PB-5 rats showed little evidence of withdrawal while PB-20 rats demonstrated the greatest degree of withdrawal. Peak withdrawal scores were observed to be 1, 3.8 and 5 for PB-5, PB-13, and PB-20, respectively. Withdrawal scores for group PB-13 and PB-20 were found to be significantly greater than either control or PB-5 but were not significantly different from each other. Body weight for PB-13 and PB-20 mice declined slightly (nonsignificant) during the drug-free period while a significant decrease (40% decline) in water consumption was demonstrated by 24 hours of this period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intensity of the withdrawal syndrome varies with duration of pentobarbital administration. 262 53

The objective of this study was to describe, quantitate and compare naloxone-induced abstinence syndromes in rats infused centrally (Sylvian aqueduct) with agonists that are currently the most selective for mu [( D-Ala2, MePhe4, Gly-ol5]enkephalin), delta [( D-Pen2, D-Pen5]enkephalin) and kappa (3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide) (U-50,488H) opioid receptors, respectively. Morphine, ethylketazocine and dynorphin A served as reference compounds. After 70 hr of infusion from s.c. implanted osmotic minipumps, three levels of abstinence were associated with the injection of naloxone (3 mg/kg s.c.): 1) negligible syndromes (scores of less than 21) were obtained in rats on water or the kappa-directed ligands, U-50,488H and dynorphin A; 2) a low-to-moderate abstinence score (37-38) was recorded with rats receiving [D-Pen2, D-Pen5]enkephalin and ethylketazocine; and 3) a high abstinence score (64-73) was obtained with rats on morphine and DAGO. These results reinforce the concept of developing selective, nonbenzomorphan kappa agonists as clinically useful analgesics and emphasize that, when evaluating new analgesics, high selectivity for delta receptors does not, in itself, guarantee freedom from physical dependence.
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PMID:Direct dependence studies in rats with agents selective for different types of opioid receptor. 290 90

The technique of chronic schedule-induced drug solution intake was used to determine the possible addiction liability of the short-acting benzodiazepine midazolam. Schedule-induction produces polydipsia over a wide range of fluids as a function of the imposed schedule of food availability. The inducing schedule used presented food pellets automatically once per minute, fixed time (FT) 1-min, for 3 h daily. Two groups of rats, drinking either water or 0.05 mg/ml midazolam solution, were exposed to schedule-induction sessions for approx. 2 months. Then, other FT-values (0, 0.5, 3 and 5 min) were instituted on occasion for single sessions. Each of these 'probe' session determinations was done twice. Although midazolam concentration had been adjusted so that the mean group intakes were equal at FT 1-min, probe values greater than 1 min revealed a greater acceptance of midazolam compared to water. This technique produced session midazolam intakes as great as 25 mg/kg. In the next phase, the entire experiment was repeated except both groups were offered a choice between water and midazolam solution during sessions. Only at FT 0 and FT 5-min was there an indication that midazolam was preferred over water. Two additional groups of animals were exposed to the same schedule-induced polydipsia regimen, drinking water and midazolam solution, respectively. Pre-session administration of doses of Ro 15-1788, CGS 8216 (benzodiazepine antagonists) or midazolam had no effects on either water or midazolam intakes, although the higher dose of midazolam (2 mg/kg, s.c) had a moderately suppressive effect on the non-tolerant water-polydipsic group. All groups were tested on occasion for physical dependence on midazolam with an auditory stimulus as the precipitator and midazolam polydipsic groups were found to have a mild to moderate dependence (clonic seizures, running fits).
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PMID:Midazolam oral self-administration. 316 May 67

Daily injections of the alcohol dehydrogenase inhibitor 4-methylpyrazole (4MP) were administered to C57BL/6J mice offered continuous free access to food, water and 10% v/v ethanol. There was a significant correlation (r = -0.82) between the rate of ethanol consumption during pretreatment and the effect of 4MP on subsequent intake. Mice drinking more than 2.5 g/kg per day decreased their intake, while subjects drinking less than this amount increased the quantity of ethanol self-administered. The elevated concentrations of plasma ethanol which resulted from voluntary consumption were sufficient to produce intoxication but did not induce physical dependence. Presenting mice with 10% ethanol as their only fluid or offering them a choice of water and saccharin-sweetened ethanol increased intake but failed to raise plasma ethanol to the concentrations observed in mice offered unflavored ethanol and water, and treated with 4MP. The evidence suggests that plasma ethanol does not limit voluntary drinking in untreated mice and that concentrations of 135 to 250 mg/dl are not avoided by C57 mice in a free-choice situation.
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PMID:Voluntary consumption of ethanol and its consequences in C57 mice treated with 4-methylpyrazole. 316 23

Since cholecystokinin (CCK) has been suggested to be an endogenous opiate antagonist, we tried to evaluate if this peptide could be involved in the development of tolerance to morphine. Naive rats were chronically administered morphine, either alone or concomitantly with proglumide or benzotript, two putative CCK receptor antagonists. Chronic treatments with both CCK antagonists alone were also established. Drugs were administered by the oral route, dissolved in the drinking water. At the end of the chronic treatments, the development of tolerance to morphine was assessed by an evaluation of the analgesic responses evoked by graded doses of acutely injected morphine in the tail-flick and hot plate tests. Proglumide and benzotript were able to inhibit the shift to the right of the dose-response curve for morphine, i.e. they prevented the development of tolerance to morphine-induced analgesia. Chronically given alone, the two CCK antagonists never modified the responses to the acute challenge with morphine. We also determined the development of physical dependence by looking at the withdrawal syndrome precipitated by graded doses of acutely injected naloxone. In these experiments the concomitant treatment with morphine and proglumide or benzotript did not modify the occurrence of dependence. These observations are consistent with the hypothesis of CCK being an endogenous opiate antagonist, involved in the development of tolerance to morphine-induced analgesia but not of dependence. Moreover, tolerance to and dependence on morphine can be pharmacologically dissociated.
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PMID:Dissociation of tolerance and dependence to morphine: a possible role for cholecystokinin. 358 Aug 99

Groups of rats drank either a solution of the ultrashort-acting benzodiazepine midazolam or water under schedule-induced polydipsia conditions in chronic, daily, 3-hr sessions. In Experiment 1, the physical dependence status of animals was tested after 9 months by the precipitated withdrawal method using the benzodiazepine-blocking agent Ro 15-1788 and by exposure to a brief audio stimulus at 1.5, 12 and 24 hr following drug withdrawal. Ro 15-1788 failed to produce withdrawal signs, while the audio stimulus plus withdrawal did. In Experiment 2, similar groups were periodically tested for susceptibility to audiogenically-induced seizures at 3, 6, 12, 15, 18, 21, 24 and 26 weeks 90 minutes after their drug or vehicle intake sessions. In the midazolam-drinking group, physical dependence developed at about 12 weeks and increased in severity over the course of the study. Serum measures confirmed that continuous elevation of drug and active metabolite levels are not necessary for the development of physical dependence. A chronic, daily, single elevation of a few hr was sufficient.
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PMID:Development of physical dependence on midazolam by oral self-administration. 360 36

An acute administration of MCI-2016 at the doses of 30, 100 and 300 mg/kg (p.o.), and 10, 20 and 30 mg/kg (i.p.) produced a slight CNS depression in rats, such as, sedation, ptosis, decrease in motor activity and systemic muscle relaxation. In a direct physical dependence test, rats were fed the MCI-2016-admixed food together with drinking water ad libitum for 24 hours daily for 51-71 days (mean MCI-2016 intake 29.9-210.7 mg/kg/day), on the gradedly increased dosage schedule with a dosage level of 0.25 and 0.5 mg/g food to 4 mg/g food. In a natural withdrawal following administration of MCI-2016, no significant withdrawal signs were observed in any group. In a naloxone-precipitation test the rats that were treated with MCI-2016-admixed food did not show any withdrawal signs. In a substitution test in either morphine or barbital dependent rats, no suppression of withdrawal signs or maintenance of dependence were observed by cross-administration of MCI-2016. In conclusion, MCI-2016 was considered to have no physical dependence potential.
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PMID:[Physical dependence liability test of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016) in rats]. 362 10

The plasma concentrations of morphine and glucose, the body weight, and the severity of the naloxone-precipitated withdrawal syndrome were studied in female rats in which morphine dependence was induced by administration of the opiate, with or without sucrose, in their drinking water. It was found that sucrose encouraged the animals to consume more morphine and that the initial plasma concentrations of the opiate, as well as the rate of development of physical dependence, were higher than the group not given sucrose. Plasma glucose concentrations, maximum plasma morphine levels and the maximum severity of the naloxone-precipitated withdrawal syndrome were, however, not significantly different between the two groups. The findings suggest that both regimens of administering the opiate in drinking fluid are effective in inducing morphine dependence in rats; the addition of sucrose tends to speed up the development of physical dependence, probably by increasing intake of the opiate through consuming more sucrose solution.
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PMID:Production of physical dependence in rats by drinking a morphine solution. 378 51

Dogs, surgically implanted with a chronic gastric fistula, were chronically dosed with N-desmethyldiazepam (32 mg/kg/day) in four divided doses to attain N-desmethyldiazepam plasma levels comparable to those observed in dogs dependent on diazepam (60 mg/kg/day). The time course of N-desmethyldiazepam abstinence was studied, beginning not less than 2 weeks after stabilization levels had been achieved. The abstinence syndrome observed after abrupt discontinuation of N-desmethyldiazepam was similar to the diazepam abstinence syndrome but differed in several important aspects. In diazepam-dependent dogs, there was a short burst of tremor very early in withdrawal (approximately 1-2 hr after the last dose of diazepam) that was not seen in N-desmethyldiazepam-dependent dogs. Signs of abstinence such as tremor, hot foot walking and twitches and jerks were more frequently observed in N-desmethyldiazepam-dependent dogs than in diazepam-dependent dogs as were decreases in food and water intake and in body weight. The overall intensity of abstinence, as measured by the Diazepam Withdrawal Abstinence Scale, was greater in N-desmethyldiazepam-dependent dogs than in dogs dependent on either lorazepam or diazepam. Plasma levels of N-desmethyldiazepam and oxazepam were nearly equal in dogs dependent on diazepam or on N-desmethyldiazepam and were 4 to 10 times greater than the plasma levels of diazepam or lorazepam in diazepam- or lorazepam-dependent dogs, respectively. Furthermore, the plasma levels of N-desmethyldiazepam and oxazepam declined much more slowly than the levels of diazepam and lorazepam. These results suggest that physical dependence on diazepam is caused by the accumulation and actions of N-desmethyldiazepam.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:N-desmethyldiazepam physical dependence in dogs. 393 42

Altered water-electrolyte status resulting from chronic alcohol dependence has been reported, although the nature of any such derangement is controversial. To illuminate this problem, four groups of rats were exposed chronically to schedule-induced polydipsia conditions with a single fluid available: 5% ethanol, 0.9% NaCl solution of 5% ethanol, 0.9% NaCl solution, or distilled water. An ad lib control group was also used. The water-electrolyte status of these groups was evaluated in two ways. First, the diuretic response to hydrochlorothiazide doses (8-12 mg/kg) was measured after 3.5 months of chronic polydipsia. Second, after approximately two additional months of polydipsia, extracellular fluid volume, as well as plasma volume and electrolytes were measured. Both alcohol-intake groups drank approximately 11.5 g ethanol/kg/day over the course of the experiment. Urinary volume response to the diuretic agent did not reveal that chronic ethanol led to either water retention or dehydration, even when extra NaCl intake was imposed chronically (NaCl-EtoH group). Animals that were overdrinking either water or the 0.9% NaCl solution had extracellular fluid volumes that were greater than the NaCl-EtOH-polydipsic group, but they were not significantly larger than ad lib controls. There were no significant differences with respect to serum electrolyte concentration measures among the groups. In conclusion, animals that drank ethanol chronically in a pattern known to produce physical dependence revealed no altered water-electrolyte status when evaluated by acute responses to a diuretic agent, a chronically-imposed extra NaCl load, or body fluid compartment and electrolyte concentration measures.
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PMID:Chronic alcohol dependence and water-electrolyte status. 396 36


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