Induction Of Physical Dependence Research Articles

Heroin Abuse Results in Shifted RNA Expression to Neurodegenerative Diseases and Attenuation of TNF\u03b1 Signaling Pathway

Repeated administration of heroin results in the induction of physical dependence, which is characterized as a behavioral state of compulsive drug seeking and a high rate of relapse even after periods of abstinence. However, few studies have been dedicated to characterization of the long-term alterations in heroin-dependent patients (HDPs). Herein, we examined the peripheral blood from 810 HDPs versus 500 healthy controls (HCs) according to the inclusion criteria. Compared with the control group, significant decreases of albumin, triglyceride, and total cholesterol levels were identified in HDPs (P < 0.001) versus HCs coupled with an insignificant decrease in BMI. Meanwhile, RNA-sequencing analyses were performed on blood of 16 long-term HDPs and 25 HCs. The results showed that the TNFα signaling pathway and hematopoiesis related genes were inhibited in HDPs. We further compared the transcriptome data to those of SCA2 and posttraumatic stress disorder patients, identified neurodegenerative diseases related genes were commonly up-regulated in coupled with biological processes “vesicle transport”, “mitochondria” and “splicing”. Genes in the categories of “protein ubiquitination” were down-regulated indicating potential biochemical alterations shared by all three comparative to their controls. In summary, this is a leading study performing a series of through investigations and using delicate approaches. Results from this study would benefit the study of drug addiction overall and link long-term heroin abuse to neurodegenerative diseases.

Opioid receptor types involved in the development of nicotine physical dependence in an invertebrate (Planaria) model

Recent data suggest that opioid receptors are involved in the development of nicotine physical dependence in mammals. Evidence in support of a similar involvement in an invertebrate (Planaria) is presented using the selective opioid receptor antagonist naloxone, and the more receptor subtype-selective antagonists CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) (μ, MOR), naltrindole (δ, DOR), and nor-BNI (norbinaltorphimine) (κ, KOR). Induction of physical dependence was achieved by 60-min pre-exposure of planarians to nicotine and was quantified by abstinence-induced withdrawal (reduction in spontaneous locomotor activity). Known MOR and DOR subtype-selective opioid receptor antagonists attenuated the withdrawal, as did the non-selective antagonist naloxone, but a KOR subtype-selective antagonist did not. An involvement of MOR and DOR, but not KOR, in the development of nicotine physical dependence or in abstinence-induced withdrawal was thus demonstrated in a sensitive and facile invertebrate model.

Riluzole decreases the abstinence syndrome and physical dependence in morphine-dependent mice

The effects of the antiglutamatergic agent, riluzole, were examined on the antinociceptive action of morphine, on the induction of physical dependence, and on the expression of the abstinence syndrome to the opiate in mice. Morphine was administered as a single dose (200 mg/kg) of a slow-release preparation. Acute and chronic administration of riluzole decreased the analgesic response to morphine, the intensity of abstinence behavior (administered 30 min before a dose of naloxone), and the development of physical dependence (repeatedly administered during the period of chronic morphine treatment).

Pharmacokinetics of nordiazepam in physical dependence and precipitated abstinence in dogs

Previous studies suggested that the extensive accumulation of benzodiazepines is an important factor in the induction of physical dependence. The mechanistic basis for accumulation of nordiazepam (ND) and its metabolite, oxazepam (OX), have been examined in crossover studies in drug-naive and in ND-dependent dogs that exhibited a flumazenil-precipitated abstinence syndrome. ND and parent OX have similar pharmacokinetic profiles. Steady-state plasma levels of ND and OX cannot be predicted from single-dose pharmacokinetics. Reduced plasma clearance of ND and altered plasma protein binding were observed in dogs physically dependent upon ND. The benzodiazepine antagonist, flumazenil. significantlyreduces steady-state plasma levels of total and free ND.

Withdrawal precipitation by benzodiazepine receptor antagonists in dogs chronically treated with diazepam or the novel anxiolytic and anticonvulsant beta-carboline abecarnil.

The effects of the benzodiazepine (BZ) receptor antagonists flumazenil (Ro 15-1788) and the beta-carboline ZK 93426 were compared in dogs before and after chronic treatment with diazepam or the novel BZ receptor ligand abecarnil (ZK 112119). Abecarnil, a beta-carboline, is thought to act as partial (low efficacy) and/or subtype selective agonist at central BZ receptors. Diazepam and abecarnil were administered at doses which, based on previous experiments on anticonvulsant activity, resulted in about equieffective drug concentrations during treatment. In dogs treated with diazepam, 6 mg/kg/day p.o., for 2 weeks, severe abstinence symptoms, including seizures, were precipitated in all animals by i.v. infusion of the BZ receptor antagonists, differences being found in the type of symptoms caused by flumazenil and ZK 93426. In dogs treated with abecarnil, 4 mg/kg/d s.c., for 6 weeks, only relatively mild abstinence symptoms were precipitated by infusion of flumazenil or ZK 93426, although pharmacologically active plasma concentrations of abecarnil had been maintained throughout the period of treatment. This suggests that BZ receptor ligands which act as partial and/or selective agonists might be more favourable than traditional agonists, such as diazepam, regarding the induction of physical dependence.

Demonstration of physical dependence following chronic continuous methadone delivery via osmotic minipumps in pregnant rats

The effects of a 14-day (gestation days 7–20) chronic methadone (6.3–9.0 mg/kg/day) infusion via osmotic minipumps were studied on the induction of physical dependence in both pregnant and nonpregnant female rats. Following continued methadone exposure, an acute injection of naloxone (2.0 mg/kg, SC) produced the following symptoms of withdrawal in both pregnant and nonpregnant methadone-exposed rats: increased frequency of head shakes, teeth-chattering and face-rubbing episodes, as well as the induction of burrowing, diarrhea, facial tremor, squeaking and vaginal sniffing. Increased fetal movement in the maternal abdomen was also observed in the pregnant rats. In the saline-exposed pregnant controls, naloxone failed to induce a significant effect. In addition, brain and plasma methadone levels during the various stages of pregnancy (gestation days 8–20) were determined. The methadone levels in plasma were initially variable (gestation days 8–12) but became more constant (approximately 50 ng/ml) from gestation day 14 to 20. Methadone brain levels also followed a similar pattern, except that the brain methadone content was at least 20-fold greater than plasma concentrations at any given time. Thus, relative to the high brain levels, the present data suggest that acute changes in methadone plasma concentration may not be a good index of pharmacological effect.

Induction of physical dependence on pentobarbital by new infusion method in the rat

1. A new intermittent intravenous infusion method was developed for the induction of tolerance to and physical dependence on pentobarbital in rats. 2. Female and male rats were injected with pentobarbital (20 mg/kg/injection) through an implanted intravenous cannula. 3. The rats were allowed to receive an injection after the completion of a fixed amount of behavioral activity counted from the preceding injection, and therefore, the sedative and hypnotic effects of pentobarbital were used as an index in the determination of the injection intervals. 4. During pentobarbital treatment, the number of pentobarbital injections per day rapidly increased and stabilized (approximately 40: male, approximately 30: female) on the third to fifth day. 5. Upon withdrawal, the female and male rats who were maintained on pentobarbital administration of more than 30 and 40 injections/day for approximately 10 days manifested withdrawal signs which included spontaneous convulsion. 6. These results suggest that a new infusion method exists to produce a high degree of physical dependence in rats on a short-acting barbiturates, pentobarbital.

The concentration of morphine in serum of rats made dependent using a drug-admixed food method

The present study reports on the induction of physical dependence in rats using morphine-admixed food and addresses the question of the resulting concentration of morphine in serum. The stability of morphine in food is good, since no decrease in concentration could be observed. The concentration of morphine in serum during the experiment was measured using a radioimmunoassay technique. A correlation was found between the food intake during a 7-hour period and the concentration of morphine in the serum at the end of that period, both for a 1 g/kg and a 2 g/kg batch of morphine-admixed food. The concentration of morphine in serum was also found to be dose-related during a period of 6–23 days when the rats were fed for a prolonged period. After long-term administration of 1 g/kg morphine in food a steady-state level of about 0.5 mg/l serum was obtained. Similarly with 2 g/kg morphine in food a steady-state level of 0.8–1.1 mg/l serum was reached. After withdrawal of morphine the serum concentration of morphine dropped to 0.1 mg/l within 24 hours and to below the detection limit within 48 hours. During the witdrawal period sharp drops were noted in body weight (20%) and food intake (50%) after one day.

Cerebral alteration in calmodulin levels associated with the induction of physical dependence upon ethanol in rats

Calmodulin levels were measured in different areas of brain in rats rendered physically dependent and after single doses (6 g/kg) of ethanol. After single doses of ethanol no changes in the calmodulin levels were found in the cortex, but those in the hippocampus and caudate nuclei were increased while those in the cerebellum were reduced. In the dependent intoxicated (prodromal) rats, calmodulin levels were elevated in all these brain regions except the cerebellum. In rats undergoing ethanol withdrawal syndrome, the calmodulin levels decreased in all regions of the brain except caudate nuclei.

Sex Differences in the Induction of Physical Dependence on Pentobarbital in the Rat

Sex differences in physical dependence on sodium pentobarbital in the rat were studied by the drug-admixed food (DAF) method. With male rats, the concentration of pentobarbital in the food was gradually increased from 2 to 30 mg/g over a period of 50 days. The final level of drug intake was approximately 1.7 g/kg/day. At pentobarbital concentrations of 20 and 22 mg/g of food, sedation and mild muscle relaxation were observed. At the highest drug concentration, 30 mg/g of food, marked muscle relaxation was noted. With female rats, the concentration of pentobarbital in the food was gradually increased from 1 to 16 mg/g over a period of 47 days. The final level of intake was approximately 1.0 mg/kg/day. At drug concentrations of 12 and 14 mg/g, sedation and mild muscle relaxation appeared. At 16 mg/g, female rats showed marked muscle relaxation similar to that of the male rats. To produce severe loss of muscle tone, the male rats required twice as much pentobarbital as the female rats. After substitution of normal food for the pentobarbital-admixed food, various signs of pentobarbital withdrawal occurred in both sexes. These signs included vocalization, irritability, muscle rigidity, tremors and convulsions. Onset of withdrawal was more rapid in the females, and the maximum weight loss was greater, 8.0% compared to 3.8% in the males. Physical dependence on pentobarbital was easily developed in both sexes by the DAF method. There was a marked sex difference in withdrawal which we attribute to sex differences in drug metabolizing enzyme activity.

Induction of Physical Dependence on Codeine in the Rat by Drug-Admixed Food Ingestion

The developmental process of physical dependence on codeine has been explored in rats treated with codeine-admixed food (0.5 mg/g food) during 1 to 7 days. In rats treated with codeine for more than 2 days, body weight loss was markedly observed after the abrupt codeine withdrawal. The intensity and time course of body weight loss increased according to the duration of codeine treatment. After the codeine withdrawal, behavioral signs such as diarrhea, ptosis and vocalization were observed. In the naloxone-precipitated withdrawal test, rats treated with codeine for 1 day manifested a loss of body weight after naloxone challenge, and the intensity of body weight loss increased according to the duration of codeine treatment. After naloxone injection, the codeine-treated rats showed abnormal behaviors such as diarrhea, ptosis, teeth chattering, salivation, body shakes, vocalization, nose bleed, irritability, lacrimation and writhing. The total score, evaluated by the ranking system for precipitated withdrawal behaviors, was correlated with the duration of codeine treatment. These results suggest that naloxone-precipitated withdrawal signs are powerful in comparison with that after codeine withdrawal, and the weight loss is a common index for quantitative assessment of physical dependence on narcotics in the natural and naloxone-precipitated withdrawal tests. It is concluded that the drug-admixed food ingestion method has the advantage of rapidly inducing a high degree of physical dependence on codeine.

Induction of Physical Dependence on Morphine in Mice by the Drug-Admixed Food Method

The drug-admixed food method was applied to ICR strain mice for studying development of physical dependence on morphine. Mice were treated with morphine-admixed food of increasing concentration (1, 2 and 3 mg/g food) every third day for 9 days. During the treatment, the mice did not show any signs of toxicity. Plasma and brain morphine levels were quantitatively related to the morphine concentration in drug-admixed food. The plasma morphine level showed a circadian rhythm, and the level was higher than 0.1 5 μg/ml throughout the day. The morphine-treated mice manifested body weight loss, diarrhea and ptosis from 4 hr after morphine withdrawal and showed maximum body weight loss at 12 hr. In the naloxone-precipitated test, jumping and body shakes were observed in mice treated with morphine-admixed food (2 mg/g food) at least for 1 day. Moreover, in mice treated with morphine (2 mg/g food) for 3 days, marked jumping and body shakes and some writhing were observed after naloxone administration. These results suggest that the drug-admixed food method has advantages of easily and rapidly inducing the physical dependence on morphine in mice without causing toxicity and death.

Induction of physical dependence on codeine in the rat by drug-admixed food ingestion.

The developmental process of physical dependence on codeine has been explored in rats treated with codeine-admixed food (0.5 mg/g food) during 1 to 7 days. In rats treated with codeine for more than 2 days, body weight loss was markedly observed after the abrupt codeine withdrawal. The intensity and time course of body weight loss increased according to the duration of codeine treatment. After the codeine withdrawal, behavioral signs such as diarrhea, ptosis and vocalization were observed. In the naloxone-precipitated withdrawal test, rats treated with codeine for 1 day manifested a loss of body weight after naloxone challenge, and the intensity of body weight loss increased according to the duration of codeine treatment. After naloxone injection, the codeine-treated rats showed abnormal behaviors such as diarrhea, ptosis, teeth chattering , salivation, body shakes, vocalization, nose bleed, irritability, lacrimation and writhing. The total score, evaluated by the ranking system for precipitated withdrawal behaviors, was correlated with the duration of codeine treatment. These results suggest that naloxone-precipitated withdrawal signs are powerful in comparison with that after codeine withdrawal, and the weight loss is a common index for quantitative assessment of physical dependence on narcotics in the natural and naloxone-precipitated withdrawal tests. It is concluded that the drug-admixed food ingestion method has the advantage of rapidly inducing a high degree of physical dependence on codeine.

Induction of physical dependence on morphine in mice by the drug-admixed food method.

The drug-admixed food method was applied to ICR strain mice for studying development of physical dependence on morphine. Mice were treated with morphine-admixed food of increasing concentration (1, 2 and 3 mg/g food) every third day for 9 days. During the treatment, the mice did not show any signs of toxicity. Plasma and brain morphine levels were quantitatively related to the morphine concentration in drug-admixed food. The plasma morphine level showed a circadian rhythm, and the level was higher than 0.15 microgram/ml throughout the day. The morphine-treated mice manifested body weight loss, diarrhea and ptosis from 4 hr after morphine withdrawal and showed maximum body weight loss at 12 hr. In the naloxone-precipitated test, jumping and body shakes were observed in mice treated with morphine-admixed food (2 mg/g food) at least for 1 day. Moreover, in mice treated with morphine (2 mg/g food) for 3 days, marked jumping and body shakes and some writhing were observed after naloxone administration. These results suggest that the drug-admixed food method has advantages of easily and rapidly inducing the physical dependence on morphine in mice without causing toxicity and death.

A study on regional brain calcium concentrations following acute and prolonged administration of ethanol in rats

Regional brain calcium concentrations were assessed after acute and chronic ethanol administration. Prolonged exposure to ethanol was accomplished by a 10-day inhalation procedure. Acute administration of ethanol in doses of 1.0, 2.0, and 3.0 g/kg failed to alter calcium content in the cerebellum, cortex, hypothalamus, midbrain, and pons-medulla 30 min after injection. However, ethanol at 4.0 g/kg reduced brain content in the hypothalamus, midbrain, and pons-medulla. When a 90-min interval between ethanol administration (2.0 g/kg) and sacrifice was used, no change was found in the calcium concentration of the five regions examined. During the induction of physical dependence on ethanol, no alteration in the brain calcium content was observed when compared with controls. In the withdrawal phase, which followed 10 days of ethanol inhalation, regional brain calcium concentrations were similar to control values. These animals were monitored up to 7 days postexposure. In experiments which involved acute administration of reserpine (5 or 10 mg/kg), it was shown that the 10 mg/kg dose decreased calcium content only in the hypothalamus by 19.6%. Based on the data derived from this investigation it appears that calcium ions may have a limited role, if any, in the central actions of ethanol when steady-state calcium ion concentrations are considered.

Induction of physical dependence on and tolerance to ethanol in rats fed a new nutritionally complete and balanced liquid diet.

Rats offered a nutritionally balanced and complete liquid diet containing 35% of energy as ethanol, 12% as fat, 21% as protein, and the balance as carbohydrate consumed greater than 9 g/kg ethanol after 10 days. Rats displayed signs of physical dependence and tolerance while showing a net gain in weight. Physical dependence was indicated by severe intensity of the following signs during withdrawal from ethanol: Muscle rigidity; tail tremors; caudal tremors; and general tremors. Severity of these signs reached a maximum intensity by 19 h after withdrawal of ethanol. Tolerance was exhibited by chronically treated rats as measured by significantly reduced time off the belt after 7 days. Concentrations of ethanol in blood were documented on selected mornings and were observed to increase. These data suggest that physical dependence and tolerance can be induced through voluntary consumption of ethanol by rats and without nutritional compromises or weight loss.

280 - Studies on drug dependence (Rept.50): Induction of physical dependence in rats by short treatment of morphine-admixed food.

280 - Studies on drug dependence (Rept.50): Induction of physical dependence in rats by short treatment of morphine-admixed food.

Reversal of tolerance to ethanol associated with the induction of physical dependence on ethanol in the rat.

Three experimental paradigms were employed to investigate the possible relationship between tolerance to and dependence on ethanol in the rat. Groups of rats were exposed to ethanol vapor at various concentrations for different periods of time (e.g., 10 mg/l ethanol vapor for 10 days; 15 mg/l for 0.5 to 10 days; 20 mg/l for up to 12 hours). Tolerance was tested by measuring the concentration of ethanol in the breath at loss of righting reflex of the animal and the withdrawal syndrome was assessed behaviorally. Tolerance developed rapidly and was observed to reverse in association with the development of physical dependence.

Induction of physical dependence on ethanol using animal models

This review presents a summary and evaluation of the various techniques used in the production of physical dependence on ethanol in animals. The procedures for induction of the major withdrawal signs are classified according to the route of ethanol administration designed to circumvent the animals' inherent aversion to the taste of ethanol. Although it is possible to design an animal model of physical dependence on ethanol, the critical determinants of the process of alcoholism remain unknown.

Induction of physical dependence on cyclazocine and pentazocine in the rat

Rats were treated fro 24, 48 or 72 h with slow release (SR) emulsions of morphine (75, 100 and 150 mg/kg), cyclazocine (75, 100 and 150 mg/kg) or pentazocine (100, 200 and 400 mg/kg). At these times the degree of physical dependence was assessed by examining the abstinence behaviour (jumps + wet shakes), changes in body temperature and body weight induced by naloxone (5 mg/kg). The effects of SR treatments on brain levels of noradrenaline (NA), dopamine (DA), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were also determined at these times. The results shows that all three opiates induce physical dependence in the order of severity of morphine > cyclazocine > pentazocine. An elevation of 5-HT turnover also appears to be associated with the dependence produced by these opiates. These findings indicate that the increase in brain 5-HT metabolism is not a primary causative factor during opiate dependence, but occurs in response to some other process.