Evidence Of Physical Dependence Research Articles

Opioid-like adverse effects of tianeptine in male rats and mice.

Tianeptine is a mu-opioid receptor (MOR) agonist with increasing reports of abuse in human populations. Preclinical data regarding the abuse potential and other opioid-like adverse effects of tianeptine at supratherapeutic doses are sparse. The present study evaluated tianeptine in a rat model of abuse potential assessment and in mouse models of motor, gastrointestinal, and respiratory adverse effects. Abuse potential was assessed in adult male Sprague-Dawley rats using an intracranial self-stimulation (ICSS) procedure to determine effects of acute and repeated tianeptine on responding for electrical brain stimulation. Male ICR mice were used to determine the effects of tianeptine in assays of locomotor behavior and gastrointestinal motility. Male Swiss-Webster mice were monitored for respiratory changes using whole-body plethysmography. In rats, acute tianeptine produced weak and delayed evidence for abuse-related ICSS facilitation at an intermediate dose (10mg/kg, IP) and pronounced, naltrexone-preventable ICSS depression at a higher dose (32mg/kg, IP). Repeated 7-day tianeptine (10 and 32mg/kg/day, IP) produced no increase in abuse-related ICSS facilitation, only modest tolerance to ICSS depression, and no evidence of physical dependence. In mice, tianeptine produced dose-dependent, naltrexone-preventable locomotor activation. Tianeptine (100mg/kg, SC) also significantly inhibited gastrointestinal motility and produced naloxone-reversible respiratory depression. Tianeptine presents as a MOR agonist with resistance to tolerance and dependence in our ICSS assay in rats, and it has lower abuse potential by this metric than many commonly abused opioids. Nonetheless, tianeptine produces MOR agonist-like acute adverse effects that include motor impairment, constipation, and respiratory depression.

Prevalence of Drug and Alcohol Use among Undergraduate Medical Students in a Nigerian Private University

Aim: This study was carried out to determine the prevalence of drug and alcohol use among medical students in a private University based in Abuja, Nigeria.
 Study Design: A descriptive cross-sectional survey.
 Place and Duration of Study: College of Health Sciences (CHS), Nile University of Nigeria, Abuja, between June 2018 and September 2018.
 Methodology: Using a semi-structured, self-administered questionnaire, information was obtained from 49 second year medical students (11 males, 38 females; age range 17-25 years), who were surveyed for the prevalence and reason of drug and alcohol use. Data retrieved was sorted, collated and subjected to statistical analysis using SPSS version 23.0 statistical package.
 Results: The mean age of students was 18.9 years and a higher proportion of respondents were female students (n=38; 77.6%). Out of the 49 students examined in this study, only 2 students currently use drugs while 8 students consume alcohol, given a prevalence of 4% and 16.3% respectively. Reasons given by one male alcohol user include: to build self-confidence (12.5%), while one female drug user uses it to escape from worries or troubles (50%). The prevalence of alcohol use was highest among male students (n=5; 62.5%), while that of drug use was highest among female students (n=2; 100%). Results also showed that the majorities of students were occasional users; and so there was no evidence of physical dependence.
 Conclusion: Findings established low prevalence of drug and alcohol use among study groups. However evaluation of full-scale university-level intervention is highly necessary.

Substance Abuse Among Medical Students – A Survey in a Medical College in Nepal

Introduction: Substance use among medical students could impact on the conduct, safety and efficiency of future doctors. Despite serious medico legal, ethical and political ramifications, there is paucity of published article on the subject, especially from Nepal.
 Objective: We aimed to explore the patterns of substance abuse among a sample of Medical students from Nepalgunj Medical College.
 Materials and Methods: A cross-sectional survey of medical students from Nepalgunj Medical College was done using a brief questionnaire schedule to identify current and lifetime use of tobacco, alcohol, cannabis and abuse of other drugs. An operational definition of substance abuse was made, 28 % of students fell within that criterion.
 Results: Male substance abusers 81% exceeded female abusers 19%. Substances most commonly abused were alcohol 60%, minor tranquilizers 48%, and tobacco 35%, and only 11% abused cannabis. While most students were multidrug users, there was a low frequency of daily drug use. A general lifetime (occasional use) prevalence of substance use of 56% was found. Drugs consumed on a daily basis were alcohol 2% and tobacco 6%. The prevalence of drug use was highest among the fourth and final year students.
 Conclusion: The majority of students were occasional abusers; there was no evidence of physical dependence. This study provides a snapshot of the problem of substance use among medical students of Nepal. Further research is needed to study nationwide patterns of substance use among medical students, and to identify important determinants and reinforce preventive measures. Strategies need to be developed for supporting students with a substance use problem.

Preclinical abuse liability assessment of ABT-126, an agonist at the α7 nicotinic acetylcholine receptor (nAChR)

ABT-126 is a nicotinic acetylcholine receptor (nAChR) agonist that is selective for the α7 subtype of the receptor. nAChRs are thought to play a role in a variety of neurocognitive processes and have been a pharmacologic target for disorders with cognitive impairment, including schizophrenia and Alzheimer's disease. As part of the preclinical safety package for ABT-126, its potential for abuse was assessed. While the involvement of the α4β2 subtype of the nicotinic receptor in the addictive properties of nicotine has been demonstrated, the role of the α7 receptor has been studied much less extensively. A number of preclinical assays of abuse potential including open-field, drug discrimination and self-administration were employed in male rats. ABT-126 had modest effects on locomotor activity in the open-field assay. In nicotine and d-amphetamine drug discrimination assays, ABT-126 administration failed to produce appreciable d-amphetamine-like or nicotine-like responding, suggesting that its interoceptive effects are distinct from those of these drugs of abuse. In rats trained to self-administer cocaine, substitution with ABT-126 was similar to substitution with saline, indicating that it lacks reinforcing effects. No evidence of physical dependence was noted following subchronic administration. Overall, these data suggest that ABT-126 has a low potential for abuse. Together with other literature on this drug class, it appears that drugs that selectively activate α7 nAChRs are not likely to result in abuse or dependence.

Low-Dose Doxepin

Doxepin binds with high specificity and affinity to the histamine H(1) receptor compared with other receptors. Therefore, at low doses, doxepin selectively antagonises H(1) receptors, which is believed to promote the initiation and maintenance of sleep. In three large, well designed, phase III trials in adult or elderly patients with chronic primary insomnia, oral, low-dose doxepin 3 or 6 mg once daily improved wake time after sleep onset, total sleep time and sleep efficiency to a significantly greater extent than placebo. Significant between-group differences in polysomnographic sleep recordings that favoured low-dose doxepin were evident after a single administration of the drug. Other efficacy measures, including patient-reported sleep quality, also favoured low-dose doxepin over placebo. Symptom control was maintained for up to 12 weeks of low-dose doxepin administration and there was no evidence of physical dependence or worsening insomnia after doxepin withdrawal. Oral, low-dose doxepin 6 mg was also significantly more effective than placebo in a large, well designed trial modelling transient insomnia in healthy adults, according to polysomnographic recordings (e.g. in latency to persistent sleep). Oral, low-dose doxepin was generally well tolerated in clinical trials.

Region-dependent changes in endocannabinoid transmission in the brain of morphine-dependent rats.

It has been suggested recently that the endocannabinoid system might be a component of the brain reward circuitry and thus play a role not only in cannabinoid tolerance/dependence, but also in dependence/withdrawal to other drugs of abuse. Here we have examined the changes in endocannabinoid ligands and their receptors in different brain regions, with particular attention to those areas related to reinforcement processes, during dependence on the powerful addictive drug, morphine. Thus, we analysed the brain contents of N-arachidonoylethanolamine (anandamide, AEA), the first discovered endocannabinoid, in rats subjected to daily injections of increasing doses of morphine, according to a schedule designed to render the animals opiate-dependent. Although evidence of physical dependence was assured by the appearance of somatic and neurovegetative responses in these animals after an acute challenge with naloxone, there were no changes in the contents of this endocannabinoid in any of the brain regions analysed. By contrast, we observed a significant decrease in the specific binding for CB(1) receptors in the midbrain and the cerebral cortex of morphine-dependent rats, with no changes in the other regions. The decrease in the cerebral cortex was, however, accompanied by a rise in the activation of signalling mechanisms by CB(1) receptor agonists, as revealed by WIN-55,212-2-stimulated [(35)S]GTPgammaS binding, whereas a reduction in this parameter was measured in the brainstem of morphine-dependent rats. In summary, the present data are indicative of the existence of an alteration of the endocannabinoid transmission during morphine dependence in rats, although the changes observed were region-dependent and affected exclusively CB(1) receptors with no changes in endocannabinoid levels. Because the changes occurred in regions of the midbrain, the cerebral cortex and the brainstem, which have been implicated in drug dependence, our data suggest that pharmacological manipulation of the endocannabinoid system might be a novel tool to reduce morphine addiction.

Anxiolytic-like effects of PNU-101017, a partial agonist at the benzodiazepine receptor.

PNU-101017 is a chemically novel ligand at the benzodiazepine recognition site of cloned GABAA receptors. It was reported to potentiate GABA-mediated chloride current in cultured cells with a moderate intrinsic activity and a biphasic dose-response relationship. In this study, we confirmed that PNU-101017 has a partial agonist-like effect in the antagonism of metrazole-induced seizures in mice. It produced no sedation or ataxia, but did antagonize diazepam-induced motor deficit of mice in the rotarod test. PNU-101017 was weakly active in anti-conflict anxiolytic tests, but attenuated the plasma corticosteroid response to mild stress in rats. It also antagonized stress-induced elevation of cerebellar cGMP levels in mice. Like chlordiazepoxide, it increased drinking of saline solution in thirsty rats. PNU-101017 did not potentiate the CNS-depressant effects of ethanol, and produced no evidence of physical dependence when administered repeatedly. Agonists with low intrinsic activity at the benzodiazepine receptor, such as PNU-101017, should be further explored for therapeutic uses.

Functional tolerance to chlormethiazole and cross-tolerance to ethanol in the rat: importance of test and mode of drug administration.

Tolerance to the effects of chlormethiazole on circular maze performance, and cross-tolerance to ethanol, were investigated in rats. Tolerance to chlormethiazole in the moving belt test was also measured in the same rats. Treatment with a total daily dose of subcutaneous chlormethiazole, 200 mg/kg, for 20 days produced clear tolerance to chlormethiazole and cross-tolerance to ethanol in the circular maze test. This treatment, however, failed to produce tolerance to chlormethiazole in the moving belt test. No evidence of physical dependence was found. In other studies, continuous intravenous infusion of chlormethiazole, 30-50 mg/kg/h for 9 days, resulted in clear functional tolerance to chlormethiazole and cross-tolerance to ethanol in the moving belt test. Similarly, chronic ethanol treatment, 4-6 g/kg daily for 3 weeks, resulted in functional tolerance to ethanol and cross-tolerance to chlormethiazole in the same test. These results indicate that the demonstration of functional tolerance to chlormethiazole and cross-tolerance to ethanol is dependent both on the sensitivity of the behavioural measurement tests employed, and on the degree of continuity of exposure of the central nervous system to the drug. It is concluded that, for doses that are equipotent in acute log-dose studies, chlormethiazole produces less tolerance and physical dependence than ethanol, perhaps because of a shorter half-life.

Alcohol Dependence and Problem Drinking in Scottish Young Offenders<xref ref-type="fn" rid="fn1"><sup>*</sup></xref>

Following the finding that 63 per cent of 200 consecutive admissions to a Scottish young offenders institution reported being drunk when committing their current offence, the sample was divided into four groups according to estimated degree of dependence on alcohol. 14.5 per cent showed evidence of physical dependence, 12.5 per cent of psychological dependence, and 36 per cent of prodromal signs of dependence. Many significant relationships between alcohol dependence and other relevant variables were found, including a tendency for dependent individuals to have more previous convictions overall and to be wine rather than beer only drinkers. Subjects reporting any dependence symptoms were older, started drinking at an earlier age and were younger when first drunk than subjects reporting no symptoms. There was also a significant tendency for physically dependent respondents to reject abstinence as a treatment goal and for psychologically dependent respondents to reject abstinence in favour of controlled drinking. Implications of the finding for educational and treatment policy are discussed.

Buprenorphine self-administration by rhesus monkey

Intravenous injections of buprenorphine, a partial opiate agonist and antagonist, maintained operant responding under second order schedule control (FR 3 VR 16:S) across a dose range of 0.005 to 0.10 mg/kg/inj. A drug naive monkey and four monkeys with a history of morphine self-administration all self-administered buprenorphine at all doses studied. Four monkeys showed dose-related increases in the total amount of buprenorphine (mg/kg) self-administered each day as the available dose increased from 0.01 to 0.10 mg/kg/inj. Injections per day remained equivalent to the number of injections at the lowest dose studied or increased significantly ( p<0.05, 0.01), as the dose per injection increased in three monkeys. Even at high buprenorphine doses, there was no evidence of sedation. Monkeys consistently self-administered significantly more buprenorphine than saline in control studies ( p<0.01). Buprenorphine's agonistic effects appear to persist for 24 to 48 hours. When saline and buprenorphine were available on alternate days, monkeys did not distinguish between them, but when 3 days of saline were alternated with 1 day of buprenorphine (0.03 mg/kg/inj), monkeys took significantly more buprenorphine than saline ( p<0.02−0.001). Abrupt discontinuation of buprenorphine (0.10 mg/kg/inj) did not result in discernible withdrawal signs. The effects of buprenorphine on food intake were inconsistent, but there were no significant changes in body weight as a function of chronic buprenorphine self-administration or withdrawal. These data indicate that buprenorphine is a positive reinforcer in rhesus monkeys and maintains behavior leading to its administration on second order schedules over a wide dose range. Despite its opiate agonist properties, there was no evidence of physical dependence.

Withdrawal Convulsions in Mice following Nitrous Oxide

Mice may be induced to convulse after (but not prior to) breathing nitrous oxide. We found that the incidence of this withdrawal phenomenon is related to the partial pressure of nitrous oxide. A minimum (threshold) value of about 0.5 atm is necessary and the majority of mice convulse following exposure to 0.9 atm or greater. Exposures of longer than 15 to 30 minutes do not significantly increase the incidence of convulsions at any given partial pressure. The mice remain susceptible to the induction of convulsions for only a brief period after removal from nitrous oxide. Although the duration of susceptibility is slightly increased after exposure to higher partial pressures, susceptibility in almost all cases is lost by 90 minutes. In mice, exposure to nitrous oxide is associated with evidence of physical dependence as evidenced by withdrawal symptoms, symptoms that be related to the appearance of excitement which sometimes follows nitrous oxide anesthesia.

Pattern of daily blood ethanol elevation and the development of physical dependence

Schedule-induced ethanol polydipsia regimens were used which produced either one or two daily peaks in blood ethanol levels. After 3 months on these regimens, rats were withdrawn from ethanol and tested for the presence of abstinence signs. No evidence of physical dependence was found, a result which contrasted with the previous finding of a severe withdrawal syndrome when blood ethanol was maintained at a more continuously elevated level prior to withdrawal. It was concluded that, as in the case of barbiturates, the development of physical dependence on ethanol requires more than an episodic peaking of the blood ethanol level once or twice per day.

Self administration of dextropropoxyphene by rhesus monkeys to the point of toxicity.

This study has shown that Rhesus monkeys will self-administer dextropropoxyphene without prior stabilization on other self-administered drugs. Throughout this program, animals maintained an inverse relationship between unit dosage of drug per injection and the rate of responding while the total daily intake of drug was directly related to the dosage unit. At no time did a monkey voluntarily discontinue self-administration of dextropropoxyphene nor was there any evidence of physical dependence when saline was substituted for the drug. The pattern of self-administration indicates that dextropropoxyphene may posses properties which limit the daily intake of drug over a wide dose range.

The toxicity of phenacetin at the range of the oral LD 50 (100 days) in albino rats

The oral LD 50 (100 days) of phenacetin or dose which produced 50% mortality after daily oral administration for 100 days, was found to be 1.12 ± 0.02 g/kg/day in young, male, albino rats. The LD 50 (100 days) was 27.1% of the acute oral LD 50 in overnight-starved young, male, albino rats. The clinical signs of toxicity were inhibition of growth, diuresis, glycosuria, proteinuria, diarrhea, ataxia, drowsiness, pallor, cyanosis, and a delayed increase in locomotor activity and fever. The most common finding after death of treated rats was chronic inflammation, probably due to infection, in the lungs and various other organs including the kidneys and liver, associated with a stress reaction, hypertrophy of the spleen and stomach, atrophy and hydration of many other organs, inhibition of spermatogenesis, and occasionally interstitial nephritis, renal papillary necrosis, and gastric ulcers. The syndrome was more marked in the winter months and in female rats. No evidence of physical dependence was found upon abrupt withdrawal of phenacetin after administration for 100 days.