Appearance Of Withdrawal Signs Research Articles

Morphine or its withdrawal affects plasma malondialdehyde, vitamin E levels and absence or presence of abstinence signs in rats

Abstract Objectives Various experimental observations show that morphine treatment generates reactive oxygen species, and that its discontinuation leads to signs of withdrawal. We therefore investigated plasma malondialdehyde and vitamin E levels under both conditions to verify the occurrence of any alterations in oxidative metabolism, and whether these are associated with behavioural changes. Methods We investigated the effects of morphine or morphine plus naloxone on plasma malondialdehyde, vitamin E levels and withdrawal signs such as jumping, wet dog shakes and faecal excretion in rats. Furthermore, isopropylnoradrenaline was injected in rabbits to verify its effects on plasma malondialdehyde levels. Key findings Morphine treatment increased free malondialdehyde and decreased vitamin E levels. The elevation in malondialdehyde levels were exacerbated by the abrupt removal of morphine by naloxone, which also led to the appearance of withdrawal signs. The increased malondialdehyde values can be attributed to the interactions of reactive oxygen species with unsaturated fatty acids, and the lowered levels of vitamin E to its interactions with reactive oxygen species. Conclusions A connection seems to exist between altered peroxide status and withdrawal signs in abstinent animals.

Morphine or its withdrawal affects plasma malondialdehyde, vitamin E levels and absence or presence of abstinence signs in rats

Various experimental observations show that morphine treatment generates reactive oxygen species, and that its discontinuation leads to signs of withdrawal. We therefore investigated plasma malondialdehyde and vitamin E levels under both conditions to verify the occurrence of any alterations in oxidative metabolism, and whether these are associated with behavioural changes. We investigated the effects of morphine or morphine plus naloxone on plasma malondialdehyde, vitamin E levels and withdrawal signs such as jumping, wet dog shakes and faecal excretion in rats. Furthermore, isopropylnoradrenaline was injected in rabbits to verify its effects on plasma malondialdehyde levels. Morphine treatment increased free malondialdehyde and decreased vitamin E levels. The elevation in malondialdehyde levels were exacerbated by the abrupt removal of morphine by naloxone, which also led to the appearance of withdrawal signs. The increased malondialdehyde values can be attributed to the interactions of reactive oxygen species with unsaturated fatty acids, and the lowered levels of vitamin E to its interactions with reactive oxygen species. A connection seems to exist between altered peroxide status and withdrawal signs in abstinent animals.

Plasma malondialdehyde levels and opiate withdrawal signs observed in rats treated with morphine plus naloxone: effects of α‐lipoic acid administration

A number of experimental studies have found that reactive oxygen species are involved during morphine treatment or withdrawal. The aims of this study were to analyse whether morphine administration and/or removal are related to peroxide generation and/or signs of withdrawal in rats, and whether the changes in antioxidant status induced by the administration of an antioxidant may modify peroxide levels and behavioural signs. We injected morphine or morphine and naloxone into rats and evaluated the plasma levels of peroxide malondialdehyde (MDA) and the appearance of withdrawal signs. We also investigated the effects on these parameters induced by the administration of the antioxidant alpha-lipoic acid (LA). Morphine treatment increased MDA levels. Abrupt naloxone-induced morphine withdrawal caused a further and significant increase in MDA, and the appearance of withdrawal signs such as abnormal fecal excretion, shortened latency times and jumping. The administration of LA lowered MDA levels in the rats treated with morphine or morphine plus naloxone, and also decreased MDA values and abstinence signs in the animals treated with morphine plus naloxone. The effects of LA were attributed to its capacity to scavenge peroxides and interfere with the biogenesis of the arachidonic acid metabolites involved in the expression of abstinence symptoms.

Influence of adenosine receptor agonists on benzodiazepine withdrawal signs in mice

The involvement of adenosine receptor agonists in benzodiazepine withdrawal signs was evaluated as the seizure susceptibility of mice. The concomitant administration of subthreshold dose of pentetrazole (55.0 or 60.0 mg/kg, s.c.) with flumazenil (10.0 mg/kg, i.p.) in mice chronically treated with temazepam or diazepam induced the appearance of withdrawal signs: clonic seizures, tonic convulsions and death episodes. The administration of the selective A 1 (CPA- N 6-cyclopentyladenosine), A 2A (CGS 21680-2- p-(2-carboxyethyl)phenethylamino-5′- N-ethylcarboxamidoadenosine hydrochloride) and the non-selective A 1/A 2A (NECA-5′- N-ethylcarboxamidoadenosine) adenosine receptor agonists (i.p.) evoked the significant attenuation of benzodiazepine withdrawal signs, and these effects were more expressed in temazepam- than in diazepam-dependent mice. CPA has shown the most apparent and dose-dependent attenuating effect. The results confirm that adenosine A 1 and A 2A receptors are involved in benzodiazepine withdrawal signs, and adenosine A 1 receptor plays a predominant role in this phenomenon.

Behavioral and molecular changes elicited by acute administration of SR141716 to Δ 9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence

Whether chronic cannabinoid consumption produces a dependent state comparable to that occurring with other drugs (e.g. the appearance of withdrawal signs when consumption is interrupted), and whether chronic cannabinoid consumption increases the risk of consuming other drugs of greater addictive power, are probably the two questions relating to cannabinoid addiction that provoke the most controversy. The present study was designed to further explore these two questions in laboratory animals. Firstly, we examined the effects of an acute challenge with SR141716 (an antagonist for the cannabinoid CB 1 receptor) in Δ 9-tetrahydrocannabinol (Δ 9-THC)-tolerant rats. This antagonist has been reported to precipitate a cannabinoid withdrawal syndrome. Thus, the administration of SR141716 to Δ 9-THC-tolerant rats reduced inactivity in the open-field test and enhanced responses as tremor, turning and retropulsion—these responses that were only slightly enhanced in control rats. The administration of SR141716 increased the plasma prolactin and the corticosterone concentration in controls, but these increases were much lesser in Δ 9-THC-tolerant rats. In addition, CRF-mRNA levels in the paraventricular hypothalamic nucleus, while reduced in SR141716-treated controls, were significantly increased in Δ 9-THC-tolerant rats. The analysis of endocannabinoids also revealed that the administration of SR141716, which was mostly inactive in control rats, was able to reverse the changes in anandamide or 2-arachidonoylglycerol concentrations found in Δ 9-THC-tolerant rats, in the striatum, limbic forebrain, diencephalon, cerebellum and brainstem, but not in the midbrain and hippocampus. As a second objective, we evaluated whether Δ 9-THC-tolerant rats were more vulnerable to morphine in a self-administration paradigm. The Δ 9-THC-tolerant and control rats self-administered morphine to a similar extent, in concordance with the similar values of dopaminergic activity in limbic and motor regions. In summary, our data indicate that Δ 9-THC-tolerant rats were not more vulnerable to the reinforcing properties of morphine. However, they responded to the blockade of CB 1 receptors by exhibiting slightly but possibly relevant differences in behavioral, endocrine and molecular parameters compared to the response in non-tolerant rats. This is indicative of the existence of a withdrawal syndrome in cannabinoid-tolerant rats that is mild compared with abstinence in opioid-dependent rats.

Concurrent chronic administration of a CCKB antagonist can decrease tolerance to the ataxic effects of ethanol

The effects of chronic administration of a CCK(B) antagonist, CAM1028, were examined on the development of tolerance to ethanol and the appearance of withdrawal signs. Ethanol was given chronically by liquid diet, and none of the dose schedules of CAM1028 affected the amount of ethanol taken in during the chronic treatment. Brain ethanol concentrations were not altered by the administration of CAM1028.The ataxic effects of ethanol were tested on a rotorod, 3 hours after cessation of the ethanol administration, and the last injections of CAM1028 were given 8 hours before withdrawal from the ethanol treatment. When administered at 0.03, 0.1 or 0.3 mg/kg, CAM1028 decreased the extent of tolerance development. Higher doses, 1 and 3 mg/kg, did not alter the tolerance development. Chronic administration of CAM1028 had a small effect in protecting against the effects of ethanol withdrawal that, in contrast to the effects on the tolerance, was seen only at the highest dose, 10 mg/kg, of CAM1028.

NMDA receptor antagonists potently suppress the spontaneous withdrawal signs induced by discontinuation of long-term diazepam treatment in Fischer 344 rats

The present study investigated the effects of the NMDA receptor antagonists dizocilpine (MK-801) and ifenprodil on the appearance of diazepam withdrawal signs caused by discontinuation of long-term diazepam treatment using a drug-admixed food (DAF) method in Fischer 344 rats. The total withdrawal score was significantly decreased by after-withdrawal treatment with dizocilpine or ifenprodil. Dizocilpine, in particular, markedly suppressed the motor withdrawal signs and body weight loss, while ifenprodil suppressed the motor and emotional withdrawal signs. Furthermore, the decrease in the food intake during withdrawal (anorexia) was significantly reduced by dizocilpine, but not by ifenprodil. These behavioral results indicated that the activation of NMDA receptors during withdrawal may play an important role in the appearance of withdrawal signs (in particular motor withdrawal signs) caused by discontinuation of chronic diazepam treatment, and that inhibitory agents for NMDA receptors may be effective in alleviation of the appearance of benzodiazepine withdrawal signs.

The role of calcium channels in drug dependence

This review aims to describe the role which calcium and calcium channels may play .in dependence on drugs of abuse. Brief details will be given of the acute actions of the drugs on calcium channels, but attention will be concentrated on work which has been done on the involvement of these channels in dependence. The majority of these sections will concentrate on dihydropyridine-sensitive calcium channels because there is considerable evidence to suggest that these sites may be important in several aspects of dependence. This, however, is largely because of the convenience of the high affinity binding of these antagonists, and there is much work still to be done on the role of the many channels which are insensitive to dihydropyridines. Throughout the review, the word ‘dependence’ is used to cover both physical dependence (as defined by the appearance of withdrawal signs) and self-administration of drugs. There are obviously very importance differences between these two phenomena and the relationship between them is the subject of much controversy and speculation among those working on drug dependence. Both have been included in this review, because, although alleviation of withdrawal symptoms does not necessarily affect the dependence of addicts on drugs, much information about the adaptive response to drugs can be obtained from understanding of the mechanisms of withdrawal behaviour and more selective treatments for withdrawal symptoms would provide therapeutic benefit. It is recognised that the relevance of animal models of self-administration of drugs to human drug dependence is also controversial, but this controversy will not be covered by this review; the models will be described in the appropriate sections. 1. cakim channels in lleumms

Alteration of convulsive threshold and sensitivity to CNS acting drugs in sedative-hypnotics-experienced rat offspring.

The present study was made to investigate the developmental toxicity of ethanol and several sedative-hypnotics (barbital, diazepam, phenobarbital) administered to rat pups via dams for 18 days (day 3-21 after parturition) from the relatively early postnatal stage in terms of changes in the threshold for pentetrazol (PTZ)-induced convulsion, tolerance to, and physical dependence on barbital (B). In the pups of all dosed groups, the convulsive threshold for PTZ is reduced significantly compared with that in the naive group. The sleeping time with B in phenobarbital-exposed offspring was also reduced significantly compared with that in the naive pups. No difference was however, noted in the B concentration of the brain or plasma upon awaking between these groups of pups, which proved that the phenobarbital-exposed pups had obviously acquired a functional tolerance to B. B-dependence formation and the ensuring weight loss and appearance of withdrawal signs, especially clonic-tonic convulsion, were made intense in the phenobarbital-experienced pups. From these results, it may be concluded that exposure to sedative-hypnotics from the early CNS developing stage makes a lowered state of convulsive threshold for PTZ, and therefore, tends to enhance B-withdrawal convulsion. These phenomena were discussed from the viewpoint of monoamine metabolism in the brain.

ALTERATION OF CONVULSIVE THRESHOLD AND SENSITIVITY TO CNS ACTING DRUGS IN SEDATIVE-HYPNOTICS-EXPERIENCED RAT OFFSPRING

The present study was made to investigate the developmental toxicity of ethanol and several sedative-hypnotics (barbital, diazepam, phenobarbital) administered to rat pups via dams for 18 days (day 3-21 after parturition) from the relatively early postnatal stage in terms of changes in the threshold for pentetrazol (PTZ)-induced convulsion, tolerance to. and physical dependence on barbital (B). In the pups of all dosed groups, the convulsive threshold for PTZ is reduced significantly compared with that in the naive group. The sleeping time with B in phenobarbital-exposed offspring was also reduced significantly compared with that in the naive pups. No difference was however, noted in the B concentration of the brain or plasma upon awaking between these groups of pups, which proved that the phenobarbital-exposed pups had obviously acquired a functional tolerance to B. B-dependence formation and the ensuing weight loss and appearance of withdrawal signs, especially clonic-tonic convulsion, were made intense in the phenobarbital-experienced pups. From these results, it may be concluded that exposure to sedative-hypnotics from the early GNS developing stage makes a lowered state of convulsive threshold for PTZ, and therefore, tends to enhance B-withdrawal convulsion. These phenomena were discussed from the viewpoint of monoamine metabolism in the brain.

Rating the presence and severity of opiate dependence.

The means for rating dependence to narcotic drugs and determining the severity of physical dependence is examined, using the administration at 0.8 mg naloxone intramuscularly and assessing the severity of dependence mainly by the presence and time of appearance of withdrawal signs. Responses were studied in 75 patients with drug abuse problems. Naloxone or saline was administered double blind and at random. In methadone‐ and opiate‐dependent sub;ects, net withdrawal scores after naloxone differed significantly from those after saline. In nonopiate‐dependent patients, there was no significant difference between net scores after naloxone and after saline. The results at the investigation were confirmed by a crossover study in which naloxone and saline were administered to 4 patients with suspected opiate dependence.