Spontaneous Withdrawal Syndrome Research Articles

BAY 11-7085 attenuates alcohol dependence induced spontaneous withdrawal syndrome in mice

Upregulation of nuclear factor kappa B plays a prominent role in drug addiction. The current study explored the neuroprotective effect of BAY 11-7085, a selective nuclear factor kappa B inhibitor, on the spontaneous alcohol withdrawal syndrome in mouse model of alcohol addiction. Administration of Alcohol (2g/kg, 10%, v/v, oral), once daily for 7 days. Assessment of behavioral parameters and exploratory parameters was done on 7 day after 8 hr. of the last ethanol administration for a period of 120 minutes. Various behavioural parameters were conducted like wall climbing test, composite withdrawal severity score, anxiety like behaviour assessed in open field and elevated plus test. Treatment with BAY 11-7085 markedly and dose dependently (p<0.05) attenuated spontaneous alcohol withdrawal syndrome in mice measured in terms of withdrawal severity score, wall climbing, locomotor sensitization by open field test and anxiety. Thus, it is suggested that activation of nuclear factor kappa B pathway is involved in the development of alcohol dependence induced withdrawal syndrome. Modulation of NFK-β may be used as therapeutic agent to overcome the problems related with alcohol dependence.

P.6.c.012 - The administration of cannabidiol reduced the spontaneous withdrawal syndrome induced by CP-55,940

P.6.c.012 - The administration of cannabidiol reduced the spontaneous withdrawal syndrome induced by CP-55,940

Assessment of abuse potential using a simple and translational model of spontaneous withdrawal syndrome in the Sprague–Dawley rat

Assessment of abuse potential using a simple and translational model of spontaneous withdrawal syndrome in the Sprague–Dawley rat

EFFECT OF MORPHINE WITHDRAWAL SYNDROME ON CEREBRAL ISCHEMIA OUTCOME IN RATS

Objective(s) Opioid abuse is still remained a major mental health problem, a criminal legal issue and may cause ischemic brain changes including stroke and brain edema. In the present study, we investigated whether spontaneously withdrawal syndrome might affect stroke outcomes. Materials and Methods Addiction was induced by progressive incremental doses of morphine over 7 days. Behavioral signs of withdrawal were observed 24, 48 and 72 hr after morphine deprivation and total withdrawal score was determined. Cerebral ischemia was induced 18-22 hr after the last morphine injection by placing a natural clot into the middle cerebral artery (MCA). Neurological deficits were evaluated at 2, 24 and 48 hr after ischemia induction, and infarct size and brain edema were determined at 48 hr after stroke. Results Morphine withdrawal animals showed a significant increase in total withdrawal score and decrease of weight gain during the 72 hr after the last morphine injection. Compared to the addicted and control animals, infarct volume and brain edema were significantly increased in the morphine deprived animals (P< 0.05) at 48 hr after cerebral ischemia. Also, neurological deficits were higher in the morphine-withdrawn rats at 48 hr after stroke (P< 0.05). Conclusion Our data indicates that spontaneous withdrawal syndrome may worsen stroke outcomes. Further investigations are necessary to elucidate mechanisms of opiate withdrawal syndrome on stroke.

Gender-linked differences in the expression of physical dependence in the rat

In earlier studies, it was shown that there were gender differences in several aspects of the pharmacological profile of morphine, including its antinociceptive activity, discriminative stimulus properties and its reinforcing effects. The purpose of the present studies was to examine whether there might also be gender-related differences in the development of physical dependence, as reflected in the expression of an opiate withdrawal syndrome upon cessation of chronic morphine administration. We found that a more severe spontaneous withdrawal syndrome was produced by chronic morphine injections or morphine pellet implantation in male rats than in females. The duration of the withdrawal syndrome was also longer. In contrast to our observations with spontaneous withdrawal, we found no gender differences in the naloxone-precipitated withdrawal syndrome induced by chronic morphine administration. These observations suggest that there are gender differences only in the expression of the spontaneous withdrawal syndrome, but not in the neuro-adaptive changes associated with the generation of physical dependence as reflected by naloxone-precipitated withdrawal.

Antagonist precipitated clonidine withdrawal in rat: Effects on locus coeruleus neurons, sympathetic nerves and cardiovascular parameters

The goal of the present study was to examine the effect of clonidine withdrawal on the neural control of blood pressure. Rats were treated for 7–13 days with clonidine via osmotic minipumps (200 μg kg −1 day −1, s.c.). Controls received saline or were sham operated. Withdrawal was precipitated by the α 2-adrenergic receptor ( α 2-AR) antagonist atipamezole. Most experiments were done under halothane anesthesia. Chronic treatment with clonidine did not change mean arterial pressure (MAP) or heart rate (HR) but raised femoral artery resistance and the activity of locus coeruleus neurons slightly. Atipamezole given to rats treated chronically with clonidine produced the following effects: no change in MAP, severe tachycardia, sustained increase in splanchnic sympathetic nerve discharge (SND; +75±13%), transient increase in lumbar SND (+23±7%), ON–OFF activity pattern in the locus coeruleus (LC). The ON phase of LC activity was synchronized with upswings of SND and with small changes in MAP. A second α 2-AR antagonist, methoxyidazoxan, produced effects identical to those of atipamezole. Atipamezole given to control rats produced no effect on MAP, HR, SND or LC activity. Atipamezole reversed the hypotension, sympathoinhibition and bradycardia produced by acute administration of clonidine. In awake rats treated chronically with clonidine, atipamezole did not change MAP but produced arterial pressure lability and tachycardia. In conclusion, under anesthesia, selective α 2-AR antagonists elicit a clonidine withdrawal syndrome that displays autonomic characteristics reminiscent of the spontaneous withdrawal syndrome found in awake rats. The most prominent features of this syndrome are tachycardia, sympathoactivation, lack of hypertension and an oscillating activity pattern of brainstem neurons leading to abrupt changes in SND and in MAP.

Similar decrease in spontaneous morphine abstinence by methadone and RB 101, an inhibitor of enkephalin catabolism.

1. The dual inhibitor of enkephalin degrading enzymes, RB 101, is able to block endogenous enkephalin metabolism completely, leading to potent antinociceptive responses potentiated by blockade of CCKB receptors. In this study we have investigated the effects induced by RB 101 given alone, or with the CCKB antagonist, PD-134,308, on a model of spontaneous morphine withdrawal and substitutive maintenance in rats. 2. Animals were chronically treated with morphine for 7 days followed, 36 h after the interruption of drug administration, by a maintenance treatment for 5 days with methadone (2 mg kg-1, i.p.), clonidine (0.025 mg kg-1, i.p.), RB 101 (40 mg kg-1, i.p.), PD-134,308 (3 mg kg-1, i.p.) or a combination of RB 101 plus PD-134,308. Several behavioural observations were made during this period in order to evaluate the acute effects as well as the consequence of chronic maintenance induced on spontaneous withdrawal by the different treatments. 3. Methadone was the most effective compound in decreasing the spontaneous withdrawal syndrome after acute administration. Both, methadone and RB 101 had similar effectiveness in reducing opiate abstinence during the period of substitutive treatment. PD-134,308 did not show any effect when administered alone and did not modify the effect of RB 101. 4. Naloxone (1 mg kg-1, s.c.) failed to precipitate any sign of withdrawal when injected at the end of the chronic maintenance treatment suggesting that, under the present conditions, methadone and RB 101 did not induce significant physical opiate-dependence. 5. The mildness of the side effects induced by chronic RB 101, suggests that systemically active inhibitors of enkephalin catabolism could represent a promising treatment in the maintenance of opiate addicts.

Repeated naltrexone administration accelerates resolution of morphine somatic withdrawal signs in morphine-dependent rats

Morphine-dependent rats were divided into two subgroups. The first was allowed to develop a spontaneous withdrawal syndrome which was still present 33 h after the last morphine administration. The second subgroup received five injections of naltrexone. While the first two injections of naltrexone precipitated a marked somatic withdrawal syndrome, subsequent naltrexone failed to worsen the somatic signs. 24 h after the last morphine administration, naltrexone was completely ineffective. It is concluded that naltrexone shortens the duration of the morphine somatic withdrawal signs in dependent rats.

Oral self-administration of triazolam, diazepam and ethanol in the baboon: drug reinforcement and benzodiazepine physical dependence.

Reinforcing and physical dependence-producing effects of oral diazepam and triazolam (0.01-1.28 mg/ml) were studied in four non-water-deprived baboons in daily 2-3-h sessions. Drinking initially was food-induced, but subsequently it was maintained for greater than year without the inducing procedures; drug intake greater than 10 mg/kg per session was attained. Triazolam and diazepam reinforcement (compared to vehicle) was concluded for only one baboon for each drug under a single-spout procedure and for two baboons for each drug under a two-spout procedure. However, all baboons showed ethanol reinforcement under a two-spout procedure. When a lever-pressing requirement was imposed for each drink (one-spout procedure), ethanol maintained requirements of 128 or 256 responses/drink, and volume of ethanol consumed was greater than vehicle. Neither benzodiazepine maintained lever pressing better than vehicle at any response requirement and drinking was suppressed by requirements of 1-32. Physical dependence to triazolam and diazepam developed after approximately 1 month of daily ingestion, evidenced by a precipitated withdrawal syndrome after injection of the benzodiazepine antagonist flumazenil. A mild spontaneous withdrawal syndrome occurred after substitution of vehicle for triazolam or diazepam. These data indicate a clear dissociation between the reinforcing and physical dependence-producing effects of triazolam and diazepam.

Withdrawal syndrome induced by the benzodiazepine receptor antagonist CGS 8216 after chronic diazepam treatment in rats

The high anxiolytic, hypnotic, and sedative potential of the benzodiazepine tranquilizers suggests that mental and physical dependence may develop on these substances if they are used for a long time. Clinical data on the frequency of withdrawal symptoms after administration of benzodiazepines are contradictory. According to some workers [8], a withdrawal syndrome is extremely rare after discontinuation of benzodiazepines. Other workers [7, 14], on the other hand, consider that a withdrawal syndrome due to long-term administration of benzodiazepine tranquilizers and their subsequent discontinuation is seen quite frequently, although as a rule it is seen in abortive forms, and in many cases is not diagnosed by clinicians. Experiments on animals and clinical observations have shown that repeated administration of benzodiazepines gives rise to increased tolerance to their sedative and anticonvulsant effects [i, 2, 4]. Under experimental conditions chronic administration of benzodiazepines in low doses does not give rise to characteristic features of withdrawal, but behavioral changes observed in animals after their discontinuation constitute what has been called the rebound syndrome, characterized by enhanced emotional reactivity, general apathy, and automatic disturbances [3]. Investigators who have used very high doses of diazepam (over i00 mg/kg daily) [I0] or chlordiazipoxide (110-800 mg/kg daily) [13] for 4 weeks have obtained a behavioral syndrome in rats which could be characterized as withdrawal. Withdrawal has been successfully obtained in these same animals by administration of the benzodiazepine receptor antagonist Ro 15-1788 [Ii, 12]. It must be noted, however, that withdrawal induced by Ro 15-1788 was weaker than the spontaneous withdrawal syndrome [Ii], evidently because of the weak benzodiazepine-like activity of Ro 15-1788 [5, 9].

Time course for development of benzodiazepine tolerance and physical dependence

Chronic benzodiazepine treatment elicits adaptive responses in the CNS, seen behaviorally as functional tolerance and physical dependence. Experiments are described in which a radioreceptor assay is used to follow benzodiazepine activity in CSF samples during daily flurazepam treatment of cats. Tolerance is evident even after the second dose, despite increasing CSF drug activity, showing a large and rapidly developing functional tolerance. Other studies are discussed which also show tolerance within 24 hours of initiating benzodiazepine treatment. In contrast, a spontaneous withdrawal syndrome is usually seen only after prolonged treatment with high doses. However, physical dependence can also be studied by precipitating abstinence with a benzodiazepine antagonist, such as Ro15-1788. Cats were treated daily with flurazepam, then Ro15-1788 was given and abstinence signs were recorded. Abstinence could be precipitated 24 hours after beginning treatment, and dependence was nearly maximal after 7 days. Dependence developed during treatment with as little as 0.5 mg/kg flurazepam, which is near threshold for any behavioral response. Chronic diazepam caused the same dependence as flurazepam. Thus, the development of tolerance and physical dependence both show a remarkably rapid adaptation of the CNS in response to benzodiazepines.

Development of morphine tolerance and physical dependence in rats depleted of brain catecholamines by 6-hydroxydopamine

The present study was undertaken to evaluate the roles of brain norepinephrine (NE) and/or dopamine (DA) in the development of morphine tolerance and physical dependence in rats. Rats were permanently depleted of brain catecholamines (CA, i.e. NE + DA) or DA by 6-hydroxydopamine (6-OHDA) treatment alone or desmethylimipramine plus 6-OHDA treatment at two weeks of age. Five weeks after either treatment, twice daily morphine injections were begun and continued for 32 consecutive days. The antinociceptive activity of morphine in the tail-flick test and the naloxone-precipitated abstinence syndrome were periodically observed throughout the course of chronic morphine treatment. A decreased antinociceptive response to morphine occurred in DA-depleted rats in both the non-tolerant and tolerant states, but the development of tolerance was not affected. The antinociceptive effect of morphine was not modified in either non-tolerant or tolerant CA (NE + DA)-depleted rats, nor was the development of tolerance affected. The spontaneous withdrawal syndrome after abrupt cessation of morphine after 32 days of treatment was markedly enhanced in CA-depleted rats. The results suggest that DA may be involved in mediating the antinociceptive effect of morphine, but not in the development of tolerance to that effect.