Nefazodone decreases anxiety during marijuana withdrawal in humans

Abstract Rationale. Symptoms of marijuana withdrawal include increased irritability, depression and anxiety, and decreased sleep quality. Nefazodone, which is an antidepressant with sedative properties, may attenuate symptoms of marijuana withdrawal. Objective. The present within-subject, placebo-controlled study investigated the effects of nefazodone during marijuana withdrawal. Methods. Marijuana smokers [n=7; averaging 6.0 (±1.3) marijuana cigarettes/day, 6.4 (±0.4) days/week], not seeking treatment for marijuana use, were maintained on two doses of nefazodone (0, 450 mg/day) for 26 days each. Each maintenance condition began with an outpatient phase (9 days) and continued with an inpatient phase (17 days) in a residential laboratory. Marijuana was smoked 5 times per inpatient day at 1000, 1300, 1600, 1900 and 2200 hours. On days 1–4 (baseline), the first four marijuana cigarettes were placebo (0.00% THC), while the final marijuana cigarette was active (3.04% THC). On inpatient days 5–8, only active marijuana was smoked, while on days 9–16, only placebo marijuana was smoked. Mood, psychomotor task performance, food intake and sleep were measured daily. The order of maintenance dose was counterbalanced between groups. Results. Nefazodone maintenance did not alter the acute effects of active marijuana as compared to placebo nefazodone maintenance. During marijuana withdrawal, nefazodone decreased ratings of "Anxious", and "Muscle Pain", while having no effect on the marked increase in ratings of "Irritable", "Miserable" or decreased sleep quality. Conclusions. Nefazodone decreased certain marijuana withdrawal symptoms, but participants still reported substantial discomfort. These data provide further evidence of marijuana withdrawal, and highlight the need for more marijuana treatment options. Electronic Publication     

Abstinence symptoms following smoked marijuana in humans

Symptoms of withdrawal after oral Δ⁹-tetrahydrocannabinol (THC) administration have been reported, yet little is known about the development of dependence on smoked marijuana in humans. In a 21-day residential study, marijuana smokers (n = 12) worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day. Food and beverages were available ad libitum from 0830 to 2330 hours. Marijuana cigarettes (0.0, 1.8, 3.1% THC) were smoked at 1000, 1400, 1800, and 2200 hours. Placebo marijuana was administered on days 1–4 . One of the active marijuana doses was administered on days 5–8, followed by 4 days of placebo marijuana (days 9–12). The other concentration of active marijuana cigarettes was administered on days 13–16, followed by 4 days of placebo marijuana (days 17–20); the order in which the high and low THC-concentration marijuana cigarettes were administered was counter-balanced between groups. Both active doses of marijuana increased ratings of “High,” and “Good Drug Effect,” and increased food intake, while decreasing verbal interaction compared to the placebo baseline (days 1–4). Abstinence from active marijuana increased ratings such as “Anxious,”“Irritable,” and “Stomach pain,” and significantly decreased food intake compared to baseline. This empirical demonstration of withdrawal from smoked marijuana may suggest that daily marijuana use may be maintained, at least in part, by the alleviation of abstinence symptoms. Received: 2 June 1998 / Final version: 11 September 1998     

Changes in aggressive behavior during withdrawal from long-term marijuana use

Rationale: Even though marijuana is the most commonly abused illicit drug in the United States, it is still undetermined whether withdrawal after chronic use results in changes in aggressive behavior in humans. Objective: The present study investigated the pattern and duration of changes in aggressive behavior in long-term marijuana users during a 28-day abstinence period verified by daily urines. Methods: Chronic marijuana users who had smoked marijuana on at least 5000 occasions (the equivalent of smoking daily for approximately 14 years) and who were smoking regularly when recruited were studied on days 0 (when they were still smoking), 1 (during acute withdrawal), 3, 7 and 28 of a 28-day detoxification period. Aggressive behavior was measured using the Point Subtraction Aggression Paradigm. Results: Compared to controls and to the pre-withdrawal data, chronic marijuana users displayed more aggressive behavior on days 3 and 7 of marijuana abstinence. These increases in aggressive responding returned to pre-withdrawal levels after 28 days and were paralleled by small, non-significant changes in depression and anxiety scores. Conclusions: Our findings confirm previous reports of an abstinence syndrome associated with chronic marijuana use and suggest that aggressive behavior should be an additional component of this syndrome. Received: 10 September 1998/Final version: 31 October 1998     

Physical withdrawal in rats tolerant to Δ-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist

Tolerance to Δ⁹-tetrahydrocannabinol (Δ⁹-THC) was produced in rats by twice daily injections (15 mg/kg i.p.) for 6.5 days. Administration of the cannabinoid antagonist SR141716A (i.p. or i.c.v.) induced a profound precipitated withdrawal syndrome in Δ⁹-THC-tolerant animals. The syndrome was characterized by a disorganized pattern of constantly changing brief sequences of motor behavior. Autonomic signs were not evident. THC-tolerant animals that were treated with vehicle remained quiet throughout the observation period.     

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

Introduction Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence. Objectives The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an α₂-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence. Materials and methods Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured. Results THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone. Conclusions These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.     

Physical withdrawal in rats tolerant to Δ-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist

Tolerance to Δ⁹-tetrahydrocannabinol (Δ⁹-THC) was produced in rats by twice daily injections (15 mg/kg i.p.) for 6.5 days. Administration of the cannabinoid antagonist SR141716A (i.p. or i.c.v.) induced a profound precipitated withdrawal syndrome in Δ⁹-THC-tolerant animals. The syndrome was characterized by a disorganized pattern of constantly changing brief sequences of motor behavior. Autonomic signs were not evident. THC-tolerant animals that were treated with vehicle remained quiet throughout the observation period.     

Hyperalgesia during withdrawal as a means of measuring the degree of dependence in morphine dependent rats

A modified flinch-jump procedure was used to detect changes in sensitivity to electric footshock in rats. In preliminary studies, dose-related increases in reaction thresholds (analgesia) were observed following intraperitoneal administration of 3, 6, or 9 mg/kg of morphine with the peak effect 60 min after injection. Analgesia and development of tolerance to the analgesic effects of morphine were detected 2–6 h and 12–24 h, respectively, after the subcutaneous (s.c.) implantation of a morphine pellet (75 mg base). In studies of withdrawal, rats made dependent by the s.c. implantation of morphine pellets showed significant decreases in reaction thresholds (hyperalgesia) and correlated decreases in body weight following removal of the pellet. The greatest changes during withdrawal occurred 12–36 h after pellet removal and the return of the reaction threshold to preremoval levels was associated with the return of normal diurnal fluctuation of body weight. Rats made dependent by s.c. administration of varying doses of morphine every 8 h for 11 days showed similar decreases in body weight and reaction threshold following abrupt cessation of drug injections. Animals receiving larger doses of morphine showed greater changes in the two measures, as well as a more rapid onset and more prolonged duration of effect. Peak effects were observed 48–60 h after the last injection of morphine. In another experiment, rats were made dependent to morphine by the pellet implantation procedure. Following i.p. administration of varying doses of naloxone, a morphine antagonist, there were dose-related decreases in reaction threshold and in body weight with the greatest decrease occurring 60–120 min after the injection. These investigations indicate that the hyperalgesia during withdrawal is a useful index of the degree of physical dependence in rats.Supported in part by Grant NS-10323 from NINDS.     

Effects of depletion of brain catecholamines during the development of morphine dependence on precipitated withdrawal in rats

Summary The significance of long term depletion of brain catecholamines (CAs) for the development of morphine dependence and for the expression of morphine withdrawal was studied in rats which were implanted with morphine pellets for 10 days. CAs were depleted by inhibition of tyrosine-hydroxylase with alpha-methyl-tyrosine (AMT) or by destruction of catecholaminergic nerve terminals with 6-hydroxydopamine (6-OHDA). In the acute experiments these drugs were applied within 24 hrs before precipitation of withdrawal; in the chronic experiments drug administration was started before the first implantation and in the case of AMT, continued repeatedly thereafter.With either method, acute depletion of brain CAs resulted in reduced intensity of withdrawal. When CAs were kept low through the whole time of morphine exposure and also at the time of withdrawal, the intensity of withdrawal was normal in the case of 6-OHDA administration and only slightly decreased in the case of AMT. When AMT administration was discontinued 40 hrs before precipitation of withdrawal the withdrawal pattern occurred with unchanged intensity.Our experimental data are compatible with the assumption that long lasting depletion of brain CAs is compensated for by induction of neuronal supersensitivity for noradrenaline (NA) and dopamine (DA). While both CAs play an important role in the full expression of the withdrawal syndrome their possible involvement in mechanisms leading to dependence seems to be unlikely although final statements cannot be made by the presented experiments.     

Nicotine self-administration and withdrawal: modulation of anxiety in the social interaction test in rats

RATIONALE: Most smokers report smoking has an anxiolytic effect, which may contribute to nicotine dependence. OBJECTIVE: To examine effects in the social interaction test (SI) of anxiety after 4 weeks' self-administered nicotine (15 infusions of 0.03 mg/kg, totalling 0.45 mg/kg per day), and after 24 and 72 h of withdrawal. The effect of exposure to the operant chamber on withdrawal responses was also examined. METHODS: Animals were trained to self-administer saline or nicotine and after 4 weeks they were tested in SI after their daily self-administration session. Animals were retested after 24 and 72 h withdrawal, when they were either taken directly from the home cage or were tested 5 min after a 30-min exposure to the operant chamber. RESULTS: Compared with the saline control group, the animals that had been self-administering nicotine for 4 weeks showed decreased social interaction with no decrease in locomotor activity, indicating a significant anxiogenic effect of the nicotine infusions. There was no change in social interaction after 24 and 72 h withdrawal from chronic nicotine, regardless of whether or not the rats were exposed to the operant chamber just prior to being tested. CONCLUSIONS: Nicotine self-administration is not maintained because of its anxiolytic effect, but despite, or because of, its anxiogenic effect. There was no evidence of an anxiogenic response after either 24 or 72 h of withdrawal and thus increased anxiety on withdrawal from nicotine does not seem to contribute to nicotine self-administration.     

Incremental validity of anxiety sensitivity in relation to marijuana withdrawal symptoms

The present investigation examined the relation between anxiety sensitivity (AS) and marijuana withdrawal severity among 84 (47 female) young adult marijuana smokers. As expected, after covarying for the theoretically-relevant variables of frequency of past 30-day marijuana use, number of cigarettes smoked per day, volume of alcohol consumed, and anxious arousal as well as anhedonic depressive symptoms, both the global AS factor and the AS-mental incapacitation concerns factor were significantly related to the severity of retrospectively reported marijuana withdrawal symptoms. Results are discussed in relation to better understanding cognitive-emotional variables related to the marijuana withdrawal.     

The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans

RATIONALE: The serotonin system has an important role in the modulation of several processes relevant to psychiatry such as anxiety, affect, aggression, and drug abuse. This review summarizes the recent progress in elucidating the function of the serotonergic system using knockout mice. This review while not exhaustive, highlights recent findings of relevance to psychopharmacology. OBJECTIVES: To familiarize the reader with the technique and the findings from serotonergic knockout mice. METHODS: Information included in this review was drawn from our own experience in this field and relevant publications from other investigators. RESULTS: We have focused on three main themes that have emerged from studies with mice bearing single-gene mutations of serotonergic genes: anxiety, aggression, and drug abuse. Mice lacking the 5-HT1A have been found to be more anxious in several behavioral paradigms. Elevated levels of aggression have been reported in mice lacking the monoamine oxidase A and the 5-HT1B receptor genes. The mice lacking the 5-HT1B receptor have also been reported to exhibit an increased vulnerability to cocaine. The molecular basis of this enhanced vulnerability has been linked to compensatory changes in the nucleus accumbens. These results and their correlation with pharmacological studies will be discussed. CONCLUSION: Mice lacking key components of the serotonin system have provided us with important animal models of genetic vulnerability to conditions such as anxiety disorders, aggression, and drug abuse. Ongoing research with these mice may help elucidate the mechanistic functioning of this complex system.     

Examining the clinical efficacy of bupropion and nortriptyline as smoking cessation agents in a rodent model of nicotine withdrawal

Rationale At present, there is a lack of an established animal model to demonstrate the clinical efficacy of smoking cessation agents in the laboratory. The aim of this study was to compare the effects of the antidepressants bupropion and nortriptyline, clinically proven smoking cessation aids, within a rodent model of a nicotine withdrawal based on somatic measures. Materials and methods Male hooded Lister rats were chronically exposed to nicotine (3.16 mg kg¹ day¹) for 7 days via SC implanted ALZET osmotic minipumps. Animals were acutely pre-treated with bupropion (10, 30 or 60 mg/kg, IP) or nortriptyline (1.5, 4.7 and 15 mg/kg, IP), and nicotine withdrawal was precipitated by mecamylamine (1 mg/kg). Results Precipitation of nicotine withdrawal led to an increase in somatic signs including body shakes, chews, eye blinks, foot licks, head shakes and ptosis. Bupropion dose-dependently decreased the total abstinence scores and reduced the occurrence of some individual somatic signs. Pre-treatment with 60 mg/kg bupropion did not result in a significant increase in total abstinence scores or individual somatic signs scores after mecamylamine challenge, compared to the mecamylamine control group, suggesting nicotine withdrawal is fully attenuated at this dose. Similarly, the highest dose of nortriptyline reduced total abstinence scores and some individual somatic signs to the level of the mecamylamine control group. However, nortriptyline was only effective at alleviating somatic measures of withdrawal at doses which also suppressed locomotor activity. Conclusion In concurrence with clinical findings proposing alleviation of withdrawal states as a possible mechanism of bupropion and nortriptyline’s smoking cessation action, both drugs were found to ameliorate somatic signs of nicotine withdrawal in rodents.     

Deficits in a sustained attention task following nicotine withdrawal in rats

Objective Behavioural consequences of spontaneous and antagonist-precipitated withdrawal from nicotine upon performance of rats were compared alongside non-nicotinic antagonists in the 5-choice serial reaction time task (5-CSRTT).Methods Male hooded Lister rats were trained to detect and respond to brief flashes of light presented every 15 s in one of five holes until a stable level of performance was achieved.Results Surgical removal of osmotic minipumps from rats having received nicotine (3.16 mg/kg per day base SC) chronically for 7 days produced marked deficits in performance. Compared to saline-treated controls, deficits were apparent 10 h and 16 h following nicotine abstinence; the percentage of omission errors increased concomitantly with modest decreases in response accuracy. Tests conducted 34 h and 106 h post-withdrawal indicated a progressive and complete recovery in attention performance, respectively. In another experiment, following the exposure to the same nicotine regime, administration of the competitive nicotine receptor antagonist dihydro--erythroidine precipitated immediate deficits in performance that were greater than those observed in saline-treated subjects. Methyllycaconitine, an ₇ nicotinic receptor antagonist failed to precipitate attention deficits in nicotine-treated rats. Tests with SCH23390 and raclopride produced impairments that were similar in profile to nicotine withdrawal contrasting with non-specific effects of dizocilpine.Conclusions These results provide evidence of a cognitive impairment resulting from nicotine deprivation in rodents. Specifically, blockade of D₁ receptors by SCH23390 produced decrements in performance that were qualitatively similar but greater in magnitude to the alterations observed following nicotine withdrawal. Overall, assessing nicotine withdrawal in the 5-CSRTT presents an animal model that exhibits robust construct and face validity.     

Fourteen well-described caffeine withdrawal symptoms factor into three clusters

Rationale  Abrupt cessation of caffeine often results in several withdrawal symptoms among habitual caffeine consumers. Objective  The objective of the study was to determine whether caffeine withdrawal symptoms co-exist as clusters in some individuals. Materials and methods  Withdrawal symptoms and caffeine intake were assessed for men (n = 126) and women (n = 369), aged 20–29, using a caffeine habits questionnaire and a semi-quantitative food frequency questionnaire, respectively. Principal components factor analysis was used to identify common underlying factors among 14 well-described caffeine withdrawal symptoms. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to determine if the likelihood of reporting a withdrawal factor was associated with habitual caffeine consumption. Results  The 14 withdrawal symptoms were grouped into three factors termed “fatigue and headache”, “dysphoric mood”, and “flu-like somatic”. The likelihood of reporting the fatigue and headache and dysphoric mood factors increased with higher levels of habitual caffeine consumption. Compared to <100 mg/day of caffeine, the ORs (95% CI) of reporting the fatigue and headache factor with a habitual intake of 100–200 mg/day and >200 mg/day were 1.97 (1.21, 3.21) and 4.44 (2.50, 7.86), respectively. The corresponding ORs (95% CI) for the dysphoric mood factor were 1.55 (0.96, 2.52) and 3.34 (1.99, 5.60). Conclusions  The 14 well-described caffeine withdrawal symptoms factor into three clusters, suggesting the existence of three distinct underlying mechanisms of caffeine withdrawal. Increasing habitual caffeine consumption is associated with an increased likelihood of reporting the fatigue and headache and dysphoric mood symptoms, but not the flu-like somatic symptoms.     

Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study

RATIONALE: Benzodiazepines have dependency-producing properties, and the majority of patients who are prescribed benzodiazepines and are treated for benzodiazepine dependency are women. Inability to cope with withdrawal symptoms may lead to continued consumption of benzodiazepines, often with the development of tolerance and dose escalation as a consequence. OBJECTIVE: In the present study we analyzed gender-related differences in reactions to placebo injections in a placebo-controlled study of the effects of the benzodiazepine antagonist flumazenil among patients previously treated for benzodiazepine dependency and healthy controls. METHODS: Ten patients and ten controls (five males and five females in each group) received two placebo injections (separated by 15 min) on two separate occasions (1-13 weeks apart). The patients had been benzodiazepine free for 47 (4-266) weeks on the first occasion. Subjective ratings of symptoms, thought to be important during/after withdrawal of benzodiazepines, were made before and after each injection, as well as registrations of blood pressure and heart rate. RESULTS: An overall difference existed between previously benzodiazepine-dependent subjects and healthy controls, with patients scoring higher on negative and somatic aggregates and lower on a positive aggregate. A four-way interaction (group x gender x occasion x time) was found for negative and somatic aggregates, which could mainly be explained by the reactions of female patients. Thus, females had the highest base-line ratings and were the only group that showed a significant reduction in symptom ratings after placebo injections on the first occasion. Gender differences were also found for systolic and diastolic blood pressure. There was no significant response to placebo among male patients or for controls (males or females) for ratings of any variable. CONCLUSIONS: The results suggest that there might be gender-specific differences in reactions to placebo injections, with female patients being more affected. Arguments for and against explanatory factors such as expectation, provider factors, habituation, regression toward the mean, and reduction of anxiety are presented.     

Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction

Rationale Enhanced reinforcing effects of nicotine during adolescence appear to contribute to the rapid development of dependence in this age group. However, the contribution of nicotine withdrawal to dependence in adolescents is unclear.Objective We compared motivational and somatic signs of nicotine withdrawal in adolescent and adult rats.Materials and methods In experiment 1, motivational signs of nicotine withdrawal were compared using intracranial self-stimulation procedures after administration of mecamylamine (1.5 mg/kg, i.p.) in adolescent and adult rats made dependent on nicotine (9 mg/kg/day). Somatic signs of withdrawal were compared in two experiments using various doses of nicotine (adolescent doses: 0, 1.6, 3.2, 4.7 mg/kg/day; adult doses: 0, 1, 2.1, 3.2 mg/kg/day, expressed as nicotine base) to produce dependence and one dose of mecamylamine (1.5 mg/kg, i.p.) to precipitate withdrawal (experiment 2) and in a subsequent experiment, using various doses of mecamylamine (0, 0.75, 1.5, 3.0 mg/kg, i.p.) to precipitate withdrawal and a dose of nicotine (adolescent dose: 4.7 mg/kg/day; adult dose: 3.2 mg/kg/day) that produced equivalent nicotine blood levels in these age groups (experiment 3).Results Adolescents did not display the decreases in brain reward function observed in adults experiencing withdrawal, and displayed fewer somatic signs of nicotine withdrawal relative to adults regardless of the dosing procedure used.Conclusion The negative effects of nicotine withdrawal are lower during adolescence relative to later periods of development. Both the enhanced rewarding effects and the diminished nicotine withdrawal likely contribute to the rapid development of nicotine use during adolescence.     

Abstinence symptoms following oral THC administration to humans

Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral Δ⁹-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in private or social recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1–3, 8–11, and 16–19. Active THC was administered on days 4–7 (20 mg qid) and on days 12–15 (30 mg qid). Both active doses of THC increased ratings of “High,”“Good Drug Effect,” and “Willingness to Take Dose Again” compared to baseline (days 1–3). THC also increased food intake by 35–45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of “Anxious,”“Depressed,” and “Irritable,” decreased the reported quantity and quality of sleep, and decreased food intake by 20–30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use. Received: 13 April 1998/Final version: 1 July 1998     

Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats

In rats implanted subcutaneously with morphine containing pellets different degrees of dependence were induced by varying the dosage, frequency of implantation and duration of exposure to morphine. Withdrawal was precipitated by intraperitoneal injection of morphine antagonists, mostly levallorphan. The absorption of morphine from the subcutaneous depots was estimated chemically.When withdrawal was precipitated with a constant dose of antagonist the frequency of occurrence of various counted signs and the presence of some checked signs were studied in respect to varying degrees of dependence. The results were compared to those obtained after administration of increasing doses of antagonist in groups of animals that had developed a constant degree of dependence.In both types of experiments the results were rather similar. Some signs became progressively more pronounced when dependence got stronger or the dose of the antagonist was increased. In contrast, other signs showed a maximal frequency at the lower degrees of dependence or after administration of the lower doses of antagonist and decreased or even disappeared when the degree of dependence was higher or the dose of antagonist further increased. Obviously, in withdrawal the intensity of recessive signs like writhing and wet dog shaking declines when dominant signs like jumping, flying (a vigorous kind of jumping) and teeth chattering increase. An inverse relationship between the occurrence of various signs could also be shown within the 30 min observation period. Changes in the integrative mechanisms controlling behaviour during withdrawal are supposed to be the reason for this shift of signs.In other experiments in which the interval between each morphine implantation was prolonged the frequency of some signs like jumping and teeth chattering tented to plateau. This finding seems to be correlated to some kind of steady state on resorption of morphine from the subcutaneous depots, as was found in chemical analysis.     

The effects of buprenorphine on fentanyl withdrawal in rats

Rationale

Fentanyl is a potent mu-opioid receptor agonist that is widely used for the treatment of severe chronic pain. Discontinuation of fentanyl administration has been shown to induce a negative emotional state.

Objectives

The aim of the present studies was to investigate the effects of the partial mu-opioid receptor agonist buprenorphine on the negative emotional state associated with precipitated and spontaneous fentanyl withdrawal in rats.

Materials and methods

Fentanyl and saline were chronically administered via osmotic minipumps. A discrete-trial intracranial self-stimulation procedure was used to provide a measure of brain reward function. Somatic signs were recorded from a checklist of opioid abstinence signs.

Results

Naloxone induced a deficit in brain reward function in rats chronically treated with fentanyl. Buprenorphine dose-dependently prevented the naloxone-induced deficit in brain reward function. Discontinuation of fentanyl administration was also associated with a deficit in brain reward function. After explantation of the minipumps, the administration of buprenorphine induced a potentiation of brain reward function in the fentanyl-withdrawing rats, but did not affect brain reward function of saline-treated control rats. Buprenorphine prevented the somatic withdrawal signs associated with spontaneous fentanyl withdrawal and attenuated the somatic signs associated with precipitated fentanyl withdrawal.

Conclusions

Buprenorphine prevents affective and somatic fentanyl withdrawal signs. Moreover, buprenorphine is rewarding in rats previously exposed to fentanyl, but not in opioid-naïve rats. This pattern of results suggests that buprenorphine may be an effective treatment for the anhedonic-state associated with fentanyl withdrawal, but further study of buprenorphine’s abuse potential is warranted.

     

Sound-induced seizures during ethanol withdrawal in mice

An ethanol withdrawal syndrome, consisting of tremors and convulsions, was induced in C57BL/6J mice by feeding them a liquid diet containing 27% of ethanol-derived calories at an environmental temperature of +12 to 13° C for 6 days. Control groups were pair-fed with liquid diets containing isocaloric amounts of sucrose or Laboratory Chow. Seven and 24 h after the beginning of withdrawal, all mice were exposed to bell ringing for 90 sec. This sound induced convulsions in nearly one-half of ethanol-consuming mice at 7 h and in a few mice at 25 h. Only one mouse of the control groups had a convulsion. These findings support the concept that the ethanol withdrawal syndrome is a partially latent state of hyperexcitability of the brain following depression by ethanol.