Impairment of cost-benefit decision making in morphine-dependent rats is partly mediated via the alteration of BDNF and p-CREB levels in the nucleus accumbens.

The ability to choose goals based on decision usefulness or the time required to reach the goals chosen are important aspects of decision making. There is considerable evidence in the literature indicating the fact that drug abuse affects different aspects of cognition. In the current study, we assessed the effects of morphine dependence and its withdrawal on cost-benefit decision making and furthermore the involvement of BDNF and p-CREB in the nucleus accumbens, a key brain area involved in decision making was measured. Different groups of male Wistar rats were trained in an effort-based and/or delay-based form of cost-benefit T-maze decision-making task. Thereafter, the animals were morphine dependent and the percentage of the high reward preference was evaluated. After behavioral tests, the BDNF level, and p-CREB/CREB ratio were measured by Western blot analysis. The results showed that during effort-based but not delay-based decision making, BDNF and p-CREB levels increased. During effort-based decision making in morphine dependent rats, BDNF decreased but there was no significant change in p-CREB. Besides, during delay-based decision making in the morphine dependent group, both BDNF and p-CREB did not show any significant change. These findings revealed that BDNF and p-CREB/CREB ratio in the NAc are essential factors for effort-based but not delay-based decision making. In addition, impairment of effort-based decision making in morphine dependent rats is related to the decrease of BDNF level but not p-CREB/CREB ratio in the NAc. However, delay-based decision making defects in morphine dependent rats did not associate with the change in BDNF and p-CREB levels in the NAc.

Naloxone-precipitated withdrawal ameliorates impairment of cost-benefit decision making in morphine-treated rats: Involvement of BDNF, p-GSK3-ß, and p-CREB in the amygdala.

Several studies indicated that morphine administration impairs cognitive brain functions. Therefore, in the current study, we investigated the effect of subchronic exposure to morphine and its withdrawal on effort- and/or delay-based forms of cost-benefit decision making and alterations in p-CREB/CREB ratio, p-GSK3ß/GSK3ß ratio, and BDNF level during decision making in the amygdala. Our data displayed an impairment of both forms of cost-benefit decision making following subchronic exposure to morphine. However, preference of high reward/high effort and/or high delay reward increased after naloxone injection. In molecular section, levels of BDNF and p-CREB/CREB ratio increased during cost-benefit decision making while p-GSK3ß/GSK3ß ratio decreased in both forms of decision making. In morphine-treated rats, level of BDNF and p-CREB/CREB ratio reduced during both forms of decision making while p-GSK3ß/GSK3ß ratio increased during delay-based and did not have a significant difference with the control group during effort-based decision making. On the withdrawal day, BDNF level raised while p-GSK3ß/GSK3ß ratio attenuated compared to morphine-treated group in both form of decision making. In addition, p-CREB/CREB ratio increased only during delay-based decision making on the withdrawal day. In conclusion, our data revealed that subchronic exposure to morphine interferes with the cost-benefit decision making may be via changes in level of BDNF, p-CREB/CREB and p-GSK3ß/GSK3ß ratio in the amygdala.

Comparative Assessment of the Effectiveness of Noncompetitive NMDA Receptor Antagonists Amantadine and Hemantane in Morphine Withdrawal Syndrome Model.

Activities of noncompetitive NMDA receptor antagonists (aminoadamantane derivatives) were assessed in random-bred rats with modeled morphine withdrawal syndrome. A single intraperitoneal injection of hemantane (10 or 20 mg/kg) significantly and dose-dependently moderated some behavioral symptoms (teeth-chattering, ptosis, and vocalization) and reduced total score of morphine withdrawal syndrome. In morphine-abstinent rats, hemantane partially prevented the decrease in the thresholds of tactile sensitivity, but had no effect on locomotor activity and body weight loss. Under conditions of morphine withdrawal, intraperitoneal injection of amantadine (10 or 20 mg/kg) decreased motor activity and promoted body weight loss in parallel with the development of mechanical allodynia, but had no effect on the total withdrawal score. Comparison of aminoadamantane derivatives by behavioral and physiological parameters demonstrated the advantage of hemantane during morphine abstinence indicating the need of its study as a promising anti-addiction remedy.

[Assessment of afobazole effects on diazepam withdrawal-induced anxiety in rats].

Long-term administration of benzodiazepines is known to be associated with drug dependence. The aim of the present work was to investigate the effects of non-benzodiazepine anxiolytic afobazole in the treatment of benzodiazepine withdrawal syndrome. Male outbred rats were treated with either diazepam (4.0 mg/kg, i.p.) or vehicle for 30 days and then abruptly withdrawn for 48 h. Animals were tested in the elevated plus maze test. In addition, neurochemical shifts were evaluated in the selected brain structures (striatum, hippocampus, hypothalamus, and frontal cortex) during diazepam withdrawal. Withdrawn animals made fewer entries and spent less time on the open arms than did vehicle-treated rats and demonstrated a decrease in the dopamine level in striatum as compared with vehicle and diazepam-treated ones. Afobazole (5.0 mg/kg, i.p.) effectively (i) ameliorated withdrawal-induced anxiety, returning behavioral pattern in the elevated plus maze test up to levels comparable to that in vehicle-treated animals, and (ii) increased withdrawal-reduced dopamine level (+23.8%, p < 0.05) in striatum. It is suggested that afobazole, due to its multitarget receptor action, can be useful in the diazepam withdrawal-induced anxiety blockade through modulation of dopaminergic system activity.

Energy expenditure and withdrawal of sedation in severe head-injured patients.

OBJECTIVES: To determine the outcome of oxygen consumption (VO2) and energy expenditure after cessation of sedation in severe head-injured patients and to assess its usefulness as a predictor of neurologic severity. DESIGN: Prospective, descriptive study. SETTING: Neurosurgical intensive care unit (ICU) in a university hospital. PATIENTS: Fifteen severe head-injured patients with tracheostomies and who were mechanically ventilated and sedated at the time of the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: VO2 and energy expenditure were measured, using indirect calorimetry during and after discontinuation of sedation. After the measurement period, the patients were divided into two groups. Group 1 included patients who were completely weaned from sedation; group 2 included patients who had to be sedated again using predetermined criteria. In both groups, energy expenditure was close to basal energy expenditure during sedation, and increased to 150% of basal energy expenditure during the recovery period, with maximum hourly values 80% above basal energy expenditure. In group 1, VO2 and energy expenditure changed from 284 +/- 44 mL/min and 1833 +/- 261 kcal/day during sedation to 390 +/- 85 mL/min and 2512 +/- 486 kcal/day for the period without sedation. During this period, there was a significant correlation between VO2 and mean arterial pressure. For the recovery period, there was no difference in mean or maximum VO2 between the two groups of patients. At 24 and 48 hrs after cessation of sedation, VO2 and energy expenditure decrease to 30% above basal energy expenditure. These changes may be due to the recovery of muscular activity, weaning from mechanical ventilation, or an increase in the amount of circulating catecholamines. CONCLUSION: In severe head-injured patients, during the first 12 hrs after the discontinuation of sedation, the patients experienced a large increase in VO2, energy expenditure, and mean arterial pressure. Although these changes have no prognostic value in our study, they have potential deleterious effects in head-injured patients. Methods that blunt these changes which have proven efficacious in anesthesia may be effective for intensive care patients.

Nitrogen economy in alcoholic patients without liver disease.

Nitrogen balance was studied in five alcoholic patients during alcohol consumption and after 1 or 2 weeks of abstinence, under metabolic ward conditions. Patients had a history of excessive ethanol intake for five years or more. They were intoxicated and otherwise asymptomatic on admission and had been drinking 150 g or more of ethanol daily, for at least one month. Subjects consumed a diet providing vitamins and minerals exceeding RDA values, 45 kcal/kg of body weight and 0.6 g/kg of proteins (as egg protein), for 33 days. During the first 11 days patients received 200 g of ethanol that were isocalorically substituted later by dietary fat and carbohydrates. The results of this study show that, in alcoholic patients while drinking and after seven days of alcohol withdrawal, nitrogen balance is significantly decreased compared to that performed after two weeks of abstinence. Ethanol metabolic rate was found to be increased, compared to controls. It was lower in four of five patients after the second week of abstinence. These results suggest that alcohol abuse increases protein requirements in chronic alcoholic patients even without histologic liver disease or clinical signs of gastroenterologic disorders.

Rebound insomnia and elimination half-life: assessment of individual subject response.

Following abrupt withdrawal of five benzodiazepine hypnotics, the presence of rebound insomnia on individual subject nights was evaluated in comparison to a placebo group. During the first three nights of withdrawal, the frequency of occurrence of rebound insomnia for drugs with relatively rapid rates of elimination (triazolam, midazolam, and lormetazepam) was significantly higher than that for the placebo control group. In contrast, the frequency of withdrawal sleep difficulty for two slowly eliminated hypnotics (flurazepam and quazepam) was similar to that of the placebo control group during each of five successive three-night segments of a 15-night withdrawal period. These findings, based on individual subject-night data, confirm and extend previous reports using group mean values that demonstrate a frequent, immediate, and intense degree of rebound insomnia following abrupt withdrawal of relatively rapidly eliminated hypnotic drugs and an infrequent, delayed, and milder degree of sleep difficulty following withdrawal of slowly eliminated drugs.

Alcohol withdrawal syndrome: treatment and assessment of therapeutic efficacy.

The acute alcohol withdrawal syndrome is a disease of many different symptoms. Although the metabolism of ethanol is well-known, no specific treatment of the withdrawal syndrome has been developed. When assessing the therapeutic efficacy of drugs in this syndrome one of the main symptoms to be followed is sleep disturbances, because inability to sleep often maintains the drinking cycle. Besides different target symptoms, the visual analogue scale and the ability to work are useful parameters. The assessment of the efficacy relies mainly on subjective parameters and comparisons with placebo are needed.