Repeated Episodes Of Withdrawal Research Articles

The oxytocin receptor rs2254298 polymorphism and alcohol withdrawal symptoms: a gene-environment interaction in mood disorders.

Alcohol use disorder (AUD) is a common mental disorder characterized by repeated withdrawal episodes. Negative emotions during withdrawal are the primary factors affecting successful abstinence. Oxytocin is a critical modulator of emotions. OXTR, the oxytocin receptor, may also be a promising candidate for treating alcohol withdrawal symptoms. Previous studies indicated that people with different genotypes of OXTR rs2254298 were reported to suffer from more significant depressive or heightened anxiety symptoms when experiencing early adversity. The present study aims to explore the modulatory role of the polymorphism OXTR rs2254298 on mood disorders during alcohol withdrawal and to help researchers better understand and develop effective relapse prevention and interventions for alcohol use disorders. We recruited 265 adult Chinese Han men with AUD. Anxiety and depressive symptoms were measured using the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Alcohol dependence levels were measured using Michigan Alcoholism Screening Test. Genomic DNA extraction and genotyping from participants' peripheral blood samples. First, a multiple linear regression was used to set the alcohol dependence level, OXTR.rs2254298, interaction terms as the primary predictor variable, and depression or anxiety as an outcome; age and educational years were covariates. There was a significant interaction between OXTR rs2254298 and alcohol dependence level on anxiety (B = 0.23, 95% confidence interval [CI]: 0.01-0.45) but not on depression (B = -0.06, 95% CI: -0.30 - 0.18). The significance region test showed that alcohol-dependent men who are GG homozygous were more likely to experience anxiety symptoms than subjects with the A allele (A allele: β = 0.27, p < 0.001; GG homozygote: β = 0.50, p < 0.001). Finally, re-parameterized regression analysis demonstrated that this gene-environment interaction of OXTR rs2254298 and alcohol dependence on anxiety fits the weak differential susceptibility model (R2 = 0.17, F (5,259) = 13.46, p < 0.001). This study reveals a gene-environment interactive effect between OXTR rs2254298 and alcohol withdrawal on anxiety but not depression. From the perspective of gene-environment interactions, this interaction fits the differential susceptibility model; OXTR rs2254298 GG homozygote carriers are susceptible to the environment and are likely to experience anxiety symptoms of alcohol withdrawal.

Neurokinin-1 receptor antagonist rolapitant suppresses anxiety and alcohol intake produced by repeated withdrawal episodes.

Neurokinin-1 receptor (NK1r) antagonists have been shown to suppress operant self-administration of alcohol, voluntary alcohol consumption and stress-induced reinstatement of alcohol-seeking behaviour. Considering the long half-life and anxiolytic-like properties of NK1r antagonist rolapitant, we expected that it may be an effective option for reducing anxiety and alcohol motivation during early withdrawal. Voluntary alcohol intake (two-bottles paradigm) was recorded in male Wistar rats during the three periods: 24 days (basal level), 6-day period when rats received 5 mg·kg-1 rolapitant or vehicle and 12-h period after repeated withdrawal episodes (alcohol cessation for 36 h). We found that upon intraperitoneal (i.p.) administration, rolapitant rapidly penetrated into specific rat brain regions - amygdala, hypothalamus and neocortex - implicated in the control of anxiety and reward. Rolapitant did not affect basal voluntary alcohol intake, but significantly suppressed anxiety-like behaviour and alcohol consumption following withdrawal episodes. Our findings suggest that rolapitant should be further investigated as a novel treatment option for relapse prevention in alcohol-dependent patients.

Mothers on Methadone: Care in the NICU

When women addicted to opioids seek prenatal care, the treatment of choice is methadone. Methadone mediates the addiction by reducing fluctuations in maternal serum opioid levels and protecting the fetus from repeated withdrawal episodes. Methadone maintenance is associated with increased maternal weight gain, decreased illegal drug use, and improved compliance with prenatal care. Although the risks are less when compared with street drugs, the risk to the fetus is physical dependence. Despite the magnitude of this national problem, there is a dearth of literature to guide NICU nurses on how to best support mothers of infants with neonatal abstinence syndrome (NAS) in the care of their infants. The purposes of this article are to review what is known about women in methadone treatment who have a history of opioid addiction and apply that evidence to guide neonatal nurses to support mothers of infants with NAS in the NICU.

Facilitation of avoidance behaviour in mice chronically treated with heroin or methadone

Although the repercussion of chronic treatment with large amounts of opioids on cognitive performance is a matter of concern, the effects of opioid drugs on passive avoidance learning have been scarcely studied. Here, we analyzed the effects of prolonged administration of heroin and methadone, as well as the impact of suffering repeated episodes of withdrawal on fear-motivated learning using the passive avoidance test. Mice received chronic treatment (39 days) with methadone (10mg/kg/24h), associated or not with repeated withdrawal episodes, or with heroin (5mg/kg/12h). Our results show that, regardless of the type of treatment received, all mice displayed similar basal thermal nociceptive thresholds during 25 days of treatment. In the hot plate test, both methadone and heroin induced antinociception 30min after drug administration. The analgesic effect was absent when measured 4h after heroin and 12h after methadone. Pain behavioural responses elicited by growing intensities of electric shock, applied on day 28th of treatment, were similar in all groups of mice. Our results indicate that chronic opioid treatment had promnesic effects on passive avoidance behaviour in mice, unrelated to changes in the nociceptive state.

Repeated Ethanol Withdrawal Delays Development of Focal Seizures in Hippocampal Kindling

Clinical studies report an increase in the prevalence of alcohol withdrawal-related seizures in patients with a history of multiple detoxifications. In order to investigate the alcohol withdrawal-related alterations in neural activity that lead to this increase in seizure propensity, basic researchers have examined both spontaneous and elicited seizures in animals undergoing withdrawal from chronic ethanol. This study was designed to further examine alcohol withdrawal-related seizure activity in a rodent model by assessing the development of electrical kindling after chronic ethanol exposure administered in multiple or single treatment episodes. Laboratory rats were exposed to either five periods of 3 days of ethanol, one 15-day period of continuous ethanol, or a period of control handling with no ethanol exposure. Ten days after a final withdrawal episode, all animals were surgically prepared with recording and stimulating electrodes. Twenty days after final withdrawal from ethanol or an equivalent period of similar handling, daily electrical stimulation of hippocampal area CA3 was initiated. Animals exposed to ethanol required more daily stimulations to become fully kindled than did ethanol-naive controls, with those animals experiencing five withdrawals requiring the most stimulations overall and more stimulations to progress from focal to generalized seizure behaviors. These results indicate that chronic ethanol exposure and withdrawal alter neuronal mechanisms important for hippocampal kindling in a manner that persists long after cessation of ethanol exposure, and they indicate that this effect is increased by exposure to repeated withdrawal episodes.

Chronic intermittent ethanol treatment in rats increases GABA(A) receptor alpha4-subunit expression: possible relevance to alcohol dependence.

Chronic administration of ethanol to rats on an intermittent regimen, for 60 repeated intoxicating doses and repeated withdrawal episodes, results in a long-lasting kindling phenomenon. This involves an increasing severity of withdrawal, including a reduced threshold to seizures produced by the GABA(A) antagonist, pentylenetetrazol. We have shown previously that muscimol-evoked 36Cl- efflux and paired-pulse inhibition (involving GABA(A)-mediated recurrent inhibition) were decreased persistently in the CA1 region of hippocampal slices from chronic intermittent ethanol (CIE)-treated rats. We now report elevated levels of mRNA in forebrain for the alpha4 subunit of the GABA(A) receptor (GABAR), considered to be a constituent of pharmacologically and physiologically novel subtypes of GABARs. Using in situ hybridization with digoxigenin-labeled RNA probes, we show that at 2 days withdrawal, 60-dose CIE leads to a significant 30% increase in alpha4 subunit mRNA levels in the dentate gyrus, 46% increase in the CA3, and 26% increase in the CA1 regions. In contrast, there was no significant change in the mRNAs for the alpha5 subunit or glutamic acid decarboxylase 67 in the same regions. This study suggests that GABAR subunit-selective alterations occur after CIE treatment, possibly resulting in the alteration of the subunit composition of GABARs, with presumably altered physiological functions. This plasticity of GABARs may contribute to the increased withdrawal severity, reduced hippocampal inhibition, and increased seizure susceptibility of this animal model of human alcohol dependence.

Effects of Chronic Ethanol Exposure on Oral Self‐Administration of Ethanol or Saccharin by Wistar Rats

The study of alcohol abuse traditionally has placed great emphasis on the development of tolerance and dependence as key factors. However, animal models of ethanol self-administration in dependent rats have been difficult to establish, caused in part by ethanol's aversive taste cues and subsequent aversive effects (i.e., "hangover" malaise) that prevent substantial ethanol consumption. In this study, this problem was addressed in animals trained to self-administer ethanol (10% w/v) in a sweetened-solution fading procedure before induction of dependence and repeated exposure to withdrawal. Once stable rates of responding for ethanol were achieved, a palatable liquid diet containing 8.7% (v/v) ethanol was introduced as the sole source of calories and fluid for one group of rats [ethanol diet (ED) group]. A second group of rats received a control diet with sucrose isocalorically substituted for ethanol (CD group). After 14-17 days of liquid diet exposure, the rats were withdrawn once a week for 4 weeks and 8 hr into each withdrawal session were allowed to self-administer ethanol or water for 60 min. As compared with CD rats, ED rats showed significantly greater intake of ethanol, but not water. No significant differences were found when separate groups of ED/CD rats were allowed to self-administer an alternate reinforcer (0.0075% saccharin solution). Rats who consistently had blood alcohol levels (BALs) above 100 mg% at the time of withdrawal sustained high levels of ethanol self-administration throughout the four withdrawal sessions. In contrast, rats who had an average BAL at withdrawal below 100 mg% showed progressive decreases in ethanol self-administration during repeated withdrawal episodes. The results demonstrated that chronic exposure to ethanol and repeated periods of abstinence are accompanied by elevated rates of ethanol intake in certain animals, and the persistence of elevated self-administration behavior of individual rats is predicted by their BAL at the time of withdrawal.

Alcohol and depression in panic disorder.

Panic disorder (PD) is a common psychiatric illness, which has many complications such as major depression, increased suicide risk, agoraphobic avoidance behaviour, alcohol abuse and dependence. A number of studies have now documented increased rates of anxiety disorders among alcoholics and of alcoholism among patients presenting with anxiety disorders. In general, it appears that PD is more prevalent in alcoholics than would be expected on the basis of general population rates. Alcohol withdrawal is clearly associated with severe anxiety symptoms. It is suggested that repeated withdrawal episodes may trigger panic through a kindling process by causing subconvulsive stimuli with increasing amounts of electrical excitability or even spontaneous seizures. Serotonergic medications are effective in treating PD and depression. They also diminish interest in drinking in ethanol-dependent patients. Serotonergic agents can also affect conditioning and learning as well as behavioral control and self-administration. The treatment of panic patients with depressive and alcohol problems usually requires long-term treatment.

The Kindling Model of Alcohol Dependence: Similar Persistent Reduction in Seizure Threshold to Pentylenetetrazol in Animals Receiving Chronic Ethanol or Chronic Pentylenetetrazol

Rats on a chronic intermittent ethanol (CIE) regimen showed a persistent reduction in seizure threshold to the convulsant drug pentylenetetrazol (PTZ). CIE rats were given ethanol by intubation on an alternate day schedule and tested at selected intervals for seizure threshold with PTZ. A significant reduction in seizure threshold, a sign of withdrawal, was observed 20 hr after the first dose. The severity of withdrawal intensified on repetition of the ethanol administration and depression-hyperexcitability cycle, with the seizure threshold reaching a maximum decrease after 12 doses and remaining reduced up to 60 doses. The reduction in seizure threshold persisted for at least 40 days of no alcohol following the 60th dose. The long-lasting decrease in seizure threshold following CIE treatment resembled the "kindling" phenomenon produced by chronic administration of PTZ (25 mg/kg, 3 times/week). The CIE rats developed, in addition, a tolerance to the anticonvulsant action of ethanol, which occurred well after the decrease in PTZ seizure threshold, and a tolerance to the hypothermic effect of ethanol, which developed rapidly. PTZ kindled rats that had never been exposed to ethanol also exhibited tolerance to the hypothermic effect of ethanol. We propose that kindling contributes to the mechanism of the development of dependence on central nervous system depressants like benzodiazepines, barbiturates, and alcohol, drugs that act on the gamma-aminobutyric acid-A receptor chloride ion channel complex. Repeated episodes of depression and withdrawal hyperexcitability are postulated to produce kindling during the repeated withdrawal episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of repeated withdrawal episodes on subsequent withdrawal severity in ethanol-treated rats

Male rats were given ethanol via an intragastric catheter (8.0–11.0 g/kg per day) for either 8 weeks daily or for four 2-week periods with a 2-week period of no drug treatment intervening between each period of ethanol administration (binge). Older rats were administered ethanol for 2 weeks, to assess the effects of age on ethanol withdrawal as age can alter an animal's sensitivity to ethanol. The presence of physical dependence during withdrawal was assessed on an open field test. Rats that experienced repeated episodes of withdrawal (binge) showed more severe withdrawal signs in successive withdrawal episodes. Older animals showed more severe signs of withdrawal than younger animals after 2 weeks of ethanol treatment. The results of this study lend support to the hypothesis that the experience of withdrawal from ethanol can alter an animal's subsequent response to the drug. Aging appeared to contribute to this effect, but further work is needed to delineate its role.

The effect of repeated withdrawal episodes on acquisition and loss of tolerance to ethanol in ethanol-treated rats

Male rats were administered ethanol via an intragastric catheter (8.0–12.0 g/kg/day) either continuously for 8 weeks or on a binge schedule with four 2 week cycles of drug administration separated from each successive cycle by a 2 week period of no drug treatment. Older rats were administered ethanol for 2 weeks, to provide an age control for the binge-treated animals as age can alter an animal's sensitivity to ethanol. Acquisition and loss of tolerance to ethanol-induced motor impairment were measured on a dowel task while acquisition and loss of tolerance to ethanol-induced hypothermia were assessed by measuring rectal temperature. Acceleration of tolerance development to both ethanol-induced motor impairment and hypothermia was observed in animals subjected to repeated withdrawal episodes (binge-Study 1) but not in the controls for total dose and duration of drug treatment who experienced withdrawal only once (continuous-Study 2). Persistence of tolerance to ethanol-induced motor impairment occurred in both binge and continuously treated animals while persistence of tolerance to ethanol-induced hypothermia was seen only in the binge treated animals. Age (3 to 7 months) did not affect tolerance development or decay. After three cycles of drug treatment (three withdrawal episodes), binge treated animals showed an impairment in motor ability when blood ethanol levels were near zero. This impairment disappeared when the animals were administered ethanol, indicating a normalizing effect of ethanol on motor behavior in animals subjected to repeated episodes of withdrawal. A similar, but not significant, effect was seen in continuously treated animals. Thus, in an animal exposed to prolonged ethanol treatment, persistent changes in responding to the drug were found. The persistance of these changes was enhanced by the experience of withdrawal from ethanol.