Diazepam and pentobarbital dependence in the rat

Diazepam (100–133 mg/kg/day), administered chronically through a gastric fistula, and pentobarbital (ca 692 mg/kg/day), administered chronically in food, were studied for their dependence producing properties in Sprague-Dawley female rats. The diazepam abstinence syndrome was apparent 10 to 20 hours after withdrawal, persisted for over 60 hours and consisted of poker tail, explosive awakenings, digging in sawdust, jerks, tremors, wet dog shakes, hostility, decreased food and water consumption and weight loss. The pentobarbital abstinence syndrome came on rapidly peaking within 10 hours and was largely over by 16 hours. The pentobarbital abstinence syndrome differed from diazepam's by the presence of grand mal, clonic and atypical convulsions. Diazepam completely and in a dose related way suppressed the diazepam abstinence syndrome. Similarly pentobarbital suppressed the pentobarbital abstinence syndrome. The signs which could be suppressed in a dose related manner were different for the diazepam and pentobarbital abstinence syndromes. Diazepam only partially suppressed the pentobarbital abstinence syndrome and pentobarbital only partially suppressed the diazepam abstinence syndrome. These data indicate that diazepam and pentobarbital produce different types of dependencies in the rat and are not equivalent in suppressing signs of abstinence.     

Cerebrospinal fluid from morphine-dependent rats precipitates opiate abstinence syndrome

Cerebrospinal fluid (CSF) was withdrawn from opiate-dependent rats following six hours of abstinence. It was infused into the third ventricle of opiate-dependent rats, precipitating immediate abstinence signs. The effect was similar to that of infusing the opiate antagonist naloxone, suggesting that opiate-dependent organisms may secrete an endogenous opiate antagonist substance. CSF withdrawn from non-dependent rats failed to precipitate an abstinence syndrome in morphine-dependent recipients. Conversely, CSF withdrawn from opiate-dependent rats following six hours of abstinence failed to precipitate an abstinence syndrome in non-dependent recipients. The active factor in the CSF is probably a peptide since it is filterable through a 10,000 MW filter and its activity is destroyed by three different proteolytic enzymes.     

Dissociated Grey Matter Changes with Prolonged Addiction and Extended Abstinence in Cocaine Users

Extensive evidence indicates that current and recently abstinent cocaine abusers compared to drug-naïve controls have decreased grey matter in regions such as the anterior cingulate, lateral prefrontal and insular cortex. Relatively little is known, however, about the persistence of these deficits in long-term abstinence despite the implications this has for recovery and relapse. Optimized voxel based morphometry was used to assess how local grey matter volume varies with years of drug use and length of abstinence in a cross-sectional study of cocaine users with various durations of abstinence (1–102 weeks) and years of use (0.3–24 years). Lower grey matter volume associated with years of use was observed for several regions including anterior cingulate, inferior frontal gyrus and insular cortex. Conversely, higher grey matter volumes associated with abstinence duration were seen in non-overlapping regions that included the anterior and posterior cingulate, insular, right ventral and left dorsal prefrontal cortex. Grey matter volumes in cocaine dependent individuals crossed those of drug-naïve controls after 35 weeks of abstinence, with greater than normal volumes in users with longer abstinence. The brains of abstinent users are characterized by regional grey matter volumes, which on average, exceed drug-naïve volumes in those users who have maintained abstinence for more than 35 weeks. The asymmetry between the regions showing alterations with extended years of use and prolonged abstinence suggest that recovery involves distinct neurobiological processes rather than being a reversal of disease-related changes. Specifically, the results suggest that regions critical to behavioral control may be important to prolonged, successful, abstinence.     

Adaptation to periodic hypoxia decreases ethanol consumption and abstinence-related damages to the internal organs during withdrawal in chronically alcoholized animals]

Adaptation to intermittent hypoxia in a hypobaric altitude chamber reduced two-fold ethanol consumption in chronically alcoholized rats and limited or eliminated abstinence syndrome. The effect of the adaptation was evident from prevented development of abstinence analgesia, enhanced alcohol consumption following deprivation, abstinence activation of lipid peroxidation in the liver, and release of hepato-specific enzymes fructose monophosphate and gamma-glutamyl transpeptidase into blood. At the same time adaptation prevented the fall of cardiac fibrillation threshold and pronounced disturbance of ventricular contraction and relaxation. The problem is discussed of using adaptation to intermittent hypoxia in the treatment for those forms of alcoholism in which abstinence plays the key role.     

Analog of neuropeptide FF attenuates morphine abstinence syndrome.

The octapeptide FLFQPQRFamide (neuropeptide FF or F8Fa) may play a role in opiate dependence and subsequent abstinence syndrome. Previously, NPFF precipitated opiate abstinence syndrome, while IgG from NPFF antiserum attenuated subsequent naloxone-precipitated abstinence signs in dependent rats. The peptide desamino YFLFQPQRamide (daY8Ra) was synthesized as a possible NPFF antagonist. At a dose of 600 ng ICV, daY8Ra significantly attenuated (p less than 0.001) the number of abstinence-like signs subsequently induced by 10 micrograms NPFF ICV, suggesting that daY8Ra does have antagonist activity against NPFF. Pretreatment of morphine-dependent rats with the same dose of daY8Ra also significantly attenuated (p less than 0.001) the abstinence signs subsequently precipitated by 10 micrograms naloxone ICV. Pretreatment with 600 ng of NPFF itself, or of NPFF modified at the N-terminal only (daY9Fa), failed to attenuate subsequent naloxone-precipitated abstinence, suggesting that the C-terminal modification is critical for NPFF antagonist activity. It should be noted, however, that higher doses of daY8Ra (2 micrograms or more) can precipitate some abstinence signs in a manner similar to NPFF.     

Interactions between cannabidiol and delta9-THC during abstinence in morphine-dependent rats.

Male rats, each implanted with a pellet containing 75 mg morphine, were administered naloxone 72 hours later to precipitate abstinence. Two hours before naloxone, animals were pretreated acutely with either 10 mg/kg cannabidiol (CBD) or the vehicle. One hour later, an injection of the vehicle or a low dose of Δ⁹-THC that we have shown to exhibit slight efficacy in attenuating morphine abstinence signs was administered to each of the groups previously receiving the vehicle or CBD. Interactions between CBD and Δ⁹-THC were assessed during abstinence, precipitated one hour after the last series of injections. CBD had little effect on abstinence scores, but significantly increased the abstinence attenuating properties of Δ⁹-THC, Rotational behavior (turning), induced by Δ⁹-THC during abstinence, was also potentiated by CBD. These data extend previous reports of potentiation of pharmacological effects of THC by CBD to abstinence-attenuating properties and other effects of THC in morphine-dependent rats.     

Impaired Response Inhibition in the Rat 5 Choice Continuous Performance Task during Protracted Abstinence from Chronic Alcohol Consumption

Impaired cognitive processing is a hallmark of addiction. In particular, deficits in inhibitory control can propel continued drug use despite adverse consequences. Clinical evidence shows that detoxified alcoholics exhibit poor inhibitory control in the Continuous Performance Task (CPT) and related tests of motor impulsivity. Animal models may provide important insight into the neural mechanisms underlying this consequence of chronic alcohol exposure though pre-clinical investigations of behavioral inhibition during alcohol abstinence are sparse. The present study employed the rat 5 Choice-Continuous Performance Task (5C-CPT), a novel pre-clinical variant of the CPT, to evaluate attentional capacity and impulse control over the course of protracted abstinence from chronic intermittent alcohol consumption. In tests conducted with familiar 5C-CPT conditions EtOH-exposed rats exhibited impaired attentional capacity during the first hours of abstinence and impaired behavioral restraint (increased false alarms) during the first 5d of abstinence that dissipated thereafter. Subsequent tests employing visual distractors that increase the cognitive load of the task revealed significant increases in impulsive action (premature responses) at 3 and 5 weeks of abstinence, and the emergence of impaired behavioral restraint (increased false alarms) at 7 weeks of abstinence. Collectively, these findings demonstrate the emergence of increased impulsive action in alcohol-dependent rats during protracted alcohol abstinence and suggest the 5C-CPT with visual distractors may provide a viable behavioral platform for characterizing the neurobiological substrates underlying impaired behavioral inhibition resulting from chronic intermittent alcohol exposure.     

不同禁欲时间对少精、弱精精液质量的影响

目的:了解不同禁欲时间对少精、弱精精液质量的影响,为临床治疗不育提供参考。方法:对正常精液、少精症、弱精症患者分别根据禁欲天数随机分成两组,禁欲2-4天为A组,禁欲5-7天为B组,对上述各组进行精液分析。结果:在正常组、少精组及弱精组中,A组的精液量、精子密度及精子总量低于B组,A组a b级精子百分率高于B组,差异有统计学意义。在少精组及弱精组中A组精子正常形态率高于B组,差异有统计学意义。结论:正常精液及弱精症患者禁欲2-4天的精液质量最好,少精症患者禁欲5-7天的精液质量最好。     

Use of periodic abstinence in Bangladesh: do they really understand?

Data from a nationally representative study in Bangladesh (BDHS 1996-97) were analysed to identify significant predictors of use of periodic abstinence, in comparison with other modern contraceptive methods. The study found that women in Bangladesh mostly use modern methods during their peak reproductive years, after which some of them switch to periodic abstinence. These women tend to be more from educated and from higher socioeconomic backgrounds and with at least one living son. Another set of data from the Matlab DSS was analysed and the results were in the same direction. Focus group discussions found that women were using the periodic abstinence method incorrectly, abstaining for more days than is necessary. For Bangladeshi contraceptive users to reach a higher degree of use-effectiveness for period abstinence, more IEC materials need to be developed.     

Myocardial levels of calcium, glycogen and triglycerides in ethanol-fed turkey poults treated with allopurinol

Effect of allopurinol treatment on myocardial levels of calcium, glycogen and triglyceride and on plasma levels of triglyceride was evaluated in turkey poults during a period of chronic ethanol consumption and following a period of ethanol abstinence. Allopurinol treatment had no significant effect on myocardial levels of calcium. Allopurinol treatment plus abstinence was slightly more effective than abstinence alone in restoring myocardial levels of glycogen and triglyceride and plasma levels of triglyceride in ethanol-fed poults to that seen in control poults.     

Characteristics of the abstinence syndrome induced by the administration of the benzodiazepine antagonist CGS 8216 to rats following chronic treatment with diazepam

Male rats were treated with 5 and 10 mg/kg diazepam once daily for 5-30 days. After the drug discontinuation a benzodiazepine receptor antagonist CGS 8216 (2.5-10 mg/kg) induced a behavioural syndrome that might be characterized as an abstinence syndrome. The most typical signs of abstinence were head twitches, myoclonic seizures of forepaws, emotional hyperirritability, increased muscle tone of the tail, sniffing and chewing. These behavioural changes could be observed within 1-1.5 hours after CGS 8216 injection. The abstinence syndrome was induced by repeated CGS 8216 injections for 10-15 days after diazepam discontinuation. Further analysis has shown that that the intensity of abstinence was dependent on the dose and duration of chronic diazepam, as well as on CGS 8216 dose. It is suggested that CGS 8216-induced abstinence syndrome in rats chronically treated with diazepam might be used as a tool for studying the addictive potential of benzodiazepines.     

Effect of glutaminic acid on the activity of the sympatho-adrenal system and the concentration of calcium in urine under conditions of development of the alcohol abstinence syndrome

The paper deals with the influence of glutaminic acid on the functional activity of the sympatho-adrenal system and the concentration of calcium in urine under conditions of the alcoholic abstinence syndrome development. Changes in the functional activity of sympatho-adrenal system and in the concentration of calcium in the process of the abstinence syndrome development are shown to be of the phase character. It is established that in the period of the developed abstinence syndrome glutaminic acid produces a normalizing action on the excretion of adrenaline and dopamine and also facilitates a decrease in the level of calcium in urine.     

Suppression of GABA-induced abstinence behaviour in naive rats by morphine and bicuculline.

Intraperitoneal administration of n-dipropylacetate (DPA) to naive rats produced abstinence behaviour including shaking, digging, hunchback posture, piloerection and ptosis during 15 min and increased motor activity considerably. Treatment with a subconvulsive dose of the GABA antagonist bicuculline suppressed this DPA-induced abstinence behaviour, indicating that GABA was increased at receptor sites. Also morphine in a low dose of 1 mg/kg suppressed this behaviour, while administration of naloxone after morphine treatment could release the abstinence behaviour. Simultaneous treatment with morphine and naloxone or naloxone alone were without effect. The administration to DPA treated rats of doses higher than 1 mg/kg morphine resulted in a severe depression of motor activity. It is concluded that an increased availability of GABA at its receptor sites plays an important role in the behaviour observed after DPA administration. The experiments with morphine and naloxone suggest that morphine receptors are involved in DPA-induced abstinence behaviour.     

The effect of a benzodiazepine antagonist, RO15-1788, in diazepam dependent rats

A benzodiazepine antagonist, RO15-1788, was administered intragastrically to diazepam-dependent gastric fistula rats and a precipitated abstinence syndrome was observed. The intensity of the RO15-1788 precipitated abstinence syndrome, calculated by the Precipitated Abstinence Scale, increased in intensity in a log-dose manner over a dose range of 1.0 to 15.0 mg/kg of RO15-1788 and plateaued at the 15.0 mg/kg dose. The RO15-1788 precipitated diazepam abstinence syndrome differed both qualitatively and quantitatively from the diazepam withdrawal syndrome.     

Aspects of opiate dependence in the myenteric plexus of the guinea-pig.

Myenteric plexus-longitudinal muscle strips prepared from tolerant/dependent guinea-pigs and continuously exposed to normorphine, display a contracture upon naloxone challenge. This phenomenon represents a sign of abstinence. Removal of the opiate by extensive washing resulted in the failure of naloxone to induce the abstinence sign, while the plexus still displayed considerable, although reduced, tolerance to morphine. Reexposure of withdrawn preparations to normorphine reinduced the ability to display the abstinence sign. Highly tolerant preparations exhibited a 30 fold increase in sensitivity to serotonin and prostaglandin E₁ when tested a few minutes after naloxone-precipitated withdrawal. Supersensitivity rapidly declined when normorphine was washed off the preparation, while reincubation of withdrawn tissues with the opiate resulted in reinduction of supersensitivity. The data confirms a close relationship between a state of tolerance and dependence (including display of the abstinence sign) and supersensitivity to putative neurotransmitters or neuromodulators, becoming evident following administration of naloxone.     

Brain‐derived neurotrophic factor genotype is associated with brain gray and white matter tissue volumes recovery in abstinent alcohol‐dependent individuals

Neuroimaging studies have linked the methionine (Met) allele of the brain‐derived neurotrophic factor (BDNF) gene to abnormal regional brain volumes in several psychiatric and neurodegenerative diseases. However, no neuroimaging studies assessed the effects of this allele on brain morphology in alcohol use disorders and its demonstrated change during abstinence from alcohol. Here we assessed the effects of the BDNF Val66Met (rs6265) polymorphism on regional brain tissue volumes and their recovery during short‐term abstinence in treatment‐seeking alcohol‐dependent individuals. 3D T1 weighted magnetic resonance images from 62 individuals were acquired at 1.5 T at one week of abstinence from alcohol; 41 of the participants were rescanned at 5 weeks of abstinence. The images were segmented into gray matter (GM), white matter (WM) and cerebrospinal fluid and parcellated into regional volumes. The BDNF genotype was determined from blood samples using the TaqMan technique. Alcohol‐dependent Val (Valine)/Met heterozygotes and Val homozygotes had similar regional brain volumes at either time point. However, Val homozygotes had significant GM volume increases, while Val/Met heterozygotes increased predominantly in WM volumes over the scan interval. Longitudinal increases in GM but not WM volumes were related to improvements in neurocognitive measures during abstinence. The findings suggest that functionally significant brain tissue volume recovery during abstinence from alcohol is influenced by BDNF genotype.     

Influence of acute alcohol intake and alcohol withdrawal on circulating levels of IL-6, IL-8, IL-10 and IL-12

Cytokine balance alterations are responsible for some of the systemic and hepatic manifestations of alcoholism. The present study was aimed to evaluate the influence of both acute alcohol abstinence (in alcoholics) and acute alcohol intake (in healthy subjects) on serum IL-6, IL-8, IL-10, and IL-12 levels. Serum cytokine concentrations were determined on admission and after a median of 6 days of ethanol abstinence in 29 patients with alcohol withdrawal syndrome. The same determinations were made in five healthy volunteers at baseline and after 36 h of a single 60 g-dose alcohol intake. Increased serum levels of IL-6, IL-10 and, to a lesser extent IL-8, declined in the few days after alcohol abstinence in patients with alcohol withdrawal syndrome. Serum IL-8 values increased after alcohol intake in healthy subjects. Rapid variation of serum cytokine levels along with alcohol intake or abstinence should be taken into account in cytokine studies in alcohol abusers.     

Inhibition of the morphine withdrawal syndrome by a nitric oxide synthase inhibitor,NG-nitro-L-arginine methyl ester

The hypothesis that an arginine-nitric oxide (NO) synthase-NO system mediates the morphine abstinence syndrome was tested in adult male rats implanted subcutaneosly for 3 days with one morphine (75 mg) pellet followed by naloxone-precipitated withdrawal (0.5 mg/kg). Injection with a NO synthase inhibitor, N^G-nitro-L-arginine methyl ester (NAME, 100 mg/kg subcutaneous), shortly before naloxone-induced withdrawal significantly inhibited abstinence signs by 25–80%. Continuous infusion of NAME via subcutaneous osmotic pumps during the development of morphine physical dependence and during naloxone-precipitated withdrawal also inhibited morphine abstinence signs. In addition, treatment with isosorbide dinitrate, a NO donor, induced a quasi morphine-abstinence syndrome (QMAS) that was significantly suppressed by implantation of a morphine pellet 3 days before isosorbide dinitrate treatment. These results indicate that NO mediates part of the expression of the morphine abstinence syndrome.     

Anxiety level during morphine abstinence correlates with the status of nitrergic system in the rat hippocampus

Opiate addiction is accompanied by long-term structural and functional changes in brain regions persisting during abstinence, this status being an experimental model of the aberrant neuroplasticity. Nitric oxide is known to be involved in mechanisms of psychopathological events during opiate abstinence. In this study, indices of a nitregic system (nitric synthase activity--NOS, nitrites and nitrates concentration--NOx-) were measured in the rat brain region during morphine abstinence. Prior to this, the rats were tested for anxiety in an elevated plus maze. NOS activity increased in hippocampus 3 days after morphine withdrawal, while NOx--6 days after withdrawal. No changes of the nitrergic system could be revealed in other brain regions under study. Six days (but not 3 days) after morphine withdrawal, rats visited the open arms of the plus maze more frequently and spent more time in these arms as compared with respective controls. The data suggest that nitrergic system changes in the hippocampus may be involved in molecular mechanisms of behavioural alteration during morphine abstinence in rats.