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Alcohol dependence (AD) leads to altered innate and adaptive immune responses, and frequently co-occurs with inflammation. Therefore, inflammatory cytokines potentially play a crucial role in the development of alcohol-related illnesses. This study evaluated changes in plasma cytokine concentrations, liver function, cravings, depression severity, and cognitive function in male patients with AD, during the course of an alcohol-detoxification program. A total of 78 male patients with AD were recruited for a conservative detoxification program; and cytokine levels, depressive score, and cognitive impairment applying the Trail Making Test (TMT) were evaluated during early withdrawal (baseline) and after 4 weeks of abstinence from alcohol. Healthy volunteers (86 males) were also recruited as controls. Inflammatory cytokine expression in all participants was assessed by multiplex magnetic bead assay. AD patients during early withdrawal demonstrated higher cytokine levels than the healthy controls (P≤0.001 for all cytokines). However, the levels of cytokine expression were significantly lower after 4 weeks of abstinence from alcohol (P≤0.001, except for IL-1β and IL-5). Higher liver function marker levels, depressive severity, and TMT times were observed in patients at the beginning of the detoxification program than in healthy controls. Fortunately, these functions significantly ameliorated after 4 weeks of abstinence. (P≤0.001). Levels of circulating cytokines, liver function, and cognitive function may markers of alcohol use disorder., (Copyright © 2016. Published by Elsevier Ltd.)

The effects of chronic ethanol consumption and ethanol withdrawal on serum cholinesterase (ChE) activity and passive avoidance task in rats were investigated. Ethanol was administered to rats by a modified liquid diet with 4.8% (v/v) ethanol for 3 days followed by 25 days on a liquid diet in which the ethanol concentration was increased to 7.2%. Control rats were pair fed with an isocaloric liquid diet not containing ethanol. ChE activity and blood ethanol concentration were measured at the end of the 4.8% ethanol consumption and after 25 days of ethanol (7.2%) feeding and, just before and 24th and 72nd h of ethanol withdrawal period. Passive avoidance acquisition was evaluated for 150 s (cut-off time) in three individual groups of ethanol-administered, ethanol withdrawn (24th and 72nd h of withdrawal) and control rats. Locomotor activity of the rats was also measured and evaluated. The daily ethanol consumption of the rats ranged from 11.5 to 14.9 g/kg. ChE activities of the ethanol feeding rats were significantly increased as compared to control rats at the 3rd (4.8% ethanol) and 25th days of chronic ethanol (7.2%) consumption and 24th h of ethanol withdrawal. It returned to control values at the 72nd h of the withdrawal. Blood ethanol levels were measured as 200 and 2.2 mg/dl at just before ethanol withdrawal and 24th h of ethanol withdrawal, respectively. Both chronic ethanol consumption and late period of ethanol withdrawal produced some significant decreases in passive avoidance latency of the rats. Our results suggest that chronic ethanol consumption and late period of ethanol withdrawal may be related to impairment of passive avoidance task in rats. In addition, serum ChE levels do not seem to be involved in impairment of cognitive functions in ethanol dependent-rats.

Previous studies in crosses between the C57BL/6J (B6) and the DBA/2J (D2) mice have implicated a role of the genes encoding for the 67- and 65-kDa isoforms of the glutamate decarboxylase (Gad1 and Gad2) in the manifestation and severity of multiple ethanol-related traits such as acute ethanol withdrawal severity [Buck, K.J., Metten, P., Belknap, J.K., Crabbe, J.C., 1997. Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. J. Neurosci. 17, 3946-3955], ethanol preference [Phillips, T.J., Belknap, J.K., Buck, K.J., Cunningham, C.L., 1998. Genes on mouse chromosomes 2 and 9 determine variation in ethanol consumption. Mamm. Genome 9, 936-941] and ethanol-induced locomotion [Demarest, K., McCaughran Jr., J., Mahjubi, E., Cipp, L., Hitzemann, R., 1999. Identification of an acute ethanol response quantitative trait locus on mouse chromosome 2. J. Neurosci. 19, 549-561]. Strain-specific sequencing experiments as well as gene expression studies in drug-naive and ethanol-treated D2 and B6 mice were carried out. The Gad1 sequence was similar, the Gad2 cDNA carried only a silent polymorphism (1017 G>C) between both strains. In addition, no significant GAD65 or GAD67 expression differences were detected in either drug-nai;ve or acute ethanol withdrawn animals by Western blot experiments. Therefore, these results do not support the hypothesis of an involvement of Gad1 or Gad2 in the pathophysiology of acute ethanol withdrawal severity and the other ethanol related traits.

In this study the level of a substance P endopeptidase (SPE)-like activity was measured in different regions of the rat central nervous system (CNS) after chronic administration of morphine. Male rats (200-220 g) were randomly divided into four groups. Two groups were injected (s.c.) with morphine (10 mg/kg) twice daily, whereas the other two received saline under identical conditions. After 8 days, when animals were completely tolerant to morphine, one of the morphine-treated groups and one group of saline-injected rats were given naloxone (s.c. 2 mg/kg). Withdrawal signs were observed and recorded. The enzyme activity was measured in extracts of the various CNS tissues by following the conversion of synthetic substance P (SP) to its N-terminal fragment SP(1-7) using a radioimmunoassay detecting this product. In discrete CNS areas including periaqueductal grey, spinal cord, substantia nigra and ventral tegmental area (VTA) a significant increase in enzyme activity was observed in the withdrawal group, while tolerant rats exhibited decreased SPE-like activity in the striatum (see Table 1). The enhanced enzyme activity during withdrawal is in agreement with our previous observation that the levels of SP(1-7) in rat brain are affected following naloxone precipitated withdrawal. In some tissues, including VTA, a correlation between the SPE-like activity and the intensity of the opioid abstinence was observed. Our result suggests that the elevated SPE-like activity is responsible for enhanced release of SP(1-7) in rats during morphine withdrawal, affirming a modulatory or regulative role of this enzyme in this state of opioid dependence.

Behavioural and biochemical studies were carried out in rats given a single daily dose (1 mg/kg, i.p.) of haloperidol for 30 days and subsequently withdrawn for 7 days. Long-term administration of haloperidol resulted in supersensitivity of dopamine receptors. This was manifested by enhanced stereotypic biting, rearing, locomotor and floor activity of haloperidol withdrawn rats when challenged to a low dose of apomorphine (0.5 mg/kg, s.c.) on the 8th day. Chronic haloperidol treatment significantly decreased dopamine synthesis and release as evidenced by low activity of tyrosine hydroxylase and low level of homovanillic acid in striatum. Dopamine levels did not change in the frontal cortex, striatum and midbrain. Haloperidol treatment significantly increased striatal gamma-aminobutyric acid content and glutamic acid decarboxylase activity by 17% and 16% respectively. The decreased tyrosine hydroxylase activity and homovanillic acid level in corpus striatum might, in part, be due to an inhibitory effect of GABAergic neurons on dopaminergic system. Rats withdrawn from chronic haloperidol treatment showed significant increases in GABA level and glutamic acid decarboxylase activity. This probably resulted in further inhibition of dopamine release as evidenced by marked accumulation of dopamine in the corpus striatum and midbrain. No significant alterations in the endogenous levels of norepinephrine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in haloperidol-treated and subsequently withdrawn rats. These data suggest that chronic haloperidol treatment and subsequent withdrawal results in the development of behavioural dopamine supersensitivity as well as biochemical alterations in dopaminergic and GABAergic system. The changes in these two neuronal systems seem to be interrelated.