Previous studies have demonstrated that a moderate dose of ethanol induced a significant increase in the plasma beta-endorphin content of subjects from families with a history of alcoholism (high risk (HR)), but not subjects from families without a history of alcoholism (low risk (LR)). The objective of this study was to examine the response of the pituitary beta-endorphin and adrenal cortisol systems to various concentrations of ethanol in male and female subjects at high and low risk of the future development of alcoholism.
All subjects participated in four experimental sessions. In each session the subjects were given a drink containing one of the following doses of ethanol: 0, 0.25, 0.50, and 0.75 g of ethanol per kilogram of body weight (for a 60- to 70-kg individual). Blood samples were taken at 0 minutes and at 15, 45, 120, and 180 minutes after the drink for estimation of the blood alcohol, plasma beta-endorphin, and plasma cortisol levels.
The concentration of alcohol in the blood at various intervals after the drink was similar among the subjects, regardless of the risk group. Ethanol increased the plasma level of beta-endorphin-related peptides of the HR but not of the LR subjects in a dose-dependent manner. All subjects showed a small decrease in plasma cortisol level with time, but ethanol ingestion did not significantly alter the plasma cortisol levels.
This study indicates that the pituitary beta-endorphin system, but not the adrenal cortisol system, of the HR subjects shows an enhanced sensitivity to ethanol, which may be an important factor in controlling ethanol consumption.
"In accordance with the OPT, if alcohol-mediated MOR or DOR stimulation (Marinelli et al., 2004, 2005; Lam et al., 2008; Jarjour et al., 2009) produces positive hedonic states (Amalric et al., 1987; Shippenberg et al., 1987), then a compensatory mechanism could be increased DYN and/or function of KORs, stimulation of which produces negative hedonic states (Mucha and Herz, 1985). Under conditions of chronic alcohol use (see Figure 2), the predicted response of the endogenous opioidergic system would be attenuated MOR signaling and exacerbated DYN/KOR system activity, both of which are supported in the literature (Gianoulakis et al., 1996; Przewlocka et al., 1997; Turchan et al., 1999; Chen and Lawrence, 2000; Lindholm et al., 2000; Saland et al., 2004; Lindholm et al., 2007). In addition, chronic alcohol exposure has been shown to alter various neuropeptide systems (e.g., corticotropin-releasing factor (CRF), neuropeptide Y and nociceptin; Cowen and Lawrence, 2006; Ciccocioppo et al., 2009; Koob, 2010) that may contribute to the development of alcohol dependence and/or negative affective states. "
[Show abstract][Hide abstract] ABSTRACT: Alcoholism is a chronic relapsing disorder characterized by continued alcohol use despite numerous adverse consequences. Alcohol has been shown to interact with numerous neurotransmitter systems to exert its pharmacological effects. The endogenous opioid system (EOS) has been strongly implicated in the positive and negative reinforcing effects of alcohol. Traditionally recognized as dysphoric/anhedonic in nature, the dynorphin/kappa-opioid receptor (DYN/KOR) system has recently received considerable attention due to evidence suggesting that an upregulated DYN/KOR system may be a critical contributor to the complex factors that result in escalated alcohol consumption once dependent. The present review will discuss alcohol-induced plasticity in the DYN/KOR system and how these neuroadaptations could contribute to excessive alcohol seeking and consumption.
"A few studies however, have not found support for the efficacy of naltrexone (Killeen et al., 2004; Kranzler et al., 2000; Krystal et al., 2001). Alcohol has a complex pharmacological profile involving affinity for multiple receptor types; the reinforcing effects are thought to be due to the combined release of endogenous opioids like β-endorphin and dopamine (from the midbrain), targeting neurons in the nucleus accumbens (NAc) downstream (Gianoulakis et al., 1996; Volpicelli, 2001). Current models of the effects of naltrexone posit that it acts by diminishing the dopamine response to ethanol in the NAc, which has been supported by pre-clinical research (Benjamin et al., 1993). "
[Show abstract][Hide abstract] ABSTRACT: Naltrexone, one of four FDA-approved pharmacotherapies for alcohol dependence, has shown moderate efficacy in clinical trials. Pharmacogenetic effects have been reported such that allelic variation at the gene encoding the mu-opioid receptor (OPRM1, rs1799971) predicts naltrexone-induced blunting of the positively reinforcing effects of alcohol. However, naltrexone also binds, albeit to a lesser degree, to kappa and delta opioid receptors in the brain. This alternate binding presents the possibility that single nucleotide polymorphisms (SNPs) in the kappa and delta opioid receptor (OPRK1 and OPRD1) genes may contribute to naltrexone pharmacogenetics. Therefore, the goal of this exploratory study was to re-examine data from a double-blind placebo controlled laboratory trial of naltrexone for pharmacogenetic effects at kappa and delta opioid receptor tag SNPs. Participants were 40 heavy drinkers (12 female) who underwent an intravenous alcohol challenge paradigm after receiving naltrexone (50mg) or placebo in randomized and crossover fashion. Dependent variables were self-reported alcohol-induced stimulation, sedation, and craving. Multilevel models revealed a significant Naltrexone×OPRK1 Genotype (rs997917) interaction predicting alcohol-induced sedation, such that TT homozygotes reported lower naltrexone-induced alcohol sedation as compared to carriers of the C allele. Moreover, there was a significant Naltrexone×OPRD1 Genotype (rs4654327) interaction predicting alcohol-induced stimulation and craving, such that carriers of the A allele at this locus reported greater naltrexone-induced blunting of alcohol stimulation and alcohol craving compared to GG homozygotes. These findings suggest that additional pharmacogenetic effects in the opioid receptor system may account for individual differences in response to naltrexone in the human laboratory.
"The model proposes that FHP manifests in heightened sensitivity to alcohol on the ascending limb of the BEC curve coupled with greater acute tolerance on the descending limb. Numerous studies have found support for this model in humans (Conrod et al. 2001; Gianoulakis et al. 1996; Holdstock et al. 2000; King et al. 2002; Peterson et al. 1996). While the heightened sensitivity the Differentiator model refers to concerns the stimulating effects of alcohol rather than ataxia, these animals still fit the philosophy behind the model, although it is related to a different response. "
[Show abstract][Hide abstract] ABSTRACT: Propensity to develop acute functional (or within session) tolerance to alcohol (ethanol) may influence the amount of alcohol consumed, with higher drinking associated with greater acute functional tolerance (AFT). The goal of this study was to assess this potential correlated response between alcohol preference and AFT in second and third replicate lines of mice selectively bred for high (HAP2 and HAP3) and low (LAP2 and LAP3) alcohol preference drinking. Male and female mice were tested for development of AFT on a static dowel task, which requires that animals maintain balance on a wooden dowel in order to prevent falling. On test day, each mouse received one (1.75 g/kg; Experiment 1) or two (1.75 and 2.0 g/kg; Experiment 2) injections of ethanol; an initial administration before being placed on the dowel and in Experiment 2, an additional administration after the first regain of balance on the dowel. Blood samples were taken immediately after loss of balance [when blood ethanol concentrations (BECs) were rising] and at recovery (during falling BECs) in Experiment 1, and after first and second recovery in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BECs than LAP mice following the initial injection of ethanol and were therefore more sensitive to its early effects. Furthermore, Experiment 1 detected significantly greater AFT development (BECfalling - BECrising) in HAP mice when compared with LAP mice, which occurred within ∼30 min, supporting our hypothesis. However, AFT was not different between lines in Experiment 2, indicating that ∼30-60 min following alcohol administration, AFT development was similar in both lines. These data show that high alcohol drinking genetically associates with both high initial sensitivity and very early tolerance to the ataxic effects of ethanol.
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