**6. β-endorphin and chronic alcohol use**

Though genetics certainly contribute to the liability toward alcohol use disorders, excessive drinking in virtually anyone will lead to neural adaptations that underlie dependence, and β-endorphin is also implicated in those changes. The hedonic dysregulation model suggests that a decrease in opioid peptide function (along with other adaptations) following chronic alcohol consumption results in dysregulation of opioid-mediated reward transmission. This blunted reward circuitry is expressed phenotypically as a negative affect that exacerbates the potency of negative reinforcement following drug administration or adds increased salience to relapse related cues (Koob 2008).

Indeed, empirical studies in humans have provided an extensive body of evidence supporting opioid dysregulation following chronic alcohol abuse. Chronic alcoholic patients exhibit decreased synthesis and release of β-endorphin as measured by plasma levels (Aguirre et al., 1990; see Zalewska-Kaszubska & Czarnecka, 2004 for review), and HPA axis dysregulation is a primary characteristic of withdrawal (Adinoff et al., 2005). Furthermore, the functional response of the mu-opioid receptor (which has a high affinity for βendorphin) is impaired after chronic exposure to EtOH (He & Whistler, 2011). It is thus likely that overactivity of the HPA is at least partly a result of low β-endorphin and that this change contributes to chronically higher basal levels of anxiety and stress during withdrawal (Aguirre et al., 1990; Aguirre et al., 1995 Wand, 2001).

Investigations of recovering alcoholics have shown that levels of plasma β-endorphin are inversely correlated with self-rated measures of anxiety during the withdrawal period (Kiefer et al., 2002). Augmented negative reinforcement following alcohol consumption for subjects with low β-endorphin is likely because of its role in inhibiting CRH secretion. High levels of cortisol act as negative feedback for HPA axis stress response, (Buckingham, 1986) implicating β-endorphin in both behavioral allostasis and endocrine allostasis. Thus, it is likely that an alcohol-induced reduction of increased basal anxiety levels is a strong negative reinforcing factor in the maintenance of chronic alcohol dependence (Goldowitz et al., 2006; Kiefer et al., 2002).

Further support for the dysregulation models comes from Aguirre et al. (1995) who examined the possibility of classifying individuals as alcoholics or non-alcoholics based on plasma β-endorphin levels. They were able to identify alcoholics and non-alcoholics over 70% of the time by this measure alone. Even more impressively, they found a negative predictive value of 93.55% such that for every 100 people found to have normal plasma βendorphin levels, 93 would actually be non-alcoholics. The results of this study supported a previous finding that low β-endorphin levels are significantly more common in clinical cases of alcoholics (Aguirre et al., 1990).

Plasma β-endorphin levels are involved in the withdrawal process. Kiefer et al. (2006) characterized alcoholics in recovery as either high preference or low preference based on individual average EtOH intake before detoxification. Basal β-endorphin levels of high preference individuals were found to be lower in comparison with low preference subjects. Treatment with acamprosate resulted in a significant increase in β-endorphin in high preference subjects but not in low preference subjects. Because acamprosate administration decreases withdrawal symptoms and increases abstinence, the increased β-endorphin levels in only high preference implicates β-endorphin deficiency as a key aspect in EtOH

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#### **7. Conclusion**

In conclusion, a growing body of research suggests that sub-optimal levels of β-endorphin result in compromised allostasis of the HPA axis, and that the consequent enhanced sensitivity to stressors facilitates high drinking. Sex differences may play a moderating role in the interaction between stress sensitivity, β-endorphin levels and EtOH. In general, individuals with deficient β-endorphin levels are likely to find EtOH more rewarding from both exaggerated positive and negative reinforcement. Chronic EtOH consumption leads to alterations in β-endorphin activity, and these changes are responsible in part for feelings of anxiety during withdrawal and relapse. Thus, especially in stressful situations, alcohol is likely to serve as an alternative coping mechanism with particular potency for those with labile β-endorphin and therefore predisposed to enhanced sensitivity to its anxiolytic effects.

### **8. Acknowledgements**

This publication was made possible by NIH Grant Numbers P20 RR-016461 from the National Center for Research Resources, AA13259 (through the INIA Stress Consortium) and AA13641 from the National Institute on Alcohol Abuse and Alcoholism.

#### **9. References**


withdrawal. In addition to acamprosate's efficacy in treating alcoholism, it has recently been

In conclusion, a growing body of research suggests that sub-optimal levels of β-endorphin result in compromised allostasis of the HPA axis, and that the consequent enhanced sensitivity to stressors facilitates high drinking. Sex differences may play a moderating role in the interaction between stress sensitivity, β-endorphin levels and EtOH. In general, individuals with deficient β-endorphin levels are likely to find EtOH more rewarding from both exaggerated positive and negative reinforcement. Chronic EtOH consumption leads to alterations in β-endorphin activity, and these changes are responsible in part for feelings of anxiety during withdrawal and relapse. Thus, especially in stressful situations, alcohol is likely to serve as an alternative coping mechanism with particular potency for those with labile β-endorphin and therefore predisposed to enhanced sensitivity to its anxiolytic effects.

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**10** 

 *USA* 

**The Role of Delta Opioid Receptors** 

**Implications for New Treatments** 

 **for Alcohol Use Disorders** 

Carsten K. Nielsen and Selena E. Bartlett

*Ernest Gallo Clinic and Research Center, University of California San Francisco,* 

**in Ethanol Consumption and Seeking:** 

There are few effective medications available for the treatment of alcohol use disorders (AUDs). To date, the opioid antagonist, naltrexone, is the most effective in reducing alcohol consumption in combination with behavioral therapy. Naltrexone has high affinity for the mu opioid peptide receptor (MOP-R) with moderate activity at the delta opioid peptide receptor (DOP-R) and kappa opioid peptide receptor (KOP-R). Preclinical studies suggest that the MOP-R plays a significant role in ethanol-mediated behaviors, however, there is evidence suggesting the DOP-R may be a better therapeutic target for treating AUDs. This chapter will review studies investigating the role of the opioid receptors in ethanol-mediated behaviors

AUDs are a major public health problem; currently the National Institute on Alcohol Abuse and Alcoholism, reports there are 17.6 million people in the United States either abuse alcohol or are alcohol dependent. There have been three medications approved by the U.S. Food and Drug Administration: disulfiram (Antabuse), acamprosate (Campral), and naltrexone (ReVia, Vivitrol) - all of which suffer from limited effectiveness due to sideeffects and compliance issues (Bouza et al., 2004; Mark et al., 2003a; Mark et al., 2003b; Pettinati et al., 2000). The aldehyde dehydrogenase blocker, disulfiram has not been very effective for treating AUDs (Johnson, 2008; O'Shea, 2000) primarily because of patient compliance (Johnson, 2008; O'Shea, 2000). Disulfiram is reportedly only clinically effective in patients who were fully compliant with taking their medication and were under supervision (Fuller et al., 1986). Acamprosate has been shown to be effective for alcohol dependence in European trials, but not in U.S. trials, and has a low incidence of side-effects (Anton et al., 2006; Bouza et al., 2004; Whitworth et al., 1996). To date, the opioid antagonist, naltrexone, appears to be the most effective medication for alcohol dependence (Anton et al., 2006;

with the view of identifying improved therapeutics for the treatment of AUDs.

**1.1 Current therapeutics for the treatment of alcohol use disorders** 

O'Malley et al., 1992; Volpicelli et al., 1992).

**1. Introduction** 

