**2. The hypothalamo-pituitary-adrenocortical axis and -endorphin**

Although a thorough understanding of this nebulous concept is lacking, stress has been operationally defined as activation of the hypothalamo-pituitary-adrenocortical (HPA) axis in response to both physical and psychological stressors (for example, Pacak and Palkovits, 2001; Uhart and Wand 2009). The stress response is coordinated by neuronal activation of the paraventricular nucleus in the hypothalamus leading to the release of corticotrophinreleasing hormone (CRH) into the hypothalamic-hypophyseal portal. CRH reaches receptors on the anterior pituitary and initiates the synthesis of ACTH from its precursor, proopiomelanocortin (POMC). ACTH is released into the bloodstream where it influences the adrenal glands, initiating production and release of cortisol into the blood (corticosterone in rodents). Cortisol plays a fundamental role in the systemic reaction that characterizes physiological stress, though high levels of cortisol act in a negative feedback loop, inhibiting further CRH and ACTH synthesis in the brain.

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fact that individuals predisposed to alcoholism have low basal levels of -endorphin and suggests that alcohol administration will ameliorate this deficiency (see Gianoulakis et al.,

Gianoulakis et al. (1996) examined the possibility that high risk individuals (as identified by familial history) will have increased sensitivity to EtOH-induced release of endogenous opioids, thus mediating the apparent enhanced reward those at high risk for alcoholism presumably experience with EtOH consumption. Subjects were between twenty and thirty years old and were categorized as either high risk (HR) or low risk (LR) based upon known family history of alcoholism. The results showed an EtOH-dose dependent increase in plasma β-endorphin levels in HR subjects, but not in LR subjects. This finding supports the notion that augmented sensitivity of β-endorphin release to EtOH could increase sensitivity

Animal studies provided further support for the idea that increased sensitivity to an EtOHmediated rise in β-endorphin might facilitate acquisition of alcohol drinking. We (Grisel et al. 1999) demonstrated that mice with low levels of β-endorphin self-administer more EtOH than either wild type (C57BL/6J) controls or mice that entirely lack the capacity for βendorphin production. In these studies we used either homozygous or heterozygous B6.129S2-*Pomc*tm1Low/J mice, commercially available from Jackson Laboratories, in Bar Harbor, ME. The mice with low β-endorphin self-administered more EtOH and exhibited higher alcohol preference than controls, regardless of EtOH dose, while those without any capacity to synthesize the peptide consistently drank the least. This experiment suggests two hypotheses. One is that those with low levels of β-endorphin are more inclined to drink.

In animals, pharmaceutical agents that increase plasma β-endorphin levels have been most effective in attenuating self-administration of EtOH. Treatment of Warsaw High and Low Alcohol Preferring rats with the opioid antagonist naltrexone, stopped the plasma βendorphin increase after EtOH administration in low-preference rats, and normalized βendorphin plasma levels in high-preferring rats so that before and after alcohol exposure plasma levels were similar. These results indicate the clinical effectiveness of naltrexone in treatment of alcoholism may in part be due to both normalization of plasma β-endorphin levels and an attenuation of alcohol-rewarding properties (Zalewska-Kaszubska et al., 2006). In the same strains of rats, β-endorphin levels and EtOH intake were examined following treatment with acamprosate, which is approved for relapse prevention in withdrawing alcoholics. Chronic administration of acamprosate decreased voluntary intake of EtOH and increased plasma β-endorphin levels in high-preferring rats. Chronic administration of acamprosate also increased β-endorphin levels in rats in withdrawal from free EtOH access, suggesting that the clinical efficacy of this novel pharmacotherapy may be mediated by

The specific influence of β-endorphin on negatively reinforcing effects of EtOH has been examined in animals. Negative reinforcement occurs as alcohol alleviates an aversive state or condition. We (Grisel et al., 2008) looked at anxious behavior as a function of basal levels of β-endorphin. These studies utilized the Light-Dark Box and Elevated Plus Maze to evaluate anxious behavior in wild-type C57BL/6J (WT), heterozygous (HT) and βendorphin deficient mice (B6.129S2-*Pomc*tm1Low/J). In these assays, anxious behavior is

2006; Herz, 1997, 1998; Zalewska-Kaszubska & Czarnecka, 2004 for reviews).

The other, that β-endorphin contributes to the rewarding effects of EtOH.

to the positive rewards of EtOH.

opioid effects.

Like stress, alcohol also leads to CRH release from the hypothalamus, initiating activation of this system (Hsu et al., 1998; see Gianoulakis, 2009; Uhart & Wand, 2009 for reviews). Indeed, the physiological effects of alcohol are in part mediated by the HPA axis and dependent upon neuronal activation of the paraventricular nucleus, and the subsequent release of CRH, ACTH and, eventually, adrenal activation (Lee et al., 2004).

Related to these endocrine changes, endogenous opioids are also synthesized and released in response to both the experience of stress and alcohol consumption (Keith et al, 1986; Sarkar & Minami, 1990; Schedlowski et al, 1995; Thiagarajan, 1989). Opioids are primarily known for their analgesic properties, but they are highly implicated in the physiological rewarding effects of alcohol and other drugs of abuse (Wei & Loh, 1976; Van Ree, 1979; Zalewska-Kaszubska et al., 2006; see Crabbe et al., 2006 for review) as well as a wide array of other behavioral states. One class of endogenous opioids is the endorphins. The primary endorphin is β-endorphin, which is both analgesic and addictive in human and animal studies (Janssen & Arntz, 2011; Wie & Loh, 1976), and contributes to the rewarding and reinforcing properties of alcohol (Grahame 1998; Grisel et al, 1999; Williams et al, 2007).
