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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 1 64-68
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

Adrenocorticotropin Responses to Naloxone in Sons of Alcohol-Dependent Men1

Gary S. Wand, Deborah Mangold and Mahmood Ali

Departments of Medicine and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Gary S. Wand, M.D., The Johns Hopkins University School of Medicine, Ross Research Building, Room 850, 720 Rutland Avenue, Baltimore, Maryland 21205. E-mail: gwand{at}welchlink.welch.jhu.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The endogenous opioid system is part of a neural circuitry functionally related to alcohol-seeking behaviors. A family history of alcoholism is the strongest predictor of future development of alcohol dependence. This study was designed to evaluate ACTH responses to opioid receptor blockade as a function of family history for alcohol dependence. The nonselective opioid antagonist naloxone stimulates ACTH secretion by blocking opioidergic input on paraventricular corticotropin-releasing factor neurons, thereby providing a methodology for comparing hypothalamic opioid tone between study groups. Sixty nonalcoholic subjects, aged 18–25 yr, were enrolled in a protocol to measure the ACTH response to naloxone. Thirty-two subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive subjects. Twenty-eight subjects were offspring of nonalcohol-dependent parents and were designated family history-negative subjects. Subjects received naloxone (125 µg/kg) or placebo (0.9% saline) in double blind, randomized order. Plasma ACTH was monitored. Family history-positive men had increased ACTH response to naloxone compared to 1) family history-positive women, 2) family history-negative men, and 3) family history-negative women. Despite differences in plasma ACTH levels after naloxone administration, plasma naloxone concentrations did not differ between study groups. This finding suggests that nonalcoholic male offspring of alcohol-dependent men have altered endogenous opioid activity directed at hypothalamic corticotropin-releasing factor neurons.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ACUTE ALCOHOL exposure activates the endogenous opioid system (1). This phenomenon has been proposed to be part of a neurobiological mechanism related to heavy alcohol-drinking behavior. At least three lines of converging evidence support this view. First, pharmacological studies indicate that opioid receptor antagonists, such as naloxone and naltrexone, decrease alcohol self-administration in rodents and monkeys in a variety of experimental conditions (2, 3, 4, 5, 6, 7). The results of these preclinical studies led to two double blind, placebo-controlled clinical trials that demonstrated that naltrexone reduced alcohol craving and relapse rates in detoxified out-patient alcoholics (8, 9). Based on such findings, the FDA approved the use of naltrexone as a pharmacotherapeutic agent for the treatment of alcohol dependence.

Evidence for involvement of the opioid system in mediating alcohol-drinking behavior is also derived from neurobiological studies, which indicate that alcohol alters opioid peptide systems. Acute alcohol exposure increases POMC and proenkephalin gene expression in discrete brain regions of rodents, increases opioid peptide release from both brain and pituitary of rodents in vitro, and increases opioid peptide release form the pituitary of rodents and humans in vivo (1, 10, 11).

Genetic studies provide the third line of evidence for functional involvement of the opioid system in mediating alcohol-drinking behavior. For example, plasma ß-endorphin responses to acute alcohol exposure differ in nonalcoholic subjects with and without a family history of alcoholism (12). It has been proposed that a genetic predisposition toward alcoholism is accompanied by increased responsiveness of the opioid system to alcohol (1, 12, 13).

The importance of a genetic component in the development of alcoholism has been well established by family, twin, and adoption studies (14, 15, 16, 17, 18, 19, 20, 21). Indeed, when the relative contributions of genetic and environmental factors to alcoholism were examined (17), genetic determinants were found to exert a strong influence in men (heritability estimate = 0.59) and to exert a lesser influence in women (heritability estimate = 0.42). These findings have led investigators to search for the presence of possible biological mediators for the development of alcoholism. In this regard, several studies have demonstrated aberrant neuroendocrine responses in male offspring of alcohol-dependent men. For example, in a 10-yr follow-up of the sons of alcoholics and controls, Schuckit and co-workers (22, 23) found that a low level cortisol response to alcohol characterized those men who were most likely to develop alcohol abuse or dependence almost a decade later. Gianoulakis and co-workers (12) demonstrated that mild alcohol intoxication induced a significant increase in plasma ß-endorphin in nonalcoholic offspring of alcohol-dependent subjects. This opioid response to alcohol was not present in individuals without a family history of alcoholism. Wand and co-workers (24) identified that nonalcoholic male offspring of alcohol-dependent men have an altered ACTH response to corticotropin-releasing factor (CRF) compared to male offspring without a family history of alcoholism.

We speculate that the reported differences in hypothalamic-pituitary-adrenal (HPA) responses to alcohol as a function of family history of alcoholism result from altered endogenous opioid activity directed at hypothalamic CRF neurons in high risk subjects. To test this hypothesis, we induced opioid receptor blockade with the opioid receptor antagonist, naloxone, to activate the HPA axis (25, 26, 27, 28, 29, 30). Naloxone, a nonselective opioid receptor antagonist, induces ACTH secretion by blocking the opioid component of inhibitory activity directed at hypothalamic CRF neurons within the paraventricular nucleus. Using this strategy, we compared plasma ACTH responses to naloxone in individuals with and without a family history of alcoholism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Subjects were recruited by newspaper from the Baltimore area; 60 healthy subjects without selected major axis I psychiatric diagnosis, including diagnosis of alcohol dependence/abuse, between the ages of 18–25 yr were enrolled (Table 1Go). All subjects gave informed consent. The alcohol and psychiatric diagnostic status of potential study subjects was established using the SemiStructured Assessment for the Genetics of Alcoholism (SSAGA I/II) which is designed to assess the physical, psychological, and social manifestations of alcoholism and related disorders (31), and the Family History Assessment Module (32). Additional assessments included the 90-day Time Line Follow Back (33) to confirm recent alcohol and other drug use patterns, the Fagerstrom test to confirm nicotine dependence (34), as well as assessment of general health using a medical history, physical examination, and standard laboratory tests (complete blood cell counts, electrolytes, liver and renal function tests, and glucose). To control for hormonal fluctuations, female subjects were studied during the follicular phase of the menstrual cycle only.


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  		Table 1. Selected characteristics of subjects

 
Exclusionary criteria

The following exclusion criteria were used: 1) meeting Diagnostic Statistical Manual IV (DSMIV) criteria for any psychoactive substance use disorder including nicotine dependence, 2) meeting Diagnostic Statistical Manual IV (DSMIV) criteria for selected major axis I and II disorders as covered by the SSAGA or being in need of or currently undergoing pharmacotherapy, 3) being pregnant, 4) experiencing a serious medical condition, 5) having abnormal liver function, 6) having a central nervous system or endocrine disorder, 7) maternal alcohol dependence, and 8) being treated within the last 10 yr with antidepressants, neuroleptics, mood stabilizers, sedative hypnotic medications, isoniazid, glucocorticoids, or psychostimulant appetite suppressants.

Designation of family status

Subjects were assigned to one of two groups [family history positive (FHP) or family history negative (FHN) for alcohol dependence] according to family history status based on clinical interview information obtained from the proband, father, and two additional family members through the Family History Assessment Module or SSAGA. A subject designated FHN had no history of alcohol abuse or dependence in any paternal first or second degree relative. A FHP subject was one with his/her biological father and at least one additional first or second relative meeting diagnostic criteria for alcohol dependence. In general, collateral interviews were conducted with the father and two additional first/second degree relatives. If the father could not be interviewed, his diagnostic status was validated by interview with three first or second degree relatives. Subjects were excluded if confirmation of family status was unable to be obtained.

Neuroendocrine protocol

Subjects reported for sessions at 1230 h after fasting since breakfast at 0900 h. At each session, an iv catheter was inserted into a forearm vein at 1300 h. One hour after iv line placement, naloxone (125 µg/kg) dissolved in 0.9% saline or placebo (0.9% saline) was administered over 1 min as a bolus dose. Baseline blood samples were obtained 15 min before and immediately before drug administration. After drug or placebo administration, blood samples were drawn at 15, 30, 45, 60, 90, and 120 min. Naloxone and placebo were administered double blind in randomized dose order.

ACTH and naloxone assays

Plasma concentrations of ACTH were assayed by a two-site immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA). Intra- and interassay coefficients of variance were less than 9%. Plasma naloxone concentrations were determined by high performance liquid chromatography with dual electrode electrochemical detection. (National Medical Services, Willow Grove, PA). Intra- and interassay coefficients of variation were 3% and 6%, respectively.

Statistical analyses

Demographic data. {chi}2 analysis was used to insure equal representation by gender and family history. An ANOVA was used to test for differences between family history and gender groups on those subject characteristics that may systematically covary with family history or gender and confound the effects observed on neuroendocrine responses.

Neuroendocrine data. The effects of three independent variables (time, family history, and gender) on two measures of ACTH responses (ACTH time point differences and area under the ACTH curve) were examined. Significance was evaluated at a P value of 0.05 or less. All analyses were conducted with the Statistical Package for the Social Sciences. Analyses were chosen to test the hypotheses 1) that FHP subjects would demonstrate a different ACTH response across time during study sessions compared to FHN subjects, and 2) that FHP males would demonstrate a greater ACTH response across time compared to the other subjects. Where indicated, significant multivariate effects were followed by specified contrast tests to examine differences between FHP males and other groups at individual time points. To provide supplemental support for the time point data, the area under the ACTH-time curve (AUC) was calculated using the trapezoidal rule. Multivariate analyses were used to assess the effects of family history and family history x gender. Contrast tests were used to examine differences between individual groups.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Selected characteristics for the 60 subjects are presented in Table 1Go. Subjects were predominantly Caucasian, in their early twenties, and equally distributed into gender and family history categories, with no significant differences between groups in body mass or ethanol ingestion histories. One hundred percent of FHP subjects had fathers meeting diagnostic criteria for alcohol dependence; 89% of FHP males and 83% of FHP females had second degree paternal relatives meeting diagnostic criteria for alcohol dependence, and 18% of FHP males and 28% of FHP females had second degree maternal relatives meeting diagnostic criteria for alcohol dependence.

Placebo administration

The results of a repeated measures analysis of ACTH response across time points after placebo administration found no significant effect for time, family history, or family history x gender x time.

Naloxone administration

Analyses of ACTH response across time points after naloxone administration found a significant effect for time (F = 1.62; P < 0.01; 7/43 df). There was no significant difference between family history groups. However, there was a significant interaction between family history status and gender on ACTH response (F = 3.654; P < 0.05; 2 df). Figure 1AGo shows that FHP males had significantly greater ACTH responses than all other groups at the following time points: 15 (t = 3.30; P < 0.01; 50 df), 30 (t = 2.56; P < 0.05; 50 df), 45 (t = 2.48; P < 0.05; 50 df), 60 (t = 3.42; P < 0.001; 50 df), and 90 (t = 2.62; P < 0.05; 50 df) min.



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  		Figure 1. Plasma ACTH response to naloxone administration. A, Plasma ACTH vs. time. B, Area under the plasma ACTH-time curve.

 
The results of a multivariate analysis of ACTH (AUC) after naloxone administration by family history and family history x gender provides supplemental support for the findings reported from the time point data. There were no differences in ACTH (AUC) between family history groups. However, the effect of the interaction between family history status and gender on ACTH (AUC) was significant (F = 3.86; P < 0.05; 2 df). Contrast tests (Fig. 1BGo) showed that FHP males had a significantly greater ACTH (AUC) value compared with the other groups (P = 0.047).

ACTH responses to naloxone did not correlate with age, body mass index, drinks/episode, or drinking episodes per week. Serum naloxone concentrations over the 120 min session did not differ by family history, gender, or family and gender (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
A positive family history of alcoholism is the strongest predictor of risk for the development of alcoholism (1, 35, 36, 37, 38). The data reported in this study suggest that the male offspring of alcohol-dependent fathers demonstrate a more robust ACTH response to opioid receptor blockade than members of the other study groups. These findings extend work generated in our previous studies, which demonstrated significant differences in HPA axis dynamics as a function of family history of alcoholism (24), as a function of alcohol dependence (39), and as a function of mild alcohol intoxication in social drinkers (40). Our results are also in line with other studies demonstrating differences in ß-endorphin, cortisol, and PRL responses to ethanol ingestion as a function of family history of alcoholism (1, 12, 23, 41) as well as differences between alcoholic and controls in TSH responses to TRH (42).

Enhanced ACTH response to naloxone in FHP men cannot be explained by factors related to race, age, education, or nicotine or alcohol exposure, as these were similar between family history/gender groups and were not correlated with the magnitude of the ACTH response. It is also unlikely that differences in naloxone metabolism among the four subject groups explain group differences in plasma ACTH, because the plasma naloxone concentration was identical between groups after naloxone administration.

In total, these findings lend further support to the contention that males from families with a high density of alcohol dependence have altered HPA axis dynamics. Indeed, the HPA axis may serve as a marker to distinguish individuals at increased risk for alcoholism. This is plausible for several reasons. First, glucocorticoids enhance dopamine generation within the nucleus accumbens, the primary drug reward center of the brain (43, 44). Second, arcuate nucleus CRF neurons, which are responsible for initiating the HPA axis response to stress, are modulated by the candidate neurotransmitter systems implicated in neurobiological vulnerability for alcoholism (45); CRF neurons are under inhibitory control by opioidergic and {gamma}-aminobutyric acid-ergic neurons and are under stimulatory control by serotonergic and catecholaminergic systems (46). These four neurotransmitter systems not only modulate CRF secretion, but also modulate mesolimbic dopamine accumulation within the nucleus accumbens, a process that may influence the magnitude of hedonic effects after ethanol ingestion (47, 48).

Animal and human studies have shown that endogenous opioids play an important role in ethanol-seeking behavior (1). It is plausible that if opioid activity differs in FHP men vs. the other subject groups, then a neuroendocrine system modulated by opioid activity (e.g. CRF neurons) will also differ as a function of the interaction of male gender and positive family history of alcoholism. Therefore, we speculate that our finding signifies differences in hypothalamic opioid activity directed at CRF neurons for FHP males. However, there are other interpretations for this finding. First, it is also possible that the induction of opioid blockade, resulting in the disinhibition of CRF neurons, merely unmasked family history/gender differences in serotonin, {gamma}-aminobutyric acid, and/or noradrenergic tone on the CRF neuron. Second, as naloxone binds to both µ- and {delta}-opioid receptors, this finding may represent the combined effects of family history and gender on the ratio of {delta}/µ-opioid receptor expression within the hypothalamus. Third, arginine vasopressin (AVP) potentiates the effects of CRH on ACTH release. Previous studies have shown that the ACTH response to CRH is augmented by naloxone, suggesting that naloxone induces AVP as well as CRH release (49). Therefore, it is also possible that the enhanced ACTH response to naloxone observed in FHP men results from greater AVP levels in this group. Regardless of etiology, we speculate that this finding is part of a neurochemical milieu in FHP males generating altered HPA axis responses to alcohol and perhaps other stressors as well. This is especially interesting now that the long acting opioid antagonist, naltrexone, has shown to be useful in reducing the craving for alcohol and attenuating relapse (8, 9).

At this time we are uncertain why ACTH responses to naloxone in FHP women are not more similar to responses observed in FHP men. However, it is known that estrogen enhances CRF and ß-endorphin gene expression (50, 51). It is plausible that estrogenization of the hypothalamus alters CRF and ß-endorphin expression sufficiently to diminish the CRF secretion induced by opioid blockade. Furthermore, although there is an inherited contribution to alcoholism in women, the overall effect of genetic determinants is modest and perhaps less important than the contribution of inherited factors in the development of alcoholism in men (52). Although our finding may reflect genetic determinants for opioid tone, recent studies have shown that chronic stress can alter opioid activity and perhaps could cluster in dysfunctional families (53).

In summary, nonalcoholic male offspring from families with a high density of alcohol-dependent individuals have an enhanced plasma ACTH response to opioid receptor blockade compared to those of FHP women and FHN men and women. This implies that FHP men have altered neurotransmitter activity directed at hypothalamic CRH neurons, possibly representing group differences in opioid activity.


   Footnotes
 
1 This work was conducted at The Johns Hopkins University School of Medicine General Clinical Research Center, supported by Grant MO1-RR-00052, NIAAA Grant RO-1–10158, The Alcoholic Beverage Medical Research Foundation, and a generous gift from the Kenneth Lattman Foundation. Back

Received August 24, 1998.

Revised September 23, 1998.

Accepted September 30, 1998.


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 Introduction
 Subjects and Methods
 Results
 Discussion
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