Family History of Alcoholism and Hypothalamic Opioidergic Activity

Wand, Gary S.; Mangold, Deborah; Deiry, Samer El; McCaul, Mary E.; Hoover, Donald B.

doi:10.1001/archpsyc.55.12.1114

Cited by 116 publications

(120 citation statements)

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“…Subjectively, some fraction of the rewarding effects of alcohol ingestion in high-risk subjects can be blocked by naltrexone (King et al, 1997). Moreover, Wand et al (1998Wand et al ( , 2002 found that both family history and the Asp40 variant explained some variance in the release of corticotrophin-releasing factor (CRF) after stimulation with naloxone. Taken together, these findings suggest a possible mechanism for naltrexone response in which the clinical effects of the drug on reducing alcohol consumption may be enhanced in those with the Asp40 genotype, while having only marginal efficacy in those homozygous for the Asn40 variant.…”

Section: Table 1 Baseline Demographics and Clinical Characteristics Omentioning

confidence: 99%

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

Oslin

Berrettini

Kranzler

et al. 2003

Neuropsychopharmacol

545

399

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This study examined the association between two specific polymorphisms of the gene encoding the m-opioid receptor and treatment outcomes in alcohol-dependent patients who were prescribed naltrexone or placebo. A total of 82 patients (71 of European descent) who were randomized to naltrexone and 59 who were randomized to placebo (all of European descent) in one of three randomized, placebo-controlled clinical trials of naltrexone were genotyped at the A +118 G (Asn40Asp) and C +17 T (Ala6Val) SNPs in the gene encoding the m-opioid receptor (OPRM1). The association between genotype and drinking outcomes was measured over 12 weeks of treatment. In subjects of European descent, individuals with one or two copies of the Asp40 allele treated with naltrexone had significantly lower rates of relapse (p ¼ 0.044) and a longer time to return to heavy drinking (p ¼ 0.040) than those homozygous for the Asn40 allele. There were no differences in overall abstinence rates (p ¼ 0.611), nor were there differences in relapse rates or abstinence rates between the two genotype groups among those assigned to placebo. These preliminary results are consistent with prior literature demonstrating that the opioid system is involved in the reinforcing properties of alcohol and that allelic variation at OPRM1 is associated with differential response to a m-receptor antagonist. If replicated, these results would help to identify alcohol-dependent individuals who may be most likely to respond to treatment with naltrexone.

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Section: Table 1 Baseline Demographics and Clinical Characteristics Omentioning

confidence: 99%

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

Oslin

Berrettini

Kranzler

et al. 2003

Neuropsychopharmacol

545

399

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“…Corticotropin releasing factor (CRF) neurons within the paraventricular nucleus of the hypothalamus initiate activation of the hypothalamic-pituitary-adrenal (HPA) axis (Bell et al 1998 (Wand et al 1998). Recently, a common A118G nucleotide exchange in exon 1 of the muopioid receptor has been identified that causes an Asn40Asp substitution polymorphism in the extracellular N-terminal domain of the mu-opioid receptor (Bergen et al 1997;Wendel and Hoehe 1998).…”

Section: An A118g Nucleotide Exchange In Exon 1 Of the Mu-opioid Recementioning

confidence: 99%

“…Abnormalities in the stress response heighten an individual's vulnerability to endocrine, metabolic, psychiatric, and immunological disorders (Kreek and Koob 1998; Bjorntorp and Rosmond 2000a,b;Chrousos 2000). The unique characteristics of an individual's stress response are the product of genetic and environmental determinants (Francis et al 1999;Wust et al 2000).Corticotropin releasing factor (CRF) neurons within the paraventricular nucleus of the hypothalamus initiate activation of the hypothalamic-pituitary-adrenal (HPA) axis (Bell et al 1998 (Wand et al 1998). Recently, a common A118G nucleotide exchange in exon 1 of the muopioid receptor has been identified that causes an Asn40Asp substitution polymorphism in the extracellular N-terminal domain of the mu-opioid receptor (Bergen et al 1997;Wendel and Hoehe 1998).…”

mentioning

confidence: 99%

“…The CRF neurons express mu-opioid receptors and are modulated by inhibitory tone imposed by ␤ -endorphin neurons originating in the arcuate nucleus (Wand et al 1998). Recently, a common A118G nucleotide exchange in exon 1 of the muopioid receptor has been identified that causes an Asn40Asp substitution polymorphism in the extracellular N-terminal domain of the mu-opioid receptor (Bergen et al 1997;Wendel and Hoehe 1998).…”

mentioning

confidence: 99%

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The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

Wand

2002

Neuropsychopharmacology

230

166

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An A118G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptor's extracellular domain. In vitro studies show that the Asp40 variant of the mu-opioid receptor binds ␤ -endorphin three times more avidly than the more commonStress threatens homeostasis and is counteracted by a series of physiological and behavioral responses that improve the chances for survival. A successful response to stress plays an important role in maintaining health and well-being. Abnormalities in the stress response heighten an individual's vulnerability to endocrine, metabolic, psychiatric, and immunological disorders (Kreek and Koob 1998; Bjorntorp and Rosmond 2000a,b;Chrousos 2000). The unique characteristics of an individual's stress response are the product of genetic and environmental determinants (Francis et al. 1999;Wust et al. 2000).Corticotropin releasing factor (CRF) neurons within the paraventricular nucleus of the hypothalamus initiate activation of the hypothalamic-pituitary-adrenal (HPA) axis (Bell et al. 1998 (Wand et al. 1998). Recently, a common A118G nucleotide exchange in exon 1 of the muopioid receptor has been identified that causes an Asn40Asp substitution polymorphism in the extracellular N-terminal domain of the mu-opioid receptor (Bergen et al. 1997;Wendel and Hoehe 1998). In vitro studies show that the Asp40 variant of the mu-opioid receptor binds ␤ -endorphin three times more avidly than the common Asn40 variant and also induces a 3-fold increase in agonist-induced activation of G protein-coupled potassium channels (Bond et al. 1998). Because the Asn40Asp substitution alters receptor binding and signal transduction, it is plausible that this polymorphism alters processes under opioidergic regulation (LaForge et al. 2000a,b). The CRF neuron is also modulated by serotonergic fibers (Contesse et al. 2000;Isogawa et al. 2000). As opposed to ␤ -endorphin, which inhibits CRF secretion, serotonin activates the CRF neuron and stimulates CRF release. The serotonin transporter regulates the concentration of serotonin within the synaptic cleft and thereby modulates magnitude and duration of serotonin-induced postsynaptic mediated signals (Lesch and Mossner 1998). Recently a functional polymorphism has been described in the promoter region of the transporter, which modulates transcriptional activity of this gene as well as tissue expression of transporter activity (Hanna et al. 1998;Heils et al. 1997;Little et al. 1998). Like the A118G polymorphism in the mu-opioid receptor, it is plausible that this functional polymorphism within the serotonin transporter is associated with altered HPA axis dynamics.The present study was designed to test whether the Asn40Asp substitution polymorphism in the mu-opioid receptor or a functional mutation in the polymorphic region of serotonin transporter influences HPA axis activation induced by opioid receptor blockade. METHODS SubjectsHealthy men were recruited by newspaper from the Baltimore area. Respondents gave informed conse...

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“…In the case of the addictive diseases, these alterations are primarily due to the pharmacological effects of drugs of abuse but are also influenced by developmental, environmental, and genetic factors. As an example of the latter, nonalcoholic sons of alcoholic fathers have altered HPA responsiveness to alcohol and mu opioid receptor antagonism compared to sons of nonalcoholic fathers (King et al, 1998;Schuckit et al, 1987;Wand et al, 1998). In fact, up to 50% of interindividual differences in basal and stress-induced cortisol levels in healthy human volunteers may be explained by genetic factors (Federenko et al, 2004;Linkowski et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Altered Levels of Basal Cortisol in Healthy Subjects with a 118G Allele in Exon 1 of the Mu Opioid Receptor Gene

Bart

LaForge

Borg

et al. 2006

Neuropsychopharmacol

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The mu opioid receptor is centrally involved in the development of the addictive diseases. It also modulates the stress responsive hypothalamic-pituitary-adrenal axis. Receptors encoded by the variant 118G polymorphism in exon 1 of the mu opioid receptor gene have a threefold increase in beta-endorphin binding and beta-endorphin is three times more potent in receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels. Humans with this variant have increased stress response following opioid antagonism. Here, we study basal levels of adrenocorticotropic hormone and cortisol in subjects with this variant. In all, 59 healthy adults were genotyped and had morning levels of adrenocorticotropic hormone and cortisol measured following intravenous administration of saline placebo. Subjects with a 118G allele had significantly greater levels of cortisol than subjects with the prototype gene. Groups did not differ in levels of adrenocorticotropic hormone. A planned comparison revealed significantly greater cortisol in females with at least one copy of the 118G allele compared to females with the prototype gene. There was no significant effect of gender alone, nor was there a significant interaction between gender and genotype, on ACTH or cortisol. Subjects with at least one copy of the 118G allele have increased basal levels of cortisol, which may influence the susceptibility to and treatment of the stress responsive dyscrasia.

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Family History of Alcoholism and Hypothalamic Opioidergic Activity

Cited by 116 publications

References 50 publications

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

Altered Levels of Basal Cortisol in Healthy Subjects with a 118G Allele in Exon 1 of the Mu Opioid Receptor Gene

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