Involvement of µ-Opioid Receptors and Endogenous Opioids in Craving for Alcohol

Jon-Kar Zubieta, M.D., Ph.D.

University of Michigan

Funded in September, 2000: $100000 for 2 years
LAY SUMMARY . BIOGRAPHY . HYPOTHESIS . FINDINGS . SELECTED PUBLICATIONS .

INVESTIGATOR BIOGRAPHIES

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Jon-Kar Zubieta, M.D., Ph.D.

Assistant Professor
University of Michigan

HYPOTHESIS

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Hypothesis:
The endogenous opioid system, including the µ-opioid receptors, is involved in the regulation of emotions, responses to stress, and the actions of substances of abuse. It is hypothesized that the µ-opioid receptors mediate emotional responses to the use and withdrawal from alcohol, inducing urges for that substance.

Goals:
To examine the function of the endogenous opioid system and µ-opioid receptors in alcohol-dependent volunteers. We are to relate the function of this system with the experience of craving for alochol under controlled experimental conditions. For that purpose, µ-opioid receptor availability in vivo will be quantified at baseline and during craving induced by autobiographical scripts of situations associated with craving for alcohol. The change in µ-opioid receptor availability will be compared with the change in craving experienced. This data will help understand the mechanisms and possible therapeutic avenues to treat craving for alcohol.

Methods:
Mu opioid receptor availability in vivo will be estimated with positron emission tomography and the radiotracer [11C]carfentanil, a selective µ-opioid receptor ligand. Measures of receptor binding potential (Bmax/Kd) will be obtained during a neutral state and while experiencing craving, together with ratings of the desire to use alcohol. Image data and behavioral ratings will be compared on a pixel by pixel basis with SPM.

FINDINGS

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Scientific Results:

Twelve alcohol-dependent volunteers and 12 age and gender-matched healthy controls were studied with positron emission tomography and the radiotracer [11C]carfentanil, a selective mu opioid receptor radioligand. Dependent volunteers were recruited who were otherwise healthy, were detoxified from alcohol use for at least 3 weeks prior to the study, and who were experiencing high levels of urges for alcohol. Mu opioid receptor binding measures were obtained under two conditions, elicited using previously prepared individualized scripts: (1) a neutral state, during which the volunteers were instructed to focus on an event not associated with craving for alcohol, and (2) a craving state, when the volunteers were instructed to focus on an event associated with high levels of craving for alcohol. The difference between neutral and craving scans was utilized to obtain an estimate of changes in endogenous opioid release, reflected by the changes in in vivo receptor availability between conditions. Binding estimates obtained during the neutral scan were compared with those of an age-matched control group.

Baseline mu opioid receptor binding was found reduced in alcohol-dependent volunteers in the right amygdala, a region involved in emotional processing and the encoding of emotional memory. Comparisons between neutral and craving scans revealed regional increases in mu opioid receptor availability in vivo during craving. These increases reflect reductions in baseline endogenous opioid release, and were detected in the left anterior thalamus, amygdala and subgenual anterior cingulate. The deactivation of the endogenous opiois system and mu opioid receptors in the left amygdala correlated with increases in alcohol craving scores in the left amygdala.

These findings indicate both a dysregulation of mu opioid receptor mechanisms in alcohol-dependent volunteers (reductions in binding at baseline in the right amygdala, reflecting either increased release or a downregulation of the system), as well as the involvement of this neurotransmitter system in the mediation of the experience of craving for alcohol. Reductions in the baseline level of activation of the mu opioid neurotransmitter system during craving for alcohol were detected in limbic and paralimbic regions involved in emotional regulation (left anterior cingulate, anterior thalamus and amygdala).

SELECTED PUBLICATIONS

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Zubieta J., Greenwald M.K., Lombardi U., Woods J.H., Kilbourn M.R., Jewett D.M., Koeppe R.A., Schuster C.R., and Johanson C.E. Buprenorphine-induced dose-dependent changes in mu-opioid receptor availability in heroin-dependent volunteers. Neuropsychopharmacology. 2000 Sep;23(3):326-34.

Zubieta J.K., Dannals R.F., and Frost J.J. Gender and age influences on human brain mu opioid receptor binding measured by PET. Am J Psychiatry. 1999 Jun;156(6):842-8.

Zubieta J.K., Gorelick D.A., Stauffer R., Ravert H.T., Dannals R.F., and Frost J.J. Increased µ-opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine craving.. Nat Med. 1996 Nov;2(11):1225-9.