Brain mu-opioid receptor binding: Relationship to relapse to cocaine use after monitored abstinence

University of Pittsburgh School of Medicine Department of Radiology Pittsburgh PA USA
Psychopharmacology (Impact Factor: 3.88). 11/2008; 200(4):475-486. DOI: 10.1007/s00213-008-1225-5


RationaleCocaine users have increased regional brain mu-opioid receptor (mOR) binding which correlates with cocaine craving. The relationship
of mOR binding to relapse is unknown.

ObjectiveTo evaluate regional brain mOR binding as a predictor of relapse to cocaine use is the objective of the study.

Materials and methodsFifteen nontreatment-seeking, adult cocaine users were housed on a closed research ward for 12weeks of monitored abstinence
and then followed for up to 1year after discharge. Regional brain mOR binding was measured after 1 and 12weeks using positron
emission tomography (PET) with [11C]carfentanil (a selective mOR agonist). Time to first cocaine use (lapse) and to first two consecutive days of cocaine use
(relapse) after discharge was based on self-report and urine toxicology.

ResultsA shorter interval before relapse was associated with increased mOR binding in frontal and temporal cortical regions at 1
and 12weeks of abstinence (Ps < 0.001) and with a lesser decrease in binding between 1 and 12weeks (Ps < 0.0008). There were significant positive correlations between mOR binding at 12weeks and percent days of cocaine use
during first month after relapse (Ps < 0.002). In multiple linear regression analysis, mOR binding contributed significantly to the prediction of time to relapse
2 = 0.79, P < 0.001), even after accounting for clinical variables.

ConclusionsIncreased brain mOR binding in frontal and temporal cortical regions is a significant independent predictor of time to relapse
to cocaine use, suggesting an important role for the brain endogenous opioid system in cocaine addiction.

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Available from: David A Gorelick
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    • "In human SUD, opioid neurotransmission has been examined with positron emission tomography (PET). For example, [ 11 C] carfentanil has been used to image mu opioid receptor binding in smokers [25] [26] [27], and in abusers of heroin [28], alcohol [29] [30] [31], and cocaine [32] [33] [34] [35]. More proximally to the current goals, PENK gene variants that have a functional relationship with gene expression levels have been associated with increased risk for marijuana use disorder [36] and opioid use disorder [37] [38]. "
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    ABSTRACT: Chronic exposure to drugs of abuse perturbs the endogenous opioid system, which plays a critical role in the development and maintenance of addictive disorders. Opioid genetics may therefore play an important modulatory role in the expression of substance use disorders, but these genes have not been extensively characterized, especially in humans. In the current imaging genetics study, we investigated a single nucleotide polymorphism (SNP) of the protein-coding proenkephalin gene ( PENK: rs2609997, recently shown to be associated with cannabis dependence) in 55 individuals with cocaine use disorder and 37 healthy controls. Analyses tested for PENK associations with fMRI response to error (during a classical color-word Stroop task) and gray matter volume (voxel-based morphometry) as a function of Diagnosis (cocaine, control). Results revealed whole-brain Diagnosis × PENK interactions on the neural response to errors (fMRI error>correct contrast) in the right putamen, left rostral anterior cingulate cortex/medial orbitofrontal cortex, and right inferior frontal gyrus; there was also a significant Diagnosis × PENK interaction on right inferior frontal gyrus gray matter volume. These interactions were driven by differences between individuals with cocaine use disorders and controls that were accentuated in individuals carrying the higher-risk PENK C-allele. Taken together, the PENK polymorphism - and potentially opioid neurotransmission more generally - modulates functioning and structural integrity of brain regions previously implicated in error-related processing. PENK could potentially render a subgroup of individuals with cocaine use disorder (i.e., C-allele carriers) more sensitive to mistakes or other related challenges; in future studies, these results could contribute to the development of individualized genetics-informed treatments. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jul 2015 · Behavioural brain research
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    • "Acute oral amphetamine administration has been shown to induce endogenous opioid release in many brain regions frequently implicated in addiction, including the basal ganglia, frontal cortex areas, thalamus, and striatum (Colasanti et al, 2012; Mick et al, 2014). Further, elevated frontal/temporal cortical μ-opioid receptor binding has been observed in cocaine dependence, the degree of which was shown to positively correlate with self-reported cocaine craving (Gorelick et al, 2005), and relate to relapse following treatment (Ghitza et al, 2010; Gorelick et al, 2008). NTX has been shown to block ethanol-induced β-endorphin and subsequent dopamine release in the nucleus accumbens and provide a blockade of ethanol-induced β-endorphin inhibition of GABAergic inhibitory interneurons in the ventral tegmental area (Johnson, 2008; Zalewska-Kaszubska et al, 2006). "
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    ABSTRACT: Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5- day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared to placebo. NTX decreased overall subjective ratings of "crave drug," "stimulated," and "would like drug access," decreased the the post MA administration timecourse of "anxious" and increased ratings of "bad drug effects," as compared to placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence as well as ongoing clinical trials for MA.Neuropsychopharmacology accepted article preview online, 24 March 2015. doi:10.1038/npp.2015.83.
    Full-text · Article · Mar 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Interestingly, we have also demonstrated decreased levels of MOPr binding following cue-but not priming-induced reinstatement of cocaine seeking in AcbC and CPu, as well as decreased levels of MOPr binding in cocaine self-administration compared with priming-induced reinstatement in CPu and VDB. Given the positive correlation between MOPr levels with relapse potential of cocaine use in former cocaine addicts (Gorelick et al. 2008), it is possible that the difference in MOPr levels observed in mice subjected to cue-and priming-induced reinstatement of cocaine seeking may at least partly underlie the differences in the magnitude of reinstatement responses induced by the light cue and the priming injection of cocaine observed in our study. Of particular interest was our finding in the BLA, where decreased levels of MOPr binding were observed following cocaine extinction compared with cocaine selfadministration . "
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    ABSTRACT: The key problem for the treatment of drug addiction is relapse to drug use after abstinence that can be triggered by drug-associated cues, re-exposure to the drug itself and stress. Understanding the neurobiological mechanisms underlying relapse is essential in order to develop effective pharmacotherapies for its prevention. Given the evidence implicating the metabotropic glutamate receptor 5 (mGlu5 R), μ-opioid receptor (MOPr), κ-opioid receptor (ΚOPr) and oxytocin receptor (OTR) systems in cocaine addiction and relapse, our aim was to assess the modulation of these receptors using a mouse model of cue- and priming-induced reinstatement of cocaine seeking. Male mice were trained to self-administer cocaine (1 mg/kg/infusion, i.v.) and were randomized into different groups: (1) cocaine self-administration; (2) cocaine extinction; (3) cocaine-primed (10 mg/kg i.p.); or (4) cue-induced reinstatement of cocaine seeking. Mice undergoing the same protocols but receiving saline instead of cocaine were used as controls. Quantitative autoradiography of mGlu5 R, MOPr, KOPr and OTR showed a persistent cocaine-induced upregulation of the mGlu5 R and OTR in the lateral septum and central amygdala, respectively. Moreover, a downregulation of mGlu5 R and MOPr was observed in the basolateral amygdala and striatum, respectively. Further, we showed that priming- but not cue-induced reinstatement upregulates mGlu5 R and MOPr binding in the nucleus accumbens core and basolateral amygdala, respectively, while cue- but not priming-induced reinstatement downregulates MOPr binding in caudate putamen and nucleus accumbens core. This is the first study to provide direct evidence of reinstatement-induced receptor alterations that are likely to contribute to the neurobiological mechanisms underpinning relapse to cocaine seeking. © 2014 Society for the Study of Addiction.
    Full-text · Article · Dec 2014 · Addiction Biology
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