Alcohol Consumption Induces Endogenous Opioid Release in the Human Orbitofrontal Cortex and Nucleus Accumbens

Mitchell, Jennifer; O’Neil, James P.; Janabi, Mustafa; Marks, Shawn; Jagust, William J.; Fields, Howard L.

doi:10.1126/scitranslmed.3002902

Cited by 206 publications

(165 citation statements)

References 55 publications

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“…Therefore, antagonism of the higher hypothalamic DRD3 levels resulting in decreased betaendorphin release in the ventral striatum might underpin how DRD3 antagonists impact on addiction. Consistent with this hypothesis, in vivo human PET imaging data have shown that alcohol consumption induces endogenous opioid release in the ventral striatum (Mitchell et al, 2012).…”

Section: D3 Receptors In Alcoholismmentioning

confidence: 75%

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Erritzoe

Tziortzi

Bargiela

et al. 2014

Neuropsychopharmacol

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Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [ 11 C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [ 11 C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [ 11 C]PHNO binding between the groups at baseline. However, baseline [ 11 C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V T : 16.5±4 vs 13.7±2.9, p ¼ 0.040), a region in which the [ 11 C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V T ) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [ 11 C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.

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Section: D3 Receptors In Alcoholismmentioning

confidence: 75%

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Erritzoe

Tziortzi

Bargiela

et al. 2014

Neuropsychopharmacol

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“…The present results join a growing number of studies, indicating that these cortical sites represent crucial loci of clinically relevant opioid action. In humans, ligand PET studies have demonstrated frontal cortical μ-opioid peptide release in association with sweetened-alcohol drinking (Mitchell et al, 2012) and μOR upregulation in frontal sites including the PFC and ACC robustly predicts the severity of craving and rapidity of relapse in cocaine users (Gorelick et al, 2008;Zubieta et al, 1996). μORs are upregulated in the PFC (along with the Acb and amygdala) in individuals with trait impulsivity, and these individuals display exaggerated stressor-induced PFC opioid release (Love et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Opioid Signaling in the Medial Prefrontal Cortex is Required for the Expression of Hunger-Induced Impulsive Action

Selleck

Lake

Estrada

et al. 2015

Neuropsychopharmacol

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Opioid transmission and dysregulated prefrontal cortex (PFC) activity have both been implicated in the inhibitory-control deficits associated with addiction and binge-type eating disorders. What remains unknown, however, is whether endogenous opioid transmission within the PFC modulates inhibitory control. Here, we compared intra-PFC opioid manipulations with a monoamine manipulation (d-amphetamine), in two sucrose-reinforced tasks: progressive ratio (PR), which assays the motivational value of an incentive, and differential reinforcement of low response rates (DRLs), a test of inhibitory control. Intra-PFC methylnaloxonium (M-NX, a limited diffusion opioid antagonist) was given to rats in a 'low-drive' condition (2-h food deprivation), and also after a motivational shift to a 'highdrive' condition (18-h food deprivation). Intra-PFC DAMGO (D-[Ala2,N-MePhe4, Gly-ol]-enkephalin; a μ-opioid agonist) and damphetamine were also tested in both tasks, under the low-drive condition. Intra-PFC M-NX nearly eliminated impulsive action in DRL engendered by hunger, at a dose (1 μg) that significantly affected neither hunger-induced PR enhancement nor hyperactivity. At a higher dose (3 μg), M-NX eliminated impulsive action and returned PR breakpoint to low-drive levels. Conversely, intra-PFC DAMGO engendered 'high-drive-like' effects: enhancement of PR and impairment of DRL performance. Intra-PFC d-amphetamine failed to produce effects in either task. These results establish that endogenous PFC opioid transmission is both necessary and sufficient for the expression of impulsive action in a high-arousal, high-drive appetitive state, and that PFC-based opioid systems enact functionally unique effects on food impulsivity and motivation relative to PFC-based monoamine systems. Opioid antagonists may represent effective treatments for a range of psychiatric disorders with impulsivity features.

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“…Endogenous opioids acting at the -opioid receptor (MOR) serve a pivotal function in reward processing and addictive behaviors (Matthes et al, 1996;Hall et al, 2001;Olive et al, 2001;Ghozland et al, 2002;Mathon et al, 2003Mathon et al, , 2005Roth-Deri et al, 2003;Solinas et al, 2004;Jarjour et al, 2009;Mitchell et al, 2012). This is especially the case for MORs regulating the ventral tegmental area (VTA) (Bozarth and Wise, 1984;Wise, 1989;Laviolette et al, 2004), which typically suppress GABAergic inputs to VTA dopamine neurons (Johnson and North, 1992;Manzoni and Williams, 1999;Bergevin et al, 2002;Jalabert et al, 2011;Matsui and Williams, 2011).…”

Section: Introductionmentioning

confidence: 99%

Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

et al. 2012

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-Opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive activity is highly relevant in the mouse VTA, as it regulates GABAergic input to dopamine neurons. Specifically, suppression of MOR constitutive activity with the inverse agonist KC-2-009 enhanced GABAergic neurotransmission onto VTA dopamine neurons. This inverse agonistic effect was fully blocked by the specific MOR neutral antagonist CTOP, which had no effect on GABAergic transmission itself. We next show that withdrawal from chronic morphine further increases the magnitude of inverse agonistic effects at the MOR, suggesting enhanced MOR constitutive activity. We demonstrate that this increase can be an adaptive response to the detrimental elevation in cAMP levels known to occur during morphine withdrawal. These findings offer important insights in the physiological occurrence and function of MOR constitutive activity, and have important implications for therapeutic strategies aimed at normalizing MOR signaling during addiction and opioid overdose.

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Alcohol Consumption Induces Endogenous Opioid Release in the Human Orbitofrontal Cortex and Nucleus Accumbens

Cited by 206 publications

References 55 publications

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Endogenous Opioid Signaling in the Medial Prefrontal Cortex is Required for the Expression of Hunger-Induced Impulsive Action

Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

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