Low Level of Brain Dopamine D<sub>2</sub> Receptors in Methamphetamine Abusers:  Association With Metabolism in the Orbitofrontal Cortex

Volkow, Nora D.; Chang, Linda; Wang, Gene‐Jack; Fowler, Joanna S.; Ding, Yu-Sin; Sedler, Mark J.; Logan, Jean; Franceschi, Dinko; Gatley, John; Hitzemann, Robert; Gifford, Andrew N.; Wong, Christopher; Pappas, Naomi

doi:10.1176/appi.ajp.158.12.2015

Cited by 834 publications

(276 citation statements)

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“…Similar to observations in obese individuals, a significant association between D2 receptor availability and metabolism in prefrontal regions was observed in drug-addicted subjects (cocaine, methamphetamine, and alcohol) [31,32,33]. The same finding in individuals at high familial risk for alcoholism [34] suggests that these abnormalities precede the change in behavior.…”

Section: Do Pet Studies Support the Concept That Obesity Is Caused Bysupporting

confidence: 68%

Brain PET Imaging in Obesity and Food Addiction: Current Evidence and Hypothesis

Iozzo

Guiducci²,

Guzzardi³

et al. 2012

Obes Facts

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The ongoing epidemics of obesity is one main health concern of the present time. Overeating in some obese individuals shares similarities with the loss of control and compulsive behavior observed in drug-addicted subjects, suggesting that obesity may involve food addiction. Here, we review the contributions provided by the use of positron emission tomography to the current understanding of the cerebral control of obesity and food intake in humans. The available studies have shown that multiple areas in the brain are involved with the reward properties of food, such as prefrontal, orbitofrontal, somatosensory cortices, insula, thalamus, hypothalamus, amygdala, and others. This review summarizes the current evidence, supporting the concepts that i) regions involved in the somatosensory response to food sight, taste, and smell are activated by palatable foods and may be hyperresponsive in obese individuals, ii) areas controlling executive drive seem to overreact to the anticipation of pleasure during cue exposure, and iii) those involved in cognitive control and inhibitory behavior may be resistant to the perception of reward after food exposure in obese subjects. All of these features may stimulate, for different reasons, ingestion of highly palatable and energy-rich foods. Though these same regions are similarly involved in drug abusers and game-addicted individuals, any direct resemblance may be an oversimplification, especially as the heterogeneities between studies and the prevalent exclusion of sensitive groups still limit a coherent interpretation of the findings. Further work is required to comprehensively tackle the multifaceted phenotype of obesity and identify the role of food dependency in its pathophysiology.

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Section: Do Pet Studies Support the Concept That Obesity Is Caused Bysupporting

confidence: 68%

Brain PET Imaging in Obesity and Food Addiction: Current Evidence and Hypothesis

Iozzo

Guiducci²,

Guzzardi³

et al. 2012

Obes Facts

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“…For example, drugs of abuse cause a reduction in the availability of D 2 -like receptors (22)(23)(24)(25)(26), and D 2 -like receptors also appear to be down-regulated relative to D 1 -like receptors in other neuropsychiatric disorders, including schizophrenia (27,28). Previous work in our laboratory has shown that D 2 down-regulation in response to drugs of abuse is mediated by interaction with GASP-1 (5).…”

Section: Discussionmentioning

confidence: 91%

Dopamine D3 Receptors Are Down-regulated following Heterologous Endocytosis by a Specific Interaction with G Protein-coupled Receptor-associated Sorting Protein-1

Thompson

Whistler

2011

Journal of Biological Chemistry

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GPCR signaling is tightly regulated by several mechanisms, including receptor trafficking. Once activated, many GPCRs are phosphorylated by GPCR kinases, recruit arrestins, and are internalized into clathrin-coated pits via a dynamin-dependent mechanism. Indeed, such a mechanism has been reported for both the D 1 (1, 2) and the D 2 (3, 4) dopamine receptors. Furthermore, following endocytosis, D 1 and D 2 differ in their post-endocytic fate. Specifically, D 1 receptors are recycled back to the plasma membrane where they may bind ligand once again, whereas D 2 receptors are targeted to the lysosomes for degradation (5). Targeted degradation of the D 2 receptor is facilitated through an interaction of the D 2 receptor with the GPCR-associated sorting protein GASP-1 (5). GASP-1 binds to distinct GPCRs from several other families as well, including the ␦-opioid receptor (6), the CB1 receptor (7), the bradykinin B 2 receptor (8), and the virally encoded chemokine receptor US28 (9), all of which are targeted for degradation after endocytosis. Members of these families that do not bind GASP-1, as well as many other GPCRs that do not bind GASP (10), are recycled rather than degraded after endocytosis. Post-endocytic degradation of GPCRs by GASP-1 has been shown to have behavioral relevance in vivo. For example, GASP-1 knock-out mice show reduced tolerance to the cannabinoid WIN5,212-2 as a consequence of reduced CB1 down-regulation (11). In addition, GASP-1 knockout mice also show reduced sensitization to the locomotor activating effects of repeated cocaine as a consequence of reduced D 2 receptor degradation (12).Unlike the D 1 and D 2 receptors, D 3 receptors do not endocytose in response to activation by dopamine (13,14). Instead, endocytosis of the D 3 receptor appears to occur through a heterologous mechanism mediated by PKC (15), requiring both the ␤ and ␦ PKC isoforms, actin-binding motif 280 and filamin A (16). This endocytosis is dependent on dynamin, indicating a clathrin component, it but appears to be GPCR kinase-and arrestin-independent (16).Importantly, no prior study has examined the post-endocytic fate of the D 3 receptor. Here, we report that the D 3 receptor is targeted for degradation following endocytosis in response to phorbol ester activation of PKC and that it does

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“…We have shown that the reductions in striatal D 2 receptors in the detoxified drug-addicted subjects were associated with decreased metabolic activity in orbitofrontal cortex (OFC), anterior cingulate gyrus (CG) and dorsolateral prefrontal cortex (DLPFC; figure 1; Volkow et al 1993Volkow et al , 2001Volkow et al , 2007a. Since OFC, CG and DLPFC are involved with inhibitory control (Goldstein & Volkow 2002) and with emotional processing (Phan et al 2002), we had postulated that their improper regulation by DA in addicted subjects could underlie their loss of control over drug intake and their poor emotional selfregulation.…”

Section: Inhibitory Control/emotional Reactivity Circuit In Addictionmentioning

confidence: 99%

Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology

Volkow

Wang

Fowler

et al. 2008

Phil. Trans. R. Soc. B

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546

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Drugs and food exert their reinforcing effects in part by increasing dopamine (DA) in limbic regions, which has generated interest in understanding how drug abuse/addiction relates to obesity. Here, we integrate findings from positron emission tomography imaging studies on DA's role in drug abuse/addiction and in obesity and propose a common model for these two conditions. Both in abuse/addiction and in obesity, there is an enhanced value of one type of reinforcer (drugs and food, respectively) at the expense of other reinforcers, which is a consequence of conditioned learning and resetting of reward thresholds secondary to repeated stimulation by drugs (abuse/addiction) and by large quantities of palatable food (obesity) in vulnerable individuals (i.e. genetic factors). In this model, during exposure to the reinforcer or to conditioned cues, the expected reward (processed by memory circuits) overactivates the reward and motivation circuits while inhibiting the cognitive control circuit, resulting in an inability to inhibit the drive to consume the drug or food despite attempts to do so. These neuronal circuits, which are modulated by DA, interact with one another so that disruption in one circuit can be buffered by another, which highlights the need of multiprong approaches in the treatment of addiction and obesity.

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Low Level of Brain Dopamine D₂ Receptors in Methamphetamine Abusers: Association With Metabolism in the Orbitofrontal Cortex

Cited by 834 publications

References 50 publications

Brain PET Imaging in Obesity and Food Addiction: Current Evidence and Hypothesis

Brain PET Imaging in Obesity and Food Addiction: Current Evidence and Hypothesis

Dopamine D3 Receptors Are Down-regulated following Heterologous Endocytosis by a Specific Interaction with G Protein-coupled Receptor-associated Sorting Protein-1

Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology

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Low Level of Brain Dopamine D2 Receptors in Methamphetamine Abusers: Association With Metabolism in the Orbitofrontal Cortex

Cited by 834 publications

References 50 publications

Brain PET Imaging in Obesity and Food Addiction: Current Evidence and Hypothesis

Brain PET Imaging in Obesity and Food Addiction: Current Evidence and Hypothesis

Dopamine D3 Receptors Are Down-regulated following Heterologous Endocytosis by a Specific Interaction with G Protein-coupled Receptor-associated Sorting Protein-1

Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology

Contact Info

Product

Resources

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Low Level of Brain Dopamine D₂ Receptors in Methamphetamine Abusers: Association With Metabolism in the Orbitofrontal Cortex