Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: Possible contributing factors

Dopamine's role in inhibitory control is well recognized and its disruption may contribute to behavioral disorders of discontrol such as obesity. However, the mechanism by which impaired dopamine neurotransmission interferes with inhibitory control is poorly understood. We had previously documented a reduction in dopamine D2 receptors in morbidly obese subjects. To assess if the reductions in dopamine D2 receptors were associated with activity in prefrontal brain regions implicated in inhibitory control we assessed the relationship between dopamine D2 receptor availability in striatum with brain glucose metabolism (marker of brain function) in ten morbidly obese subjects (BMI>40 kg/m(2)) and compared it to that in twelve non-obese controls. PET was used with [(11)C]raclopride to assess D2 receptors and with [(18)F]FDG to assess regional brain glucose metabolism. In obese subjects striatal D2 receptor availability was lower than controls and was positively correlated with metabolism in dorsolateral prefrontal, medial orbitofrontal, anterior cingulate gyrus and somatosensory cortices. In controls correlations with prefrontal metabolism were not significant but comparisons with those in obese subjects were not significant, which does not permit to ascribe the associations as unique to obesity. The associations between striatal D2 receptors and prefrontal metabolism in obese subjects suggest that decreases in striatal D2 receptors could contribute to overeating via their modulation of striatal prefrontal pathways, which participate in inhibitory control and salience attribution. The association between striatal D2 receptors and metabolism in somatosensory cortices (regions that process palatability) could underlie one of the mechanisms through which dopamine regulates the reinforcing properties of food.

[1]  David Eidelberg,et al.  An Examination of Executive Dysfunction Associated with Frontostriatal Circuitry in Parkinson's Disease , 2006, Journal of clinical and experimental neuropsychology.

[2]  M. Heo,et al.  Antipsychotic-induced weight gain: a comprehensive research synthesis. , 1999, The American journal of psychiatry.

[3]  M. Nitsche,et al.  Boosting focally-induced brain plasticity by dopamine. , 2008, Cerebral cortex.

[4]  P. Tataranni,et al.  Functional neuroimaging: a new generation of human brain studies in obesity research , 2003, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[5]  N. Volkow,et al.  Functional importance of ventricular enlargement and cortical atrophy in healthy subjects and alcoholics as assessed with PET, MR imaging, and neuropsychologic testing. , 1993, Radiology.

[6]  Jules R Altfas.  Prevalence of attention deficit/hyperactivity disorder among adults in obesity treatment , 2002, BMC psychiatry.

[7]  R. Oades,et al.  Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity , 1987, Brain Research Reviews.

[8]  W. Schultz,et al.  Relative reward preference in primate orbitofrontal cortex , 1999, Nature.

[9]  A. Dagher,et al.  Basal ganglia functional connectivity based on a meta-analysis of 126 positron emission tomography and functional magnetic resonance imaging publications. , 2006, Cerebral cortex.

[10]  C. Semenza,et al.  Decision-making in obesity: A study using the Gambling Task , 2006, Eating and weight disorders : EWD.

[11]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[12]  G. Pagnoni,et al.  Human Striatal Response to Salient Nonrewarding Stimuli , 2003, The Journal of Neuroscience.

[13]  E. Ravussin,et al.  Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. Knight,et al.  Prefrontal–cingulate interactions in action monitoring , 2000, Nature Neuroscience.

[15]  Piotr Bogorodzki,et al.  Cortical and limbic activation during viewing of high- versus low-calorie foods , 2003, NeuroImage.

[16]  S M Kosslyn,et al.  Brain mechanisms in human classical conditioning: a PET blood flow study , 1995, Neuroreport.

[17]  Jean Logan,et al.  Brain dopamine and obesity , 2001, The Lancet.

[18]  J. Fuster.  Prefrontal Cortex , 2018 .

[19]  E. Rolls,et al.  The representation of pleasant touch in the brain and its relationship with taste and olfactory areas. , 1999, Neuroreport.

[20]  H. Berthoud,et al.  Interactions between the “cognitive” and “metabolic” brain in the control of food intake , 2007, Physiology & Behavior.

[21]  Xin Huang,et al.  Dopamine transporter and D2 receptor binding densities in mice prone or resistant to chronic high fat diet-induced obesity , 2006, Behavioural Brain Research.

[22]  M. Mishkin,et al.  Conditioning and extinction of a food-rewarded response after selective ablations of frontal cortex in rhesus monkeys. , 1963, Experimental neurology.

[23]  M. Reuter,et al.  Genetically Determined Differences in Learning from Errors , 2007, Science.

[24]  T. Robbins.  Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[25]  Samuel M. McClure,et al.  Predictability Modulates Human Brain Response to Reward , 2001, The Journal of Neuroscience.

[26]  Kewei Chen,et al.  Brain abnormalities in human obesity: A voxel-based morphometric study , 2006, NeuroImage.

[27]  J S Fowler,et al.  Reproducibility of repeated measures of carbon-11-raclopride binding in the human brain. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[28]  J. Ahveninen,et al.  Effects of an acute D2-dopaminergic blockade on the somatosensory cortical responses in healthy humans: evidence from evoked magnetic fields , 2003, Neuroreport.

[29]  F. Plum.  Handbook of Physiology. , 1960 .

[30]  J. Porter,et al.  Decreased striatal D2 dopamine receptors in obese Zucker rats: changes during aging , 1992, Brain Research.

[31]  Jean Logan,et al.  Imaging endogenous dopamine competition with [11C]raclopride in the human brain , 1994, Synapse.

[32]  Nora D. Volkow,et al.  Enhanced resting activity of the oral somatosensory cortex in obese subjects , 2002, Neuroreport.

[33]  Young T. Hong,et al.  Nucleus Accumbens D2/3 Receptors Predict Trait Impulsivity and Cocaine Reinforcement , 2007, Science.

[34]  R. Sturm,et al.  The effects of obesity, smoking, and drinking on medical problems and costs. , 2002, Health affairs.

[35]  B. Christian,et al.  Brain imaging of 18F‐fallypride in normal volunteers: Blood analysis, distribution, test‐retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D‐2/D‐3 receptors , 2002, Synapse.

[36]  F. Gonon,et al.  Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo , 1993, Neuroscience Letters.

[37]  Christer Halldin,et al.  Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET. , 1999, International Journal of Neuropsychopharmacology.

[38]  Edythe D. London,et al.  Leptin replacement alters brain response to food cues in genetically leptin-deficient adults , 2007, Proceedings of the National Academy of Sciences.

[39]  J S Fowler,et al.  Reproducibility of repeated measures of endogenous dopamine competition with [11C]raclopride in the human brain in response to methylphenidate. , 1999, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[40]  Y. Hurd,et al.  D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain , 2001, Journal of Chemical Neuroanatomy.

[41]  J S Fowler,et al.  Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. , 2001, The American journal of psychiatry.

[42]  L. Talbot,et al.  Cognitive Function in Normal‐Weight, Overweight, and Obese Older Adults: An Analysis of the Advanced Cognitive Training for Independent and Vital Elderly Cohort , 2006, Journal of the American Geriatrics Society.

[43]  H. Weingarten.  Conditioned cues elicit feeding in sated rats: a role for learning in meal initiation. , 1983, Science.

[44]  G. Schoenbaum,et al.  Orbitofrontal cortex and basolateral amygdala encode expected outcomes during learning , 1998, Nature Neuroscience.

[45]  Edmund T Rolls,et al.  Enhanced affective brain representations of chocolate in cravers vs. non‐cravers , 2007, The European journal of neuroscience.

[46]  T. Robbins,et al.  Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates , 2004, Neuroscience & Biobehavioral Reviews.

[47]  M. Mesulam.  Principles of behavioral neurology , 1985 .

[48]  W. D. Halliburton,et al.  Handbook of Physiology , 1870, Edinburgh Medical Journal.

[49]  M. Nöthen,et al.  Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers , 1999, Molecular Psychiatry.

[50]  N. Volkow,et al.  Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers , 1993, Synapse.

[51]  G. Schoenbaum,et al.  Orbitofrontal Cortex and Representation of Incentive Value in Associative Learning , 1999, The Journal of Neuroscience.

[52]  N. Volkow,et al.  Food restriction markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with in‐vivo μPET imaging ([11C] raclopride) and in‐vitro ([3H] spiperone) autoradiography , 2008, Synapse.

[53]  M. Oscar-Berman,et al.  Relationship between dopaminergic neurotransmission, alcoholism, and reward deficiency syndrome , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[54]  A. Kelley.  Memory and Addiction Shared Neural Circuitry and Molecular Mechanisms , 2004, Neuron.

[55]  Yu-Shin Ding,et al.  Brain dopamine is associated with eating behaviors in humans. , 2003, The International journal of eating disorders.

[56]  P. Wolf,et al.  Relation of obesity to cognitive function: importance of central obesity and synergistic influence of concomitant hypertension. The Framingham Heart Study. , 2007, Current Alzheimer research.

[57]  Giovanni Mirabella.  Endogenous Inhibition and the Neural Basis of “Free Won't” , 2007, The Journal of Neuroscience.

[58]  D. V. von Cramon,et al.  The Effects of Insulin on the Central Nervous System - Focus on Appetite Regulation , 2006, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[59]  Fabian Grabenhorst,et al.  How cognition modulates affective responses to taste and flavor: top-down influences on the orbitofrontal and pregenual cingulate cortices. , 2008, Cerebral cortex.

[60]  F. Bloom,et al.  Cellular and molecular mechanisms of drug dependence. , 1988, Science.

[61]  P M Rossini,et al.  Median nerve somatosensory evoked potentials. Apomorphine-induced transient potentiation of frontal components in Parkinson's disease and in parkinsonism. , 1995, Electroencephalography and clinical neurophysiology.

[62]  E. Noble,et al.  Association of Seven Polymorphisms of the D2 Dopamine Receptor Gene with Brain Receptor-Binding Characteristics , 2004, Neurochemical Research.

[63]  S. Hyman,et al.  Acute Effects of Cocaine on Human Brain Activity and Emotion , 1997, Neuron.

[64]  M. Brass,et al.  To Do or Not to Do: The Neural Signature of Self-Control , 2007, The Journal of Neuroscience.

[65]  Frank Telang,et al.  High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. , 2006, Archives of general psychiatry.

[66]  Nora D. Volkow,et al.  Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement , 2007, The Journal of Neuroscience.

[67]  J. Price,et al.  The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys , 1993, The Journal of comparative neurology.

[68]  H. E. Rosvold,et al.  Topographic projections on the globus pallidus and the substantia nigra of selectively placed lesions in the precommissural caudate nucleus and putamen in the monkey. , 1971, Experimental neurology.

[69]  J. Wardle,et al.  Cognitive restraint and sensitivity to cues for hunger and satiety , 1990, Physiology & Behavior.

[70]  E. Gordon,et al.  Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. , 2007, Comprehensive psychiatry.

[71]  J. Wardle,et al.  Eating behaviour and obesity , 2007, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[72]  Paolo Leombruni,et al.  Mood, eating attitudes, and anger in obese women with and without Binge Eating Disorder. , 2003, Journal of psychosomatic research.

[73]  B. Libet,et al.  Time of conscious intention to act in relation to onset of cerebral activity (readiness-potential). The unconscious initiation of a freely voluntary act. , 1983, Brain : a journal of neurology.

[74]  R. Elliott,et al.  Selective attention to emotional stimuli in a verbal go/no‐go task: an fMRI study , 2000, Neuroreport.

[75]  N. Volkow,et al.  Effects of Blood Flow on [11C]Raclopride Binding in the Brain: Model Simulations and Kinetic Analysis of PET Data , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[76]  B. Rosen,et al.  Inhibition of stimulated dopamine release and hemodynamic response in the brain through electrical stimulation of rat forepaw , 2008, Neuroscience Letters.

[77]  J O Rinne,et al.  The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers , 1998, Molecular Psychiatry.

[78]  B. Turetsky,et al.  Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. , 2000, Archives of general psychiatry.

[79]  J. Critchley,et al.  An affected pedigree member analysis of linkage between the dopamine D2 receptor gene TaqI polymorphism and obesity and hypertension. , 2005, International journal of cardiology.

[80]  David J. Schlyer,et al.  Graphical Analysis of Reversible Radioligand Binding from Time—Activity Measurements Applied to [N-11C-Methyl]-(−)-Cocaine PET Studies in Human Subjects , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[81]  L. Epstein,et al.  Food reinforcement, the dopamine D2 receptor genotype, and energy intake in obese and nonobese humans. , 2007, Behavioral neuroscience.

[82]  E. Reiman,et al.  Less activation of the left dorsolateral prefrontal cortex in response to a meal: a feature of obesity. , 2006, The American journal of clinical nutrition.

[83]  Rita Z. Goldstein,et al.  Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. , 2002, The American journal of psychiatry.