Original article| Volume 61, ISSUE 9, P1021-1029, May 01, 2007

Decreases in Dietary Preference Produce Increased Emotionality and Risk for Dietary Relapse


      Obesity is a modern health epidemic, with the overconsumption of highly palatable, calorically dense foods as a likely contributor. Despite the known consequences of obesity, behavioral noncompliance remains high, supporting the powerful rewarding properties of such foods. We hypothesized that exposure to preferred diets would result in an amelioration of stress responsivity via activation of reward pathways that would be reversed during dietary withdrawal, increasing the risk for relapse and treatment failure.


      Mice were exposed to preferred diets high in fat or carbohydrates for 4 weeks and then were withdrawn to house chow. Behavioral, physiologic, and biochemical assays were performed to examine changes in stress and reward pathways.


      These studies revealed significant changes in arousal and anxiety-like behaviors, limbic corticotropin-releasing factor expression, and expression of reward-related signaling molecules in response to the highly preferred high-fat diet that was reversed by withdrawal. In a dietary-reinstatement model, mice withdrawn from the high-fat diet endured an aversive environment to gain access to the preferred food.


      Exposure to a highly preferred diet high in fat reduces stress sensitivity, whereas acute withdrawal from such a diet elevates the stress state and reduces reward, contributing to the drive for dietary relapse.

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        • Bailey A.
        • Davis L.
        • Lesscher H.M.
        • Kelly M.D.
        • Ledent C.
        • Hourani S.M.
        • Kitchen I.
        Enhanced morphine withdrawal and micro-opioid receptor G-protein coupling in A2A adenosine receptor knockout mice.
        J Neurochem. 2004; 88: 827-834
        • Bale T.L.
        • Anderson K.R.
        • Roberts A.J.
        • Lee K.F.
        • Nagy T.R.
        • Vale W.W.
        Corticotropin-releasing factor receptor-2-deficient mice display abnormal homeostatic responses to challenges of increased dietary fat and cold.
        Endocrinology. 2003; 144: 2580-2587
        • Bale T.L.
        • Contarino A.
        • Smith G.W.
        • Chan R.
        • Gold L.H.
        • Sawchenko P.E.
        • et al.
        Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress.
        Nat Genet. 2000; 24: 410-414
        • Blendy J.A.
        • Maldonado R.
        Genetic analysis of drug addiction: The role of cAMP response element binding protein.
        J Mol Med. 1998; 76: 104-110
        • Blundell J.E.
        • Lawton C.L.
        • Cotton J.R.
        • Macdiarmid J.I.
        Control of human appetite: Implications for the intake of dietary fat.
        Annu Rev Nutr. 1996; 16: 285-319
        • Chaki S.
        • Hirota S.
        • Funakoshi T.
        • Suzuki Y.
        • Suetake S.
        • Okubo T.
        • et al.
        Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-met hoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor.
        J Pharmacol Exp Ther. 2003; 304: 818-826
        • Colantuoni C.
        • Schwenker J.
        • McCarthy J.
        • Rada P.
        • Ladenheim B.
        • Cadet J.L.
        • et al.
        Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain.
        Neuroreport. 2001; 12: 3549-3552
        • Dallman M.F.
        • Pecoraro N.
        • Akana S.F.
        • La Fleur S.E.
        • Gomez F.
        • Houshyar H.
        • et al.
        Chronic stress and obesity: A new view of “comfort food”.
        Proc Natl Acad Sci U S A. 2003; 100: 11696-11701
        • Davis C.
        • Strachan S.
        • Berkson M.
        Sensitivity to reward: Implications for overeating and overweight.
        Appetite. 2004; 42: 131-138
        • De Araujo I.E.
        • Rolls E.T.
        Representation in the human brain of food texture and oral fat.
        J Neurosci. 2004; 24: 3086-3093
        • Dudman J.T.
        • Eaton M.E.
        • Rajadhyaksha A.
        • Macías W.
        • Taher M.
        • Barczak A.
        • et al.
        Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1.
        J Neurochem. 2003; 87: 922-934
        • Fantino M.
        • Hosotte J.
        • Apfelbaum M.
        An opioid antagonist, naltrexone, reduces preference for sucrose in humans.
        Am J Physiol. 1986; 251: R91-R96
        • Green S.M.
        • Burley V.J.
        • Blundell J.E.
        Effect of fat- and sucrose-containing foods on the size of eating episodes and energy intake in lean males: Potential for causing overconsumption.
        Eur J Clin Nutr. 1994; 48: 547-555
        • Hajnal A.
        • Smith G.P.
        • Norgren R.
        Oral sucrose stimulation increases accumbens dopamine in the rat.
        Am J Physiol Regul Integr Comp Physiol. 2004; 286: R31-R37
        • Imaizumi M.
        • Takeda M.
        • Fushiki T.
        Effects of oil intake in the conditioned place preference test in mice.
        Brain Res. 2000; 870: 150-156
        • Kelley A.E.
        Ventral striatal control of appetitive motivation: Role in ingestive behavior and reward-related learning.
        Neurosci Biobehav Rev. 2004; 27: 765-776
        • Koob G.F.
        Stress, corticotropin-releasing factor, and drug addiction.
        Ann N Y Acad Sci. 1999; 897: 27-45
        • Kreek M.J.
        • Koob G.F.
        Drug dependence: Stress and dysregulation of brain reward pathways.
        Drug Alcohol Depend. 1998; 51: 23-47
        • Levine A.S.
        • Kotz C.M.
        • Gosnell B.A.
        Sugars: Hedonic aspects, neuroregulation, and energy balance.
        Am J Clin Nutr. 2003; 78: 834S-842S
        • Li J.
        • Li Y.H.
        • Yuan X.R.
        Changes of phosphorylation of cAMP response element binding protein in rat nucleus accumbens after chronic ethanol intake: Naloxone reversal.
        Acta Pharmacol Sin. 2003; 24: 930-936
        • Marks-Kaufman R.
        • Kanarek R.B.
        Modifications of nutrient selection induced by naloxone in rats.
        Psychopharmacology (Berl). 1981; 74: 321-324
        • Marks-Kaufman R.
        • Kanarek R.B.
        Diet selection following a chronic morphine and naloxone regimen.
        Pharmacol Biochem Behav. 1990; 35: 665-669
        • McClung C.A.
        • Nestler E.J.
        Regulation of gene expression and cocaine reward by CREB and DeltaFosB.
        Nat Neurosci. 2003; 6: 1208-1215
        • Millan M.J.
        • Brocco M.
        • Papp M.
        • Serres F.
        • La Rochelle C.D.
        • Sharp T.
        • et al.
        S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: III.
        J Pharmacol Exp Ther. 2004; 309: 936-950
        • Nestler E.J.
        Molecular mechanisms of drug addiction.
        Neuropharmacology. 2004; 47: 24-32
        • Nestler E.J.
        • Barrot M.
        • Self D.W.
        DeltaFosB: A sustained molecular switch for addiction.
        Proc Natl Acad Sci U S A. 2001; 98: 11042-11046
        • Olausson P.
        • Jentsch J.D.
        • Tronson N.
        • Nestler E.J.
        • Taylor J.R.
        dFosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation.
        J Neurosci. 2006; 26: 9196-9204
        • Paxinos G.
        • Franklin K.B.J.
        The Mouse Brain in Stereotaxic Coordinates. 2nd ed. Academic Press, San Diego, CA2001
        • Pecoraro N.
        • Reyes F.
        • Gomez F.
        • Bhargava A.
        • Dallman M.F.
        Chronic stress promotes palatable feeding, which reduces signs of stress: Feedforward and feedback effects of chronic stress.
        Endocrinology. 2004; 145: 3754-3762
        • Perrotti L.I.
        • Hadeishi Y.
        • Ulery P.G.
        • Barrot M.
        • Monteggia L.
        • Duman R.S.
        • Nestler E.J.
        Induction of deltaFosB in reward-related brain structures after chronic stress.
        J Neurosci. 2004; 24: 10594-10602
        • Plaut S.M.
        • Friedman S.B.
        Stress, coping behavior and resistance to disease.
        Psychother Psychosom. 1982; 38: 274-283
        • Pluzarev O.
        • Pandey S.C.
        Modulation of CREB expression and phosphorylation in the rat nucleus accumbens during nicotine exposure and withdrawal.
        J Neurosci Res. 2004; 77: 884-891
        • Rodriguez de Fonseca F.
        • Carrera M.R.
        • Navarro M.
        • Koob G.F.
        • Weiss F.
        Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal.
        Science. 1997; 276: 2050-2054
        • Rolls E.T.
        The functions of the orbitofrontal cortex.
        Brain Cogn. 2004; 55: 11-29
        • Sarnyai Z.
        Neurobiology of stress and cocaine addiction.
        Ann N Y Acad Sci. 1998; 851: 371-387
        • Shimazaki T.
        • Iijima M.
        • Chaki S.
        Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test.
        Eur J Pharmacol. 2004; 501: 121-125
        • Sinha R.
        • Garcia M.
        • Paliwal P.
        • Kreek M.J.
        • Rounsaville B.J.
        Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.
        Arch Gen Psychiatry. 2006; 63: 324-331
        • Smith G.P.
        Accumbens dopamine mediates the rewarding effect of orosensory stimulation by sucrose.
        Appetite. 2004; 43: 11-13
        • Spooren W.P.
        • Vassout A.
        • Neijt H.C.
        • Kuhn R.
        • Gasparini F.
        • Roux S.
        • et al.
        Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents.
        J Pharmacol Exp Ther. 2000; 295: 1267-1275
        • Stein C.J.
        • Colditz G.A.
        The epidemic of obesity.
        J Clin Endocrinol Metab. 2004; 89: 2522-2525
        • Volkow N.D.
        • Wise R.A.
        How can drug addiction help us understand obesity?.
        Nat Neurosci. 2005; 8: 555-560
        • Wang G.J.
        • Volkow N.D.
        • Thanos P.K.
        • Fowler J.S.
        Similarity between obesity and drug addiction as assessed by neurofunctional imaging: A concept review.
        J Addict Dis. 2004; 23: 39-53
        • Weiss F.
        • Ciccocioppo R.
        • Parsons L.H.
        • Katner S.
        • Liu X.
        • Zorrilla E.P.
        • et al.
        Compulsive drug-seeking behavior and relapse.
        Ann N Y Acad Sci. 2001; 937: 1-26
        • Welch C.C.
        • Kim E.M.
        • Grace M.K.
        • Billington C.J.
        • Levine A.S.
        Palatability-induced hyperphagia increases hypothalamic Dynorphin peptide and mRNA levels.
        Brain Res. 1996; 721: 126-131
        • Zhang M.
        • Gosnell B.A.
        • Kelley A.E.
        Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens.
        J Pharmacol Exp Ther. 1998; 285: 908-914
        • Zhou Y.
        • Spangler R.
        • Ho A.
        • Kreek M.J.
        Increased CRH mRNA levels in the rat amygdala during short-term withdrawal from chronic “binge” cocaine.
        Brain Res Mol Brain Res. 2003; 114: 73-79