Opioid site in nucleus accumbens shell mediates eating and hedonic ‘liking’ for food: map based on microinjection Fos plumes

Microinjection of opioid agonists, such as morphine, into the nucleus accumbens shell produces increases in eating behavior (i.e. 'wanting' for food). This study (1) reports direct evidence that activation of accumbens opioid receptors in rats also augments food 'liking', or the hedonic impact of taste, and (2) identified a neural site that definitely contains receptors capable of increasing food intake. Morphine microinjections (0.5 microgram) into accumbens shell, which caused rats to increase eating, were found also to cause selective increases in positive hedonic patterns of behavioral affective reaction elicited by oral sucrose, using the 'taste reactivity' test of hedonic palatability. This positive shift indicated that morphine microinjections enhanced the hedonic impact of food palatability. The accumbens site mediating morphine-induced increases in food 'wanting' and 'liking' was identified using a novel method based on local expression of Fos induced directly by drug microinjections. The plume-shaped region of drug-induced increase in Fos immunoreactivity immediately surrounding a morphine microinjection site (Fos plume) was objectively mapped. A point-sampling procedure was used to measure the shape and size of 'positive' plumes of Fos expression triggered by microinjections of morphine at locations that caused increases in eating behavior. This revealed a functionally 'positive' neural region, containing receptors directly activated by behaviorally-effective drug microinjections. A subtraction mapping procedure was then used to eliminate all surrounding regions containing any 'negative' Fos plumes that failed to increase food intake. The subtraction produced a conservative map of the positive site, by eliminating regions that gave mixed effects, and leaving only a positive region that must contain receptors capable of mediating increases in food intake. The resulting mapped 'opioid eating site' was contained primarily within the medial caudal subregion of the nucleus accumbens shell, and did not substantially penetrate either into the accumbens core or into other subregions of the shell. Several other structures outside the nucleus accumbens (such as rostral ventral pallidum), immediately medial and adjacent to the shell, also appeared to be included in the functional site. Opioid receptors within this site thus are capable of mediating morphine-induced increases in eating, in part by enhancing the hedonic reward properties of food.

[1]  S. Haber,et al.  Shell and core in monkey and human nucleus accumbens identified with antibodies to calbindin‐D28k , 1996, The Journal of comparative neurology.

[2]  A. Kelley,et al.  Feeding induced by blockade of AMPA and kainate receptors within the ventral striatum: a microinfusion mapping study , 1997, Behavioural Brain Research.

[3]  Adam Drewnowski,et al.  Taste responses and preferences for sweet high-fat foods: Evidence for opioid involvement , 1992, Physiology & Behavior.

[4]  J. Cleary,et al.  Naloxone blocks that portion of feeding driven by sweet taste in food-restricted rats. , 1995, The American journal of physiology.

[5]  K. Berridge,et al.  Where does damage lead to enhanced food aversion: the ventral pallidum/substantia innominata or lateral hypothalamus? , 1993, Brain Research.

[6]  F. Sharp,et al.  Morphine induces c-fos and junB in striatum and nucleus accumbens via D1 and N-methyl-D-aspartate receptors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[7]  P. Kalivas,et al.  A topographically organized gamma‐aminobutyric acid projection from the ventral pallidum to the nucleus accumbens in the rat , 1994, The Journal of comparative neurology.

[8]  D. G. Herrera,et al.  Activation of c-fos in the brain , 1996, Progress in Neurobiology.

[9]  K. Berridge Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns , 2000, Neuroscience & Biobehavioral Reviews.

[10]  A. Graybiel,et al.  Spatiotemporal Dynamics of CREB Phosphorylation: Transient versus Sustained Phosphorylation in the Developing Striatum , 1996, Neuron.

[11]  R. Wise,et al.  Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward , 1996, Psychopharmacology.

[12]  E. Pothos,et al.  Neural systems for reinforcement and inhibition of behavior: Relevance to eating, addiction, and depression. , 1999 .

[13]  A. Kelley,et al.  Opiate agonists microinjected into the nucleus accumbens enhance sucrose drinking in rats , 1997, Psychopharmacology.

[14]  S. Ikemoto,et al.  Role of Dopamine D1 and D2 Receptors in the Nucleus Accumbens in Mediating Reward , 1997, The Journal of Neuroscience.

[15]  H. Groenewegen,et al.  Basal amygdaloid complex afferents to the rat nucleus accumbens are compartmentally organized , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  J. Stellar,et al.  Regional reward differences within the ventral pallidum are revealed by microinjections of a mu opiate receptor agonist , 1993, Neuropharmacology.

[17]  A. Kelley,et al.  Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus accumbens. , 1998, The Journal of pharmacology and experimental therapeutics.

[18]  D. Booth,et al.  Appetite: neural and behavioural bases , 1994 .

[19]  M. Yeomans,et al.  Effects of Naltrexone on Food Intake and Changes in Subjective Appetite During Eating: Evidence for Opioid Involvement in the Appetizer Effect , 1997, Physiology & Behavior.

[20]  S. Cooper,et al.  Opioid Mechanisms in the Control of Food Consumption and Taste Preferences , 1993 .

[21]  P. Morgane,et al.  Alterations in feeding and drinking behavior of rats with lesions in globi pallidi. , 1961, The American journal of physiology.

[22]  H. J. G. Gundersen,et al.  The new stereological tools: Disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis , 1988, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[23]  H. Akil,et al.  Autoradiographic differentiation of mu, delta and kappa opioid receptors in the rat forebrain and midbrain A. Mansour H. Khachaturian, M.E. Lewis, H. Akil and S.J. Watson, Neuroscience, 7 (1987) 2445–2464 , 1988, Pain.

[24]  K. Wȩdzony,et al.  Stimulation of food intake following opioid microinjection into the nucleus accumbens septi in rats , 1986, Peptides.

[25]  S. Cooper,et al.  Neuropharmacology of appetite and taste preferences , 1994 .

[26]  V. Pickel,et al.  Dual Ultrastructural Localization of μ-Opioid Receptors and NMDA-Type Glutamate Receptors in the Shell of the Rat Nucleus Accumbens , 1997, The Journal of Neuroscience.

[27]  R. Bodnar,et al.  General, μ and κ opioid antagonists in the nucleus accumbens alter food intake under deprivation, glucoprivic and palatable conditions , 1995, Brain Research.

[28]  K. Chergui,et al.  Burst stimulation of the medial forebrain bundle selectively increases Fos-like immunoreactivity in the limbic forebrain of the rat , 1996, Neuroscience.

[29]  S. Kiefer,et al.  Naltrexone treatment increases the aversiveness of alcohol for outbred rats. , 1997, Alcoholism, clinical and experimental research.

[30]  A. Kelley,et al.  Feeding induced by opioid stimulation of the ventral striatum: role of opiate receptor subtypes. , 1993, The Journal of pharmacology and experimental therapeutics.

[31]  R. Seeley,et al.  Neuroendocrine regulation of food intake , 1999, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[32]  K. Berridge,et al.  Central enhancement of taste pleasure by intraventricular morphine. , 1995, Neurobiology.

[33]  F. Vaccarino,et al.  Amphetamine- and morphine-induced feeding: Evidence for involvement of reward mechanisms , 1990, Neuroscience & Biobehavioral Reviews.

[34]  H. Akil,et al.  Endogenous opioids: overview and current issues. , 1998, Drug and alcohol dependence.

[35]  A. Levine,et al.  Opioids in the nucleus of the solitary tract are involved in feeding in the rat. , 1997, The American journal of physiology.

[36]  A. Chaudhuri,et al.  Neural activity mapping with inducible transcription factors. , 1997, Neuroreport.

[37]  A. Kelley,et al.  Injections of nociceptin into nucleus accumbens shell or ventromedial hypothalamic nucleus increase food intake , 1997, Neuroreport.

[38]  D. S. Zahm,et al.  Specificity in the projection patterns of accumbal core and shell in the rat , 1991, Neuroscience.

[39]  L. Heimer,et al.  Substantia innominata: a notion which impedes clinical–anatomical correlations in neuropsychiatric disorders , 1997, Neuroscience.

[40]  Gosnell Ba Central structures involved in opioid-induced feeding. , 1987 .

[41]  D. Kahneman,et al.  Well-being : the foundations of hedonic psychology , 1999 .

[42]  H. Grill,et al.  The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats , 1978, Brain Research.

[43]  H. Akil,et al.  Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: An in situ hybridization study , 1994, The Journal of comparative neurology.

[44]  G. Beauchamp,et al.  Naltrexone, an opioid blocker, alters taste perception and nutrient intake in humans. , 1991, The American journal of physiology.

[45]  Steiner Je The gustofacial response: observation on normal and anencephalic newborn infants. , 1973 .

[46]  K. Berridge,et al.  Benzodiazepines, appetite, and taste palatability , 1995, Neuroscience & Biobehavioral Reviews.

[47]  S. Haber,et al.  Organization of the output of the ventral striatopallidal system in the rat: Ventral pallidal efferents , 1993, Neuroscience.

[48]  D. S. Zahm,et al.  The patterns of afferent innervation of the core and shell in the “Accumbens” part of the rat ventral striatum: Immunohistochemical detection of retrogradely transported fluoro‐gold , 1993, The Journal of comparative neurology.

[49]  A. Levine,et al.  Naloxone's anorectic effect is dependant upon the relative palatability of food , 1993, Pharmacology Biochemistry and Behavior.

[50]  J. Stellar,et al.  NMDA-induced lesions of the nucleus accumbens or the ventral pallidum increase the rewarding efficacy of food to deprived rats , 1996, Brain Research.

[51]  A. Kelley,et al.  Investigation of the effects of opiate antagonists infused into the nucleus accumbens on feeding and sucrose drinking in rats. , 1996, The Journal of pharmacology and experimental therapeutics.

[52]  H. Groenewegen,et al.  The distribution and compartmental organization of the cholinergic neurons in nucleus accumbens of the rat , 1989, Neuroscience.

[53]  T. Herdegen,et al.  Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins , 1998, Brain Research Reviews.

[54]  Ann E. Kelley,et al.  GABA in the Nucleus Accumbens Shell Participates in the Central Regulation of Feeding Behavior , 1997, The Journal of Neuroscience.

[55]  R. Wise,et al.  Rewarding Actions of Phencyclidine and Related Drugs in Nucleus Accumbens Shell and Frontal Cortex , 1996, The Journal of Neuroscience.

[56]  J. Panksepp Affective Neuroscience: The Foundations of Human and Animal Emotions , 1998 .

[57]  M. Fantino,et al.  An opioid antagonist, naltrexone, reduces preference for sucrose in humans. , 1986, The American journal of physiology.

[58]  A. Kelley,et al.  Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[59]  S. Iversen,et al.  Increased food intake after opioid microinjections into nucleus accumbens and ventral tegmental area of rat , 1986, Brain Research.

[60]  A. Kelley,et al.  Sensitization and conditioning of feeding following multiple morphine microinjections into the nucleus accumbens , 1994, Brain Research.

[61]  L. Heimer,et al.  New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: The striatopallidal, amygdaloid, and corticopetal components of substantia innominata , 1988, Neuroscience.

[62]  F. Vaccarino,et al.  Intra-nucleus accumbens amphetamine: Dose-dependent effects on food intake , 1986, Pharmacology Biochemistry and Behavior.

[63]  A. Kelley,et al.  Enhanced intake of high-fat food following striatal mu-opioid stimulation: microinjection mapping and Fos expression , 2000, Neuroscience.

[64]  K. Berridge,et al.  Taste reactivity as a measure of the neural control of palatability , 1985 .

[65]  K. Berridge,et al.  Mapping of globus pallidus and ventral pallidum lesions that produce hyperkinetic treading , 1994, Brain Research.

[66]  L. Parker,et al.  Morphine-induced modification of quinine palatability: Effects of multiple morphine-quinine trials , 1995, Pharmacology Biochemistry and Behavior.

[67]  A. Levine,et al.  Why do we eat? A neural systems approach. , 1997, Annual review of nutrition.

[68]  K. Berridge,et al.  What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? , 1998, Brain Research Reviews.

[69]  S. Leibowitz,et al.  Multiple brain sites sensitive to feeding stimulation by opioid agonists: A cannula-mapping study , 1988, Pharmacology Biochemistry and Behavior.

[70]  L. Parker,et al.  Morphine- and naltrexone-induced modification of palatability: analysis by the taste reactivity test. , 1992, Behavioral neuroscience.

[71]  B. Gosnell Central structures involved in opioid-induced feeding. , 1987, Federation proceedings.

[72]  L. Parker,et al.  Morphine enhancement of sucrose palatability: Analysis by the taste reactivity test , 1996, Pharmacology Biochemistry and Behavior.

[73]  A. Kelley,et al.  Differential Behavioral Responses to Dopaminergic Stimulation of Nucleus Accumbens Subregions in the Rat , 1997, Pharmacology Biochemistry and Behavior.

[74]  Tanemichi Chiba,et al.  Efferent projections of the nucleus accumbens in the rat with special reference to subdivision of the nucleus: biotinylated dextran amine study , 1998, Brain Research.

[75]  G. Paxinos The Rat nervous system , 1985 .

[76]  B. Kieffer,et al.  Melanocortin receptors and δ‐opioid receptor mediate opposite signalling actions of POMC‐derived peptides in CATH.a cells , 1998, The European journal of neuroscience.

[77]  B. Gosnell Involvement of μ opioid receptors in the amygdala in the control of feeding , 1988, Neuropharmacology.

[78]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[79]  K. Berridge,et al.  Morphine enhances hedonic taste palatability in rats , 1993, Pharmacology Biochemistry and Behavior.

[80]  M. Fantino Opiacés endogènes, palatabilité et contrôle de la prise alimentaire , 1988 .

[81]  W. Nauta,et al.  Afferent and efferent relationships of the basal ganglia. , 1984, Ciba Foundation symposium.

[82]  B. Gosnell,et al.  Centrally administered opioid peptides stimulate saccharin intake in nondeprived rats , 1989, Pharmacology Biochemistry and Behavior.

[83]  A. Spector Gustatory Function in the Parabrachial Nuclei: Implications from Lesion Studies in Rats , 1995, Reviews in the neurosciences.

[84]  H. Grill,et al.  Brainstem Application of Melanocortin Receptor Ligands Produces Long-Lasting Effects on Feeding and Body Weight , 1998, The Journal of Neuroscience.

[85]  K. Berridge Food reward: Brain substrates of wanting and liking , 1996, Neuroscience & Biobehavioral Reviews.