Original Article

The Role of Mesolimbic Reward Neurocircuitry in Prevention and Rescue of the Activity-Based Anorexia (ABA) Phenotype in Rats

  • Neuropsychopharmacology volume 42, pages 22922300 (2017)
  • doi:10.1038/npp.2017.63
  • Download Citation
Received:
Revised:
Accepted:
Published:

Abstract

Patients suffering from anorexia nervosa (AN) become anhedonic; unable or unwilling to derive normal pleasures and avoid rewarding outcomes, most profoundly in food intake. The activity-based anorexia (ABA) model recapitulates many of the characteristics of the human condition, including anhedonia, and allows investigation of the underlying neurobiology of AN. The potential for increased neuronal activity in reward/hedonic circuits to prevent and rescue weight loss is investigated in this model. The mesolimbic pathway extending from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) was activated using a dual viral strategy, involving retrograde transport of Cre (CAV-2-Cre) to the VTA and coincident injection of DREADD receptors (AAV-hSyn-DIO-hM3D(Gq)-mCherry). Systemic clozapine-n-oxide (CNO; 0.3 mg/kg) successfully recruited a large proportion of the VTA-NAc dopaminergic projections, with activity evidenced by colocalization with elevated levels of Fos protein. The effects of reward circuit activation on energy balance and predicted survival was investigated in female Sprague-Dawley rats, where free access to running wheels was paired with time-limited (90 min) access to food, a paradigm (ABA) which will cause anorexia and death if unchecked. Excitation of the reward pathway substantially increased food intake and food anticipatory activity (FAA) to prevent ABA-associated weight loss, while overall locomotor activity was unchanged. Similar activation of reward circuitry, delayed until establishment of the ABA phenotype, rescued rats from their precipitous weight loss. Although these data are consistent with shifts primarily in food intake, the contribution of mechanisms including energy expenditure to survival remains to be determined. These results will inform the neurobiological underpinnings of AN, and provide insight into the mechanisms of reward circuitry relevant to feeding and weight loss.

  • Subscribe to Neuropsychopharmacology for full access:

    $481

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. , (2012). Dysregulation of brain reward systems in eating disorders: neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa. Neuropharmacology 63: 87–96.

  2. , (2006). Differential regulation of the consummatory, motivational and anticipatory aspects of feeding behavior by dopaminergic and opioidergic drugs. Neuropsychopharmacology 31: 1371–1381.

  3. , , , , , et al (2005). Association of multiple DRD2 polymorphisms with anorexia nervosa. Neuropsychopharmacology 30: 1703–1710.

  4. , (2008). Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology (Berl) 199: 457–480.

  5. , (2007). Dopamine neuron systems in the brain: an update. Trends Neurosci 30: 194–202.

  6. , , , , , et al (2016). Chemogenetic activation of dopamine neurons in the ventral tegmental area, but not substantia nigra, induces hyperactivity in rats. Eur Neuropsychopharmacol 26: 1784–1793.

  7. , , , , , (2014). Combined use of the canine adenovirus-2 and DREADD-technology to activate specific neural pathways in vivo. PLoS ONE 9: e95392.

  8. , , (2008). A high-fat diet prevents and reverses the development of activity-based anorexia in rats. Int J Eat Disord 41: 383–389.

  9. , , , , , (2016). NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise. Brain Struct Funct (e-pub ahead of print).

  10. , , (2006). The anorectic effect of the selective dopamine D1-receptor agonist A-77636 determined by meal pattern analysis in free-feeding rats. Eur J Pharmacol 532: 253–257.

  11. , (2002). Sensitivity to the rewarding effects of food and exercise in the eating disorders. Compr Psychiatry 43: 189–194.

  12. , (2012). The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci 35: 68–77.

  13. , , (2003). Development of, and recovery from, activity-based anorexia in female rats. Physiol Behav 80: 273–279.

  14. , , , , , et al (2015). Elevated cognitive control over reward processing in recovered female patients with anorexia nervosa. J Psychiatry Neurosci 40: 140249.

  15. , (1988). Actvity-based anorexia: a biobehavioral perspective. Int J Eat Disord 7: 475–485.

  16. , , (1983). A theory of activity-based anorexia. Int J Eat Disord 3: 27–46.

  17. , , , , (1994). Twenty-four-hour food intake in patients with anorexia nervosa and in healthy control subjects. Biol Psychiatry 36: 696–702.

  18. (2014). Could dopamine agonists aid in drug development for anorexia nervosa? Front Nutr 1: 19.

  19. , , , , , et al (2005). Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride. Biol Psychiatry 58: 908–912.

  20. , , , (2016a). Prediction error and somatosensory insula activation in women recovered from anorexia nervosa. J Psychiatry Neurosci 41: 304–311.

  21. , , , , , et al (2012). Anorexia nervosa and obesity are associated with opposite brain reward response. Neuropsychopharmacology 37: 2031–2046.

  22. , , , (2016b). Altered structural and effective connectivity in anorexia and bulimia nervosa in circuits that regulate energy and reward homeostasis. Transl Psychiatry 6: e932.

  23. , , (2013). Manipulating gene expression in projection-specific neuronal populations using combinatorial viral approaches. In: (ed). Current Protocols In Neuroscience 4: 4.35.1–4.35.20.

  24. , , , , , et al (2016). New insights in anorexia nervosa. Front Neurosci 10: 256.

  25. , (1998). Excess mortality of mental disorder. Br J Psychiatry 173: 11–53.

  26. (2008). Neurobiology of anorexia and bulimia nervosa. Physiol Behav 94: 121–135.

  27. , , (2009). New insights into symptoms and neurocircuit function of anorexia nervosa. Nat Rev Neurosci 10: 573–584.

  28. , , , , (2013). Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa. Trends Neurosci 36: 110–120.

  29. , (2004). Eating disorders: clinical features and pathophysiology. Physiol Behav 81: 359–374.

  30. , , , , (2015). Dopamine D2/3 receptor antagonism reduces activity-based anorexia. Transl Psychiatry 5: e613.

  31. , , , , , (2012). Dopamine is involved in food-anticipatory activity in mice. J Biol Rhythms 27: 398–409.

  32. , (1999). Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats. Br J Pharmacol 128: 21–26.

  33. , , , (2003). 7-OH-DPAT selectively reduces intake of both chow and high fat diets in different food intake regimens. Pharmacol Biochem Behav 76: 517–523.

  34. , , , , , (2016). Psychopharmacological options for adult patients with anorexia nervosa. CNS Spectr 21: 134–142.

  35. , (2017). Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat Rev Neurosci 18: 73–85.

  36. , , (2015). A reward-centred model of anorexia nervosa: a focussed narrative review of the neurological and psychophysiological literature. Neurosci Biobehav Rev 52: 131–152.

  37. , , (2014). Hungry for reward: How can neuroscience inform the development of treatment for Anorexia Nervosa? Behav Res Ther 62: 47–59.

  38. , (2000). Similar effects of D(1)/D(2) receptor blockade on feeding and locomotor behavior. Pharmacol Biochem Behav 65: 433–438.

  39. , (1967). Self-starvation of rats living in activity wheels on a restricted feeding schedule. J Comp Physiol Psychol 64: 414–421.

  40. , , , , (2006). Hunger and satiety in anorexia nervosa: fMRI during cognitive processing of food pictures. Brain Res 1114: 138–148.

  41. , , , , , et al (2016). Activity-based anorexia reduces body weight without inducing a separate food intake microstructure or activity phenotype in female rats-mediation via an activation of distinct brain nuclei. Front Neurosci 10: 475.

  42. , , , , , et al (2009). Towards a neurocircuitry in anorexia nervosa: evidence from functional neuroimaging studies. J Psychiatr Res 43: 1133–1145.

  43. , , , (2009a). Dopamine antagonism inhibits anorectic behavior in an animal model for anorexia nervosa. Eur Neuropsychopharmacol 19: 153–160.

  44. , , , , (2009b). Dopamine and serotonin release in the nucleus accumbens during starvation-induced hyperactivity. Eur Neuropsychopharmacol 19: 309–316.

  45. , , , , , (2011). The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of activity-based anorexia. Neuropsychopharmacology 36: 1349–1358.

  46. , , , , , et al (2008). Altered insula response to taste stimuli in individuals recovered from restricting-type anorexia nervosa. Neuropsychopharmacology 33: 513–523.

  47. , , , , , (2014). Rethinking food anticipatory activity in the activity-based anorexia rat model. Sci Rep 4: 3929.

  48. , , (2003). Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat. Behav Neurosci 117: 202–211.

  49. , (1995). Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83: 1197–1209.

  50. , (1972). Deficits in feeding behavior after intraventricular injection of 6-hydroxydopamine in rats. Science 177: 1211–1214.

Download references

Acknowledgements

We acknowledge the use of facilities at Monash Micro Imaging, Monash University, Victoria, Australia.

Author information

Affiliations

  1. Department of Physiology, Monash University, Clayton, VIC, Australia

    • Claire J Foldi
    • , Laura K Milton
    •  & Brian J Oldfield

Authors

  1. Search for Claire J Foldi in:

  2. Search for Laura K Milton in:

  3. Search for Brian J Oldfield in:

Corresponding author

Correspondence to Brian J Oldfield.

Supplementary information

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)