The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus.

Anhedonia is a core symptom of clinical depression. Two brain neuropeptides that have been implicated in anhedonia symptomology in preclinical depression models are dynorphin and orexin; which are concentrated along lateral hypothalamic dopamine reward pathways. These affect regulating neuropeptides modulate each other's function, implicating an interactive dysfunction between them in anhedonia symptomology. But whether their influences are modified or imbalanced within the hypothalamus or dopamine system in anhedonic preclinical depression models is not yet clear. We used radioimmunoassay to determine this in the rat social defeat model of depression; at a time that anhedonic sexual disinterest was expressed. In tissue samples of the medial prefrontal cortex (mPFC), ventral tegmental area (VTA) and nucleus accumbens, basal dynorphin levels were similar to normal animals. But orexin was reduced in the VTA and mPFC. Also, dynorphin and orexin were both diminished in the hypothalamus which is noteworthy since nearly all hypothalamic orexin cells co-express dynorphin. These findings suggest that orexin and dynorphin function may be imbalanced between the hypothalamus and mesocortical dopaminergic brain regions in depression.