Blockage of melanocortin-4 receptors by intrcnasal HS014 attenuates single prolonged stress-Pred changes in several brain regions

Melanocortin receptor four (MC4R) is implicated in regulation of stress-related functions. We previously demonstrated that intranasal infusion of MC4R antagonist HS014, shortly before single prolonged stress (SPS) animal model of post-traumatic stress disorder, lessened the development of anxiety- and depression-like behavior depending on the dose. Here, we evaluated effects of HS014 on SPS-elicited changes in hypothalamic-pituitary-adrenal axis and expression of several genes of interest in mediobasal hypothalamus, hippocampus, and locus coeruleus. Rats were given intranasal infusion of HS014 (3.5ng or 100g) and 30min later subjected to SPS stressors. Short-term responses of HS014 rats in comparison with vehicle-treated, evident 30min following SPS stressors, included smaller rise in plasma corticosterone (100g HS014), absence of induction of corticotrophin-releasing hormone mRNA in mediobasal hypothalamus and of mRNA for tyrosine hydroxylase and dopamine- hydroxylase in locus coeruleus. Long-term responses found 7days after SPS stressors, included lower induction corticotrophin-releasing hormone mRNA levels in the mediobasal hypothalamus without effect on mRNAs for the glucocorticoid receptor (GR) and FK506-binding protein 51 (FKBP5), a component of GR co-chaperone complex; and no induction of GR protein in ventral hippocampus. Thus, antagonism of MC4R prior to SPS attenuates development of several abnormalities in gene expression in regions implicated in post-traumatic stress disorder.