Brain RFamide Neuropeptides in Stress-Related Psychopathologies

Abstract

The RFamide peptide family is a group of proteins that share a common C-terminal arginine-phenylalanine-amide motif. To date, the family comprises five groups in mammals: neuropeptide FF, LPXRFamides/RFamide-related peptides, prolactin releasing peptide, QRFP, and kisspeptins. Different RFamide peptides have their own cognate receptors and are produced by different cell populations, although they all can also bind to neuropeptide FF receptors with different affinities. RFamide peptides function in the brain as neuropeptides regulating key aspects of homeostasis such as energy balance, reproduction, and cardiovascular function. Furthermore, they are involved in the organization of the stress response including modulation of pain. Considering the interaction between stress and various parameters of homeostasis, the role of RFamide peptides may be critical in the development of stress-related neuropathologies. This review will therefore focus on the role of RFamide peptides as possible key hubs in stress and stress-related psychopathologies. The neurotransmitter coexpression profile of RFamide-producing cells is also discussed, highlighting its potential functional significance. The development of novel pharmaceutical agents for the treatment of stress-related disorders is an ongoing need. Thus, the importance of RFamide research is underlined by the emergence of peptidergic and G-protein coupled receptor-based therapeutic targets in the pharmaceutical industry.

Keywords: GPCR; HPA; anxiety; coexpression; depression.

Figure 1

Schematic representation of the basic organization of the stress response to homeostatic stressors. ACTH: adrenocorticotropic hormone; Adr: adrenaline; AMY: amygdala; AVP: arginine vasopressin; CORT: glucocorticoids—in humans, cortisol, in rodents, corticosterone; CRH: corticotropin-releasing hormone; HC: hippocampus; HPA: hypothalamic–pituitary–adrenal axis; IML: intermediolateral cell column of the spinal cord; NA: noradrenaline; n.X.: nervus vagus; PFC: prefrontal cortex; PVN: hypothalamic paraventricular nucleus, the center of the HPA; SAM: sympathoadrenomedullary system.

Figure 2

The RFamide peptide family and their receptors. Thick arrows: high affinity at the receptor; thin arrows: lower affinity at the receptor with biological activity; dashed arrow: biological activity is controversial. For references, see the text.

Figure 3

Distribution of RFamide peptide receptors in brain areas associated with stress reaction in rodents. The figure shows areas of high and moderate receptor expression based on ISH data. For references, see the text. Amb: ambiguous nucleus; AMY: amygdala; AP: area postrema; BNST: bed nucleus of stria terminalis; cingulate: cingulate cortex; DMX: dorsal motor nucleus of the vagus nerve; HC: hippocampus; HTH: hypothalamus; LC: locus ceruleus; NTS: nucleus of the solitary tract; nucl.V.: spinal trigeminal nucleus, PAG: periaqueductal grey matter; raphe: raphe nuclei.

Figure 4

Summary of the effects of RFamide peptides on HPA and SAM activity and various stress-related disorders. Data are based on administration of the drugs ICV, unless otherwise indicated. Parentheses are used to indicate that the data were dependent on the behavioral test used. RF9: NPFFR1/2 antagonist. For references, see the text.