Differential monoaminergic, neuroendocrine and behavioural responses after central administration of corticotropin-releasing factor receptor type 1 and type 2 agonists.

Corticotropin-releasing factor (CRF) mediates various aspects of the stress response. To differentiate between the roles of CRF(1) and CRF(2) receptor subtypes in monoaminergic neurotransmission, hypothalamic-pituitary-adrenocortical axis activity and behaviour we compared the effects of CRF and urocortin 1 with those of the selective CRF(2) receptor ligands urocortin 2 and urocortin 3. In vivo microdialysis in the rat hippocampus was used to assess free corticosterone, extracellular levels of serotonin (5-HT) and noradrenaline (NA), and their metabolites 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively. Intracerebroventricular (i.c.v.) injection of CRF and urocortin 1, 2 and 3 (1.0 microg) increased hippocampal levels of 5-HT and 5-HIAA. CRF and urocortin 1 increased NA and MHPG, whereas urocortin 2 and urocortin 3 elevated MHPG, but not NA levels. CRF and the urocortins induced an immediate increase in behavioural activity. CRF and urocortin 1 mainly caused grooming and exploratory behaviour. In contrast, urocortin 2 and urocortin 3 both induced exploratory behaviour, but not grooming, and increased time spent eating food pellets. All urocortins, but not CRF, suppressed food intake 4-6 h after injection. Hippocampal free corticosterone levels were elevated by CRF, urocortin 1 and 3, but not by urocortin 2. The time courses of the CRF- and urocortin 1-induced responses were significantly prolonged as compared to those of the CRF(2) receptor ligands. The stimulatory changes evoked by CRF and urocortin 1 were present up to 4-6 h after injection, whereas the effects of urocortin 2 and urocortin 3 returned to baseline within 2.5 h after injection. Pre-treatment with the selective antagonist antisauvagine-30 (5.0 microg, i.c.v.) confirmed that the effects of urocortin 3 were CRF(2) receptor-mediated. The differential time course of the monoaminergic, neuroendocrine and behavioural effects of CRF and urocortin 1, as compared to urocortin 2 and urocortin 3, and the specific behavioural pattern induced by the CRF(2) receptor ligands, suggest a distinct role for CRF(2) receptors in the stress response.