Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

Rationale: Central administration of corticotropin-releasing factor (CRF) elicits a specific pattern of behavioral responses resembling a stress-like state and is anxiogenic in rodent models of anxiety. Objectives: Specific behaviors evoked by the administration of CRF were measured. The roles of CRF receptor subtypes and that of serotonergic and noradrenergic systems in mediating these responses were studied. Materials and methods: Burying, grooming, and head shakes were quantified in rats following intracerebroventricular administration of CRF and urocortin II and after pretreatment with antagonists. The role of forebrain norepinephrine in the behavioral responses to CRF (0.3 μg) was examined following pretreatment with the neurotoxin DSP-4 and that of serotonin after depletion using systemic administration of para-chlorophenylalanine (p-CPA). Results: CRF at 0.3 and 3.0 μg caused robust increases in burying, grooming, and head shakes, but urocortin II was ineffective. Pretreatment with either antalarmin or propranolol significantly attenuated the CRF-evoked behaviors. Destruction of forebrain norepinephrine pathways blocked spontaneous burying behavior elicited by CRF and conditioned burying directed towards an electrified shock probe. In contrast, depletion of 5-HT selectively attenuated CRF-evoked grooming. Conclusions: Overt behavioral responses produced by CRF, burying, grooming, and head shakes appeared to be mediated through the CRF₁ receptor. Spontaneous burying behavior evoked by CRF or conditioned burying directed towards a shock probe was disrupted by lesion of the dorsal noradrenergic bundle and may represent anxiety-like behavior caused by CRF activation of the locus ceruleus. In contrast, CRF-evoked increases in grooming were dependent on serotonin.