ABSTRACT
Excessive corticotropin-releasing hormone (CRH) secretion in limbic and prefrontal brain areas has been postulated to underly stress-related clinical conditions. Studies in mice with deleted or pharmacologically compromised CRH type 1 receptors (CRH-R1) point to a key role of the CRH/CRH-R1 signaling cascade as a potential drug target. Therefore, we compared the effect of a selective high affinity CRH-R1 antagonist (R121919) on sleep-wake behavior in two rat lines selectively bred for either high or low innate anxiety. We found that the subcutaneous injection of the solvent of R121919, a citrate buffer solution, transiently increased circulating levels of the stress hormones ACTH and corticosterone and reduced sleep, especially in high-anxiety animals. When R121919 was added to the solvent, hormone levels and sleep patterns returned to baseline and were indistinguishable between the rat lines. This finding is in accord with previous observations from a clinical trial in depressed patients and studies in rats with high innate anxiety that suggested major effects of CRH-R1 antagonism in the presence of a pathological (i.e. CRH hypersecretion) condition only.
Subject(s)
Arousal/drug effects , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Sleep Stages/drug effects , Adrenocorticotropic Hormone/blood , Animals , Corticosterone/blood , Hypothalamo-Hypophyseal System/drug effects , Limbic System/drug effects , Male , Pituitary-Adrenal System/drug effects , Prefrontal Cortex/drug effects , Rats , Rats, Wistar , Wakefulness/drug effectsABSTRACT
This vehicle-controlled study assessed the sleep effects of the naturally occurring neuroactive steroid 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC; 7.5 and 15 mg/kg), administered i.p. to rats, and compared them with those of another neuroactive steroid allopregnanolone (15 mg/kg). 3alpha,5alpha-THDOC shortened sleep latency, selectively promoted pre-REMS (a transitional state between non-REMS and REMS) and lengthened the non-REMS episodes dose-dependently. Spectral analysis of the EEG within non-REMS found significant attenuations of low-frequency activity and elevations in the spindle and higher frequency bands. The effects of 3alpha,5alpha-THDOC closely match those of allopregnanolone, indicating a common mechanism of action. Since the sleep changes produced by these steroids resemble the sleep profile of benzodiazepine hypnotics, they are probably caused by a positive allosteric modulation of GABAA receptor function.
