CRF1 not glucocorticoid receptors mediate prepulse inhibition deficits in mice overexpressing CRF.
BACKGROUND
Both corticotropin-releasing factor (CRF) and glucocorticoid receptors (GR) are implicated in the psychotic symptoms of psychiatric disorders. Correspondingly, it is of interest to determine their respective involvement in the sensorimotor gating deficits displayed by transgenic mice overexpressing CRF. These mice reveal lifelong elevations of CRF and corticosterone levels.


METHODS
Effects of the GR antagonists ORG34517 (5-45 mg/kg by mouth [PO]) and mifepristone (5-45 mg/kg PO) and the CRF(1) receptor antagonists CP154,526 (20-80 mg/kg intraperitoneally [IP]) and DMP695 (2.5-40.0 mg/kg IP) on prepulse inhibition (PPI) of the acoustic startle response were studied in mice overexpressing CRF and in their wild-type littermates. In addition, PPI was measured in both genotypes 2 weeks after adrenalectomy with or without exogenous corticosterone administration via subcutaneous pellet implant (20 mg corticosterone).


RESULTS
ORG34517 and mifepristone did not influence perturbation of PPI in mice overexpressing CRF; reducing corticosterone levels by adrenalectomy likewise did not improve PPI. Further, elevation in corticosterone levels by pellet implantation did not disrupt PPI in wild-type mice. Conversely, both CRF(1) receptor antagonists, CP154,526 (40-80 mg/kg IP) and DMP695 (40 mg/kg IP), significantly restored PPI in CRF-overexpressing mice.


CONCLUSIONS
Sustained overactivation of CRF(1) receptors rather than excessive GR receptor stimulation underlies impaired sensorimotor gating in CRF-overexpressing mice. CRF(1) receptors thus may play a role in the expression of psychotic features in stress-related psychiatric disorders.
Groenink
Lucianne
L
Psychopharmacology, Department of Pharmaceutical Sciences, Rudolf Magnus Institute of Neuroscience and Utrecht Institute of Pharmaceutical Sciences, Utrecht, the Netherlands. l.groenink@uu.nl
Dirks
Anneloes
A
Verdouw
P Monika
PM
de Graaff
Marijke
M
Peeters
Bernard W
BW
Millan
Mark J
MJ
Olivier
Berend
B
D000161:Acoustic Stimulation; D000315:Adrenalectomy; D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D005838:Genotype; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000235:genetics*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle; D013256:Steroids / Q000008:administration & dosage / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
D052117:Benzodioxoles; D006727:Hormone Antagonists; C526064:Org 34517; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D013256:Steroids; D015735:Mifepristone; D000099052:CRF Receptor, Type 1