Reversal of startle gating deficits in transgenic mice overexpressing corticotropin-releasing factor by antipsychotic drugs.
Chronically elevated levels of corticotropin-releasing factor (CRF) in transgenic mice overexpressing CRF in the brain (CRF-OE) appear to be associated with alterations commonly associated with major depressive disorder, as well as with sensorimotor gating deficits commonly associated with schizophrenia. In the present study, we tested the hypothesis that antipsychotics may be effective in normalizing prepulse inhibition (PPI) of acoustic startle in CRF-OE mice, which display impaired sensorimotor gating compared to wild-type (WT) mice. The typical antipsychotic haloperidol and atypical antipsychotic risperidone improved PPI in the CRF-OE mice, but were ineffective in WT mice. The atypical antipsychotic clozapine did not influence PPI in CRF-OE mice, but reduced gating in WT mice. This effect of clozapine in the CRF-OE mice may thus be regarded as a relative improvement, consistent with the observed effect of haloperidol and risperidone. As expected, the anxiolytic, nonantipsychotic chlordiazepoxide was devoid of any effect. All four compounds dose-dependently reduced the acoustic startle response irrespective of genotype. These results indicate that antipsychotic drugs are effective in improving startle gating deficits in the CRF-OE mice. Hence, the CRF-OE mouse model may represent an animal model for certain aspects of psychotic depression, and could be a valuable tool for research addressing the impact of chronically elevated levels of CRF on information processing.
Dirks
Anneloes
A
Department of Psychopharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. A.Dirks@pharm.uu.nl
Groenink
Lucianne
L
Westphal
Koen G C
KG
Olivier
Jocelien D A
JD
Verdouw
P Monika
PM
van der Gugten
Jan
J
Geyer
Mark A
MA
Olivier
Berend
B
D000161:Acoustic Stimulation; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D001835:Body Weight / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis* / Q000235:genetics; D003863:Depression; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D012022:Reflex, Acoustic / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D013268:Stimulation, Chemical
D014150:Antipsychotic Agents; D003346:Corticotropin-Releasing Hormone