title: CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents.
abstract: BACKGROUND
  As enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF₁ receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating.
  
  
  OBJECTIVE
  To determine the effects of CRF₁ receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs.
  
  
  METHODS
  CP154,526 (10-40 mg/kg), SSR125543 (3-30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by D-amphetamine (2.5, 3 mg/kg), ketamine (5, 30 mg/kg) and MK801 (0.2, 0.5 mg/kg) in Wistar rats, C57Bl/6J and CD1 mice, and on spontaneously low PPI in Iffa Credo rats and DBA/2J mice. PPI-disrupting effects of D-amphetamine (2.5-5 mg/kg) and MK801 (0.3-1 mg/kg) were examined in CRF-overexpressing (CRFtg) mice, which display PPI deficits. Finally, we determined the influence of CP154,526 on D-amphetamine-induced dopamine outflow in nucleus accumbens and prefrontal cortex of CRFtg mice using in vivo microdialysis.
  
  
  RESULTS
  No CRF₁-antagonists improved PPI deficits in any test. CRFtg mice showed blunted PPI disruption in response to MK801, but not D-amphetamine. Further, D-amphetamine-induced dopamine release was less pronounced in CRFtg versus wild-type mice, a response normalized by pretreatment with CP154,526.
  
  
  CONCLUSIONS
  The inability of CRF₁ receptor antagonists to block pharmacological disruption of sensorimotor gating suggests that the involvement of CRF₁ receptors in the modulation of dopaminergic and glutamatergic neurotransmission relevant for sensory gating is limited. Furthermore, the alterations observed in CRFtg mice support the notion that long-term elevated central CRF levels induce changes in these neurotransmitter systems.
authors.affiliation: Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Brain Center Rudolf Magnus, Utrecht, The Netherlands.
authors.forename: T N
authors.initials: TN
authors.lastname: Douma
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
authors.forename: D
authors.initials: D
authors.lastname: Boulay
authors.forename: G
authors.initials: G
authors.lastname: Griebel
authors.forename: P M
authors.initials: PM
authors.lastname: Verdouw
authors.forename: K G
authors.initials: KG
authors.lastname: Westphal
authors.forename: B
authors.initials: B
authors.lastname: Olivier
authors.forename: L
authors.initials: L
authors.lastname: Groenink
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D003913:Dextroamphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D007649:Ketamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D065808:Prepulse Inhibition / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects; D013843:Thiazines / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
chemical_list: C437952:(N-(2-chloro-4,6-dimethylphenyl)-1-(1-methoxymethyl)-(2-methoxymethyl)-6-methyl-1H-1,2,3-triazolo(4,5-c)pyridin-4-amine) mesylate; C101628:CP 154526; D006846:Hydrocarbons, Halogenated; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C502407:SSR125543; D013843:Thiazines; D000099052:CRF Receptor, Type 1; D007649:Ketamine; D016291:Dizocilpine Maleate; D003346:Corticotropin-Releasing Hormone; D003913:Dextroamphetamine; D004298:Dopamine