CRF1 receptor antagonists do not reverse pharmacological disruption of prepulse inhibition in rodents

T N Douma, M J Millan, D Boulay, G Griebel, P M Verdouw, K G Westphal, B Olivier, L Groenink

Research output: Contribution to journalArticleAcademicpeer-review


RATIONALE: 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.

OBJECTIVES: 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.

CONCLUSION: 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.

Original languageEnglish
Pages (from-to)1289-1303
Number of pages15
Issue number7
Publication statusPublished - Apr 2014


  • Acoustic Stimulation
  • Animals
  • Corticotropin-Releasing Hormone
  • Dextroamphetamine
  • Dizocilpine Maleate
  • Dopamine
  • Dose-Response Relationship, Drug
  • Hydrocarbons, Halogenated
  • Ketamine
  • Male
  • Mice
  • Mice, Transgenic
  • Nucleus Accumbens
  • Prefrontal Cortex
  • Prepulse Inhibition
  • Pyridines
  • Pyrimidines
  • Pyrroles
  • Rats
  • Receptors, Corticotropin-Releasing Hormone
  • Reflex, Startle
  • Thiazines


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