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Poster
549. Mood Disorders: Experimental Therapeutics and Novel Compounds
Location: South Hall A
Time: Tuesday, October 20, 2009, 8:00 am - 12:00 noon
Program#/Poster#: 549.17/X11
Topic: C.16.f. Mood disorders: Experimental therapeutics, preclinical studies
Support: Neurogen Corporation
Title: Effects of CRF1 receptor antagonists on the enhancement of acoustic startle and heart rate
activation induced by stimulation of central CRF or NE pathways
Authors: *D. C. HOFFMAN 1 , J. H. KEHNE 2 ;
1 Neurogen Corp, Branford, CT; 2 Translational Neuropharm. Consulting, LLC, Rockville, MD
Abstract: The 41 amino acid peptide corticotropin releasing factor (CRF) is a key mediator of
the behavioral, autonomic, and endocrine responses to stressors, and dysfunctional
hyperactivation of CRF neurons acting on CRF1 receptor subtypes (“CRF1 pathways”) has been
implicated in the etiology of numerous stress-related psychiatric disorders. Given clinical data
for concomitant hyperactivation of brain norepinephrine (NE) pathways, and considerable
evidence for brain CRF-NE interactions, evaluating the degree to which CRF1 receptor
antagonists can reverse states of both CRF and NE hyperactivation is of therapeutic interest. The
present study evaluated the ability of orally-active, small molecule CRF1 receptor antagonists to
reverse the autonomic (heart rate) and behavioral (acoustic startle) activation produced by
pharmacologically-induced stimulation of central CRF or NE pathways. Heart rate was measured
wirelessly in freely-moving male Sprague-Dawley rats implanted with telemetry transmitter
probes (Data Sciences International). Acoustic startle was measured in rectangular Plexiglas
cages (Med Associates) located in sound-attenuating chambers. Startle-induced displacement of
the cage was quantified by a load cell platform placed beneath the cage. In the first study,
pharmacological activation of either CRF (i.c.v. infusion of the peptide r/h CRF, 0.1-1.0 µg) or
NE (i.p. injection of the α2-adrenergic receptor antagonist, yohimbine, 0.3-10 mg/kg) pathways
produced dose-related increases in heart rate and acoustic startle. In the second study, rats were
pretreated with either the CRF1 antagonist, R121919 (10, 30 mg/kg p.o.) or NGD 98-2 (30 mg/kg
p.o.), and following the appropriate pretreatment time, injected with yohimbine or CRF at doses
which were shown in the first study to cause significant heart rate or acoustic startle elevations.
NGD 98-2 and R121919 reduced both CRF-induced elevations in heart rate and startle. In
contrast, CRF1 receptor antagonism under these conditions did not attenuate the increases in
heart rate or startle produced by yohimbine. These results indicate that blockade of CRF1
receptors can attenuate the autonomic and behavioral activation resulting from hyperactivation of