[Abstract Title]. - Society for Neuroscience

Authors: *L. A. MILES 1 , D. WALKER 2 , M. DAVIS 2 ;
1 Dept Pharmacol, 2 Psychiatry & Behavioral Sci., Emory Univ., Atlanta, GA
Abstract: Oral administration of the CRF-R1 antagonist GSK008 disrupts sustained startle
increases produced by intra-ventricular CRF infusions and sustained startle increases that occur
when rats are tested in an illuminated environment (an innate anxiety response), but not startle
increases produced by short-duration (i.e., 3.7-sec) lights that predict shock. These and other
results suggest a preferential role of CRF in sustained (vs. short) or innate (vs. conditioned) fear
reactions, or in fear reactions to vague (vs. imminent and well-defined) threats.
To evaluate these alternatives, the effects of orally administered GSK008 was evaluated using
several different fear conditioning and potentiated startle test procedures in which we attempted
to isolate the contribution of these different variables. For experiment 1, rats received variableduration
(3 sec to 8 min) 60-Hz clicker stimuli and co-terminating footshock and were later
tested for FPS to 8-min clicker presentations (long, conditioned, and unpredictable since the CS
onset to shock interval was variable). For experiment 2, rats received 3.7-sec clicker stimuli and
co-terminating footshock, and were later tested for FPS to 3.7-sec clicker presentations (i.e.,
short, conditioned, predictable). For experiment 3, rats were trained with variable duration
clicker stimuli, but were tested with 3.7-sec clicker presentations (short, conditioned,
unpredictable). FPS to 8-min (Experiment 1) but not 3.7-sec (Experiments 2 and 3) CS
presentations was blocked by GSK008. Together, these results indicate that CRF mediates longduration
fear responses irrespective of conditioning or predictability.
Previous findings indicate a similar role for the bed nucleus of the stria terminalis (BNST) - a
structure that also mediates the sustained startle increases produced by intra-ventricular CRF
infusions. To determine if the effects of oral GSK008 administration might have involved the
BNST, we next compared the effect of intra-BNST GSK008 infusions on FPS to 3.7-sec vs. 8min
CS presentations. As with oral infusions, intra-BNST GSK008 blocked FPS to the 8-min but
not 3.7-sec shock-associated CS.
We then evaluated the effect of systemic buspirone (a 5HT1A partial agonist and dopamine D2
antagonist) administration - a treatment previously shown to block FPS to 3.7-sec light and tone
CSs. Buspirone also blocked FPS to the 3.7-sec clicker CS, but had no effect on FPS to the 8min
clicker CS. Together, these results indicate a double pharmacological dissociation between
the neural substrates of short- and long-duration startle increases.
Disclosures: L.A. Miles , None; D. Walker, None; M. Davis, None.
Poster
293. Startle and Modulation of Startle
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 293.6/SS34