GABA-A and 5-HT1A Receptor Agonists Block Expression of Fear-Potentiated Startle in Mice

Abstract

The present experiments characterized the acquisition of fear-potentiated startle (FPS) and determined the sensitivity of FPS to anxiolytic compounds in DBA/1J mice. A light (30 s) conditioned stimulus (CS) and mild footshock (0.14 mA, 0.5 s) unconditioned stimulus (US) were used. First, acquisition of FPS was examined by presenting the acoustic startle probe during and after each CS-US pairing trial, allowing for a trial-by-trial measurement of experience-dependent startle plasticity. In this novel protocol, mice showed robust acquisition (larger acoustic startle reflex in the presence of the CS) of FPS after as few as eight CS-US pairings. FPS was significantly greater when the CS and US were paired explicitly (light-paired) as compared to when both the US and CS were presented randomly (unpaired), or when the CS was presented alone (no shock), indicating pairing-dependent learning of the CS. Second, the present study assessed the sensitivity of FPS in mice to anxiolytic drugs. The GABA-A receptor agonists diazepam (3 and 6 mg/kg) and chlordiazepoxide (10 mg/kg) significantly reduced the expression of FPS post-training, as did the serotonin 1A receptor partial agonist buspirone (5 and 10 mg/kg). Furthermore, all three anxiolytic drugs reduced startle responding in a cue-specific manner and without significant changes in baseline responding. These data demonstrate a novel method of studying acquisition of FPS, and support the predictive validity of the FPS model of anxiolytic drug action in mice.

Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion

“…While the impact of monoamine alterations on conditioned fear is far from clear, past studies investigating the influence of DA on cued conditioning suggest that decreases (Davis et al, 1993;Borowski and Kokkinidis, 1996;Munro and Kokkinidis, 1997), but not increases in DA mesolimbic activity may produce impairments. Concerning alterations in serotonergic activity, results obtained using the fear-potentiated startle paradigm have shown that systemic injections of buspirone, a partial 5-HT1A receptor agonist, block fear-potentiated startle Mansbach and Geyer, 1988;Risbrough et al, 2003). However, lesions of the raphe nuclei failed to block disrupt fear-potentiated startle or the effect of buspirone on potentiated startle , suggesting the modulation of DRN activity does not effect fear as measured by potentiated startle.…”

Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P2

“…Acoustic startle response. The acoustic startle test was performed by using a startle response system (SR-LAB apparatus, San Diego Instruments, San Diego, CA) as described previously (Risbrough et al, 2003). Subjects were restrained inside a Plexiglas tube with a 40 mm inner diameter in a ventilated, darkened chamber and then were exposed to clicks of defined, variable decibels at random intervals.…”

Role of corticotropin releasing factor in anxiety disorders: A translational research perspective

“…One of the translational values of studying the startle response is that the neuroanatomical and neurochemical substrates mediating and modulating startle plasticity are relatively well defined, allowing greater hypothesis generation and interpretability before and after obtaining results Davis et al, 1993;Geyer et al, 2001;Heldt et al, 2000;Lang, 1995;Mansbach and Geyer, 1988;Risbrough et al, 2003aRisbrough et al, ,2004Swerdlow et al, 2001;Walker and Davis, 2002b;Toufexis et al, this volume). A fairly recent example of the successful use of rodent startle is in the potential use of D-cycloserine as an adjunctive treatment with extinction or "exposure" therapies.…”