The startle reflex (Davis, 1989 ) provides an attractive, non-invasive methodology for examining the effects of drugs on affective response in animals and humans. The startle response to an abrupt, intense stimulus (e.g., loud noise) increases above baseline when elicited in the presence of a cue that has been paired contingently with an aversive unconditioned stimulus (e.g., electric shock: Curtin et al., 2001 (link); Grillon et al., 1991 (link); Grillon & Davis, 1997 (link)). This effect is referred to as fear-potentiated startle and substantial research with animals has confirmed that projections from the central nucleus of the amygdala (CeA) to the primary startle circuit are responsible for this startle potentiation (see Davis, 1992 , for a review).
More recently, research has identified other manipulations that also potentiate the startle reflex in animals and humans. For example, corticotropin-releasing factor (CRF; a stress hormone) has been observed to potentiate startle when administered to rats (Swerdlow et al., 1986 (link); Liang et al., 1992 (link)). Walker and Davis (1997a) (link) demonstrated that exposure to bright light increases startle above baseline in rats, a nocturnal species. Similarly, in humans, exposure to darkness (Grillon, et al., 1997b (link); Grillon et al., 2007b (link)) and unpredictable electric shock (Grillon et al., 2004 (link)) also increase startle response magnitude.
There are important differences in the nature of the response produced by CRF, non-contingent (unpredictable) shocks, and light/darkness manipulations vs. cue-contingent (predictable) electric shock administration. Specifically, cue contingent administration of electric shock produces phasic fear-potentiated startle only during the punctate cues that predict imminent shock administration. In contrast, CRF, unpredictable shock, and light/darkness manipulations produce more sustained potentiation of the startle reflex. Moreover, Davis and colleagues have demonstrated elegant double dissociations in the neural substrates underlying startle potentiation across these two classes of manipulations in animals (Walker & Davis, 1997b (link), 2008 (link); Walker et al., 2003 (link)). Specifically, lesions of the central nucleus of the amygdala (CeA) abolished fear-potentiated startle to predictable shocks but not potentiation of startle to CRF and bright light exposure. In contrast, lesions of the bed nucleus of the stria terminalis (BNST) abolished startle potentiation to CRF and bright light exposure but not fear-potentiated startle to cues predicting shock. Similar involvement of the BNST has been confirmed during unpredictable shock administration (Walker & Davis, 2008 (link)).
Given the nature of the eliciting stimuli and the time course of the response across these two categories of manipulations, researchers have offered these manipulations as laboratory models of fear vs. anxiety (Davis, 2006 (link); Grillon, et al., 2006 (link)). Specifically, contingent cue-electric shock pairings involve simple, punctate stimuli that are highly predictive of imminent aversive stimulation (electric shock administration in the next few seconds). The phasic fear-potentiation of startle selectively during these cues in response to this manipulation is proposed to model the fear response. In contrast, non-contingent (unpredictable) shock, light/darkness, and CRF involve more complex, diffuse contextual cues that are more static, or of longer duration, and provide little information about when aversive stimulation will occur. The sustained potentiation of startle response in these manipulations is proposed to model anxiety.
More recently, research has identified other manipulations that also potentiate the startle reflex in animals and humans. For example, corticotropin-releasing factor (CRF; a stress hormone) has been observed to potentiate startle when administered to rats (Swerdlow et al., 1986 (link); Liang et al., 1992 (link)). Walker and Davis (1997a) (link) demonstrated that exposure to bright light increases startle above baseline in rats, a nocturnal species. Similarly, in humans, exposure to darkness (Grillon, et al., 1997b (link); Grillon et al., 2007b (link)) and unpredictable electric shock (Grillon et al., 2004 (link)) also increase startle response magnitude.
There are important differences in the nature of the response produced by CRF, non-contingent (unpredictable) shocks, and light/darkness manipulations vs. cue-contingent (predictable) electric shock administration. Specifically, cue contingent administration of electric shock produces phasic fear-potentiated startle only during the punctate cues that predict imminent shock administration. In contrast, CRF, unpredictable shock, and light/darkness manipulations produce more sustained potentiation of the startle reflex. Moreover, Davis and colleagues have demonstrated elegant double dissociations in the neural substrates underlying startle potentiation across these two classes of manipulations in animals (Walker & Davis, 1997b (link), 2008 (link); Walker et al., 2003 (link)). Specifically, lesions of the central nucleus of the amygdala (CeA) abolished fear-potentiated startle to predictable shocks but not potentiation of startle to CRF and bright light exposure. In contrast, lesions of the bed nucleus of the stria terminalis (BNST) abolished startle potentiation to CRF and bright light exposure but not fear-potentiated startle to cues predicting shock. Similar involvement of the BNST has been confirmed during unpredictable shock administration (Walker & Davis, 2008 (link)).
Given the nature of the eliciting stimuli and the time course of the response across these two categories of manipulations, researchers have offered these manipulations as laboratory models of fear vs. anxiety (Davis, 2006 (link); Grillon, et al., 2006 (link)). Specifically, contingent cue-electric shock pairings involve simple, punctate stimuli that are highly predictive of imminent aversive stimulation (electric shock administration in the next few seconds). The phasic fear-potentiation of startle selectively during these cues in response to this manipulation is proposed to model the fear response. In contrast, non-contingent (unpredictable) shock, light/darkness, and CRF involve more complex, diffuse contextual cues that are more static, or of longer duration, and provide little information about when aversive stimulation will occur. The sustained potentiation of startle response in these manipulations is proposed to model anxiety.
