The Benzodiazepine Alprazolam Dissociates Contextual Fear from Cued Fear in Humans as Assessed by Fear-potentiated Startle Christian Grillon, Johanna M.P. Baas, Daniel S. Pine, Shmuel Lissek, Megan Lawley, Valerie Ellis, and Jessica Levine Background: The startle reflex is potentiated by aversive states. It has been proposed that phasic startle potentiation to a threat cue and sustained startle potentiation to contextual stimuli reflect distinct processes mediated by different brain structures. The present study tested the hypothesis that alprazolam would reduce the sustained startle potentiation to contextual threats but not the startle potentiation to a threat cue. Methods: Sixteen healthy subjects received each of four treatments: placebo, .5 mg of alprazolam, 1 mg of alprazolam, and 50 mg of diphenhydramine (Benadryl) in a crossover design. Participants were exposed to three conditions, including one in which predictable aversive shocks were signaled by a cue, a second in which shocks were administered unpredictably, and a third condition in which no shocks were anticipated. Acoustic startle were delivered regularly across conditions. Results: Phasic startle potentiation to the threat cue in the predictable condition was not affected by alprazolam. In contrast, the sustained increase in startle in the predictable and unpredictable conditions was reduced significantly by the high dose of alprazolam. Conclusions: Startle responses to an explicit threat cue and to an aversive context are psychopharmacologically distinct, suggesting that they may represent functionally dissociable aversive states. Key Words: Alprazolam, anxiety, benzodiazepine, context, fear, startle reflex T he startle reflex, a cross-species response to a sudden intense stimulus, is sensitive to aversive states (Davis et al 1993). Rodents show robust startle potentiation to a conditioned cue that signals an aversive event (e.g., a shock). Evidence suggests that this effect is mediated by the central nucleus of the amygdala (CeA). For example, lesions of the CeA block fear-potentiated startle to a conditioned cue previously paired with shock (Davis 1998). Although the CeA responds to various types of stressors, this structure is not always critical for fear-potentiated startle (Davis 1998) or for responses to stress in general (Hammack et al 2004). Davis and his collaborators have reported a series of studies showing no effect of lesions of the CeA on startle potentiation caused by various stressors, such as bright lights (i.e., light-enhanced startle), shock sensitization, and corticotropin-releasing hormone injection (reviewed in Walker et al 2003). Rather, another structure, the bed nucleus of the stria terminalis (BNST), was found to mediate startle potentiation in these conditions (Walker et al 2003). In an analysis of the experimental situations that do or do not require the CeA and BNST, Walker et al (2003) suggested that these structures were involved in functionally different aversive states in rodents. It was proposed that the CeA was crucial for the phasic form of fear-potentiated startle to a predictable threat cue, whereas the BNST was responsible for the more sustained form of startle potentiation induced by unpredictable or unconditioned aver- sive stimuli (Davis 1998; Gewirtz et al 1998; Walker and Davis 1997a). It was suggested further that the two aversive states mediated by the CeA and the BNST in rodents were reminiscent of fear and anxiety states in humans, respectively (Davis 1998). According to this view, fear is a response to a clearly identifiable danger that subsides shortly after the offset of a threat cue. Anxiety is a more sustained form of general distress and anxious apprehension in response to less identifiable cues (Barlow 2000; Davis 1998; Lang et al 2000). The distinction between a phasic and a more sustained form of startle potentiation also has been made in humans (Cuthbert et al 2003; Grillon et al 1991, 1997; Grillon and Davis 1997; Lang et al 2000; Pole et al 2003). Startle is potentiated by an explicit threat cue that signals an impending aversive event (e.g., a shock; Grillon et al 1993; Hamm and Vaitl 1996), such as when phobic individuals are confronted with their phobic objects (de Jong et al 1996; Globisch et al 1999). More sustained forms of startle potentiation can be found among individuals who are exposed to stressful experimental settings (Bocker et al 2001; Grillon and Ameli 1998; Pole et al 2003), when the experimental room is in complete darkness (Grillon et al 1997), or after context condi- tioning (Grillon and Davis 1997). Consistent with the animal literature, phasic and sustained forms of startle potentiation in humans appear to reflect distinct processes. For example, individuals with posttraumatic stress disorder (PTSD) or with panic disorder display normal startle to explicit threat cues that signal a shock but display enhanced startle reactivity in the experimental context in which the shocks are administered (Grillon et al 1994, 1998b; Pole et al 2003). Patients with PTSD also exhibit increased context conditioning (Grillon and Morgan 1999) and increased facilitation of startle in the dark (Grillon et al 1998a). There currently is little information on the neurobiological mechanisms that may differentiate phasic cued fear from more sustained contextual anxiety in humans. Evidence for such a neurobiological dissociation would be bolstered if one could demonstrate that these two forms of aversive states are differen- tially responsive to psychopharmacologic treatments. The main objective of this study was to obtain such evidence by using the benzodiazepine alprazolam. From the Mood and Anxiety Disorder Program, National Institutes of Mental Health, Bethesda, Maryland. Address reprint requests to Christian Grillon, Ph.D., National Institutes of Mental Health–Mood and Anxiety Disorder Program, 15K North Drive, Building 15K, Room 113, MSC 2670, Bethesda, MD 20892-2670; E-mail: christian.grillon@nih.gov. Received July 12, 2005; revised October 27, 2005; accepted November 11, 2006. BIOL PSYCHIATRY 2006;60:760 –766 0006-3223/06/$32.00 doi:10.1016/j.biopsych.2005.11.027 © 2006 Society of Biological Psychiatry