The purpose of this study is to understand the effects of the drug alprazolam (Xanax ) on anxiety.

To understand the effect of anxiety-relieving drugs on fear and anxiety, researchers often have participants anticipate unpleasant stimuli. Anticipating unpleasant stimuli increases or potentiates a simple reflex called the startle reflex. The so-called fear-potentiated startle reflex (FPS) effect may be blocked or reduced by anxiety-relieving drugs. Evidence suggests that the FPS can be mediated by two mechanisms that regulate the phasic- and sustained enhancement of startle. This study will elicit phasic and sustained FPS in participants by having them anticipate moderately painful stimuli that are administered predictably and unpredictably. The main goal of this study is to assess the affect of alprazolam on the phasic and sustained enhancement of startle.

This study comprises two pilot experiments and a main study. Participants in the study will be screened with a psychiatric history, physical examination, electrocardiogram (EKG), and blood and urine tests. Participants will four testing sessions separated by 5 to 10 days. At each session, participants will be given one of two doses of alprazolam, diphenhydramine, or placebo (an inactive pill). Questionnaires and other tests will be performed.

A lack of adequate experimental models of emotional reactions to aversive stimuli is an impediment to furthering our understanding of the psychopharmacology of fear and anxiety in humans. Finding procedures that enable us to test putative anxiety-relieving agents would greatly facilitate this type of research. The startle reflex is an ideal tool for such an endeavor. The so-called fear-potentiated startle reflex (FPS) has clear face validity, well-defined neuronal system, and cross-species generalization. In addition, in rodents the fear-potentiated startle reflex effect is blocked or reduced by drugs that are anxiolytic in humans. However, the few psychopharmacological studies conducted so far in humans have yielded inconsistent results. One possibility is that prior studies have not employed optimal designs to test the effects of anxiolytics. Our previous studies in anxious individuals and patients with anxiety disorders, as well as animal studies, suggest that the potentiation of startle by aversive states can be mediated by two distinct psychological and neurobiological mechanisms. One mediates the short-term potentiation of startle to explicit (predictable) threatening cues, and the other the long-term potentiation of startle by contextual cues. We have shown that the benzodiazepines alprazolam affect preferentially sustained forms of FPS, not on phasic FPS to explicit threat cues. The objectives of the following studies are to 1) further test the psychopharmacological validity of the model using recognized anxiolytics (the SSRI citalopram), 2) test the anxiolytic properties of compounds that are hypothesized to be anxiolytic (the angiotensin receptor blocker candesartan) based on pre-clinical data, 3) examine the role of cortisol in startle potentiation, and 4) examine the time course of the anxiolytic effect of alprazolam on FPS.

• Bitsios P, Philpott A, Langley RW, Bradshaw CM, Szabadi E. Comparison of the effects of diazepam on the fear-potentiated startle reflex and the fear-inhibited light reflex in man. J Psychopharmacol. 1999;13(3):226-34.
• Riba J, Rodriguez-Fornells A, Urbano G, Morte A, Antonijoan R, Barbanoj MJ. Differential effects of alprazolam on the baseline and fear-potentiated startle reflex in humans: a dose-response study. Psychopharmacology (Berl). 2001 Oct;157(4):358-67.
• Davis M, Falls WA, Campeau S, Kim M. Fear-potentiated startle: a neural and pharmacological analysis. Behav Brain Res. 1993 Dec 20;58(1-2):175-98. Review.

• INCLUSION CRITERIA:

Subjects will be healthy volunteers between 18-45 years old and free of current psychopathology and organic central nervous system disorders.

EXCLUSION CRITERIA:

• Any significant medical or neurological problems (e.g. cardiovascular illness, respiratory illness, neurologic illness, seizure, etc.)
• Adverse reactions to ACE inhibitors and ACE receptor antagonists (candesartan study only)
• Adverse reactions to cortisol (cortisol study only)
• History of angioedema
• Osteoporosis (Hydrocortisone study only)
• Blood pressure below 100 (candesartan study only)
• Use of potassium supplements (candesartan study only)
• A family history of mania, schizophrenia, or other psychoses
• A history of mania, schizophrenia, or other psychoses
• Current migraine
• Use of herbal medicines or dietary supplements with psychoactive properties (citalopram study only)
• Any current psychiatric disorders
• Past alcohol/drug dependence and alcohol/drug abuse in past one year
• Current use of psychotropic medication
• Use of diuretics or laxatives (candesartan study only)
• Impaired hearing
• Reduced startle reactivity
• Pregnancy
• Positive results of beta-human chorionic gonadotropin testing (females only)
• Neurological syndrome of the wrist (e.g., carpal tunnel syndrome)
• Adverse reaction to candesartan or other blood pressure lowering medications