Effect of D-cycloserine on Extinction of Fear Conditioning
Condition: Fear
Study type: Observational

Summary: 
      This study will evaluate whether the drug D-cycloserine (DCS) can improve a type of learning
      called classical conditioning, in which the brain learns to associate neutral stimuli with
      stimuli that elicit emotional or physiological responses. DCS is an antibiotic that was
      initially approved to treat tuberculosis and has been tested in clinical trials over the last
      decade for enhancing cognitive function. This protocol includes both a pilot study and a main
      study. The main study will begin after the pilot study ends.

      Healthy normal volunteers between 18 and 45 years of age may be eligible for these studies.
      Candidates will be screened with a medical and psychiatric history and a physical examination
      that includes blood and urine samples, an electrocardiogram (EKG), hearing test and startle
      test. The startle test involves recording eyeblink responses to loud noises.

      After the screening visit, those enrolled will participate in the pilot or main study, in
      which their reactions to two types of stimuli-an unpleasant, but harmless, shock to the arm
      and a mild puff of air to the eye-will be measured and recorded.

      - Pilot Study

      Session 1 - Participants will receive very brief electric shocks delivered through two
      electrodes attached to the forearm or fingers and will hear brief loud sounds that may
      startle. Geometric shapes will be presented on a computer monitor.

      Sessions 2 and 3 - The procedure is the same as in session 1, except participants will also
      be subjected to brief low-intensity tones and airpuffs to the eye.

      - Main Study

      Participants will undergo the same procedures described in the pilot study, with the
      following additions:

        -  They will have an intravenous tube placed in a vein for collecting blood during the
           test.

        -  They will take a pill each test day that contains either 100 mg DCS, 500 mg DCS, or a
           placebo (inactive substance). Subjects assigned to receive DCS will get the active drug
           on only one of the three test sessions and will be given placebo the other two sessions.
           The placebo group will receive placebo all three sessions.

      In both the pilot and main study, subjects' physiological responses to the stimuli will be
      recorded. Electrodes will be placed on two fingers (to measure sweat, or electrodermal
      activity), on the ribcage midway between the waist and armpit (to measure heart rate), and
      under one eye (to measure eye blink). Pulse will be recorded with a device attached to a
      finger, and breathing rate will be recorded with a special belt placed around the chest. At
      various times during the sessions, subjects will fill out questionnaires about their
      experience. Participants may withdraw from the study at any point.
    

Detailed description: 
      This protocol examines the effect of two drugs on fear conditioning. Study 1 tests assess
      whether D-cycloserine (DCS) facilitates extinction of fear conditioning and acquisition of
      eyeblink conditioning. Study 2 examines whether the calcium channel blocker nimodipine blocks
      acquisition of fear conditioning and eyeblink conditioning.

      Study 1: The demonstration that activation of NMDA receptors is necessary for long-term
      potentiation suggests that this subclass of amino acid may be involved in certain types of
      learning and memory. The present project will examine the effect DCS, a partial agonist at
      the glycine modulatory site on the NMDA receptor, on two associative learning tasks,
      extinction of fear conditioning and acquisition of eyeblink conditioning. The inability to
      extinguish intense fear memories is a significant clinical problem. Finding procedures or
      treatments that facilitate extinction of fear memories is of paramount importance. In
      animals, extinction of conditioned fear involves an active learning process that is blocked
      by NMDA antagonists. Recently, Dr. Michael Davis (Emory University) demonstrated that the
      administration of DCS prior to extinction produces a dose-dependent facilitation of
      extinction of conditioned fear in the rat, when assessed with fear-potentiated startle. We
      propose to examine whether the clinically important process of extinction can also be
      enhanced by DCS in humans. Another aim of the study is to examine whether DCS facilitates a
      hippocampal-mediated task, trace eyeblink conditioning. The hippocampus is particularly rich
      in NMDA receptors and DCS blocks trace eyeblink conditioning in the rabbit. The present study
      will examine the effect of placebo, 100 mg DCS, and 500 mg DCS on extinction, retention, and
      reinstatement of fear-potentiated startle conditioning and acquisition of trace eyeblink
      conditioning. The first experimental session (acquisition) will be a fear conditioning
      procedure (paired presentation of a conditioned stimulus or CS and a mildly unpleasant
      shock). During the second experimental session (extinction), DCS or placebo will be given to
      the subjects 1 hour prior to an extinction procedure (CS presented without shock). Following
      extinction, the eyeblink conditioning study will be conducted. Finally, in the third
      experimental session, retention of fear and eyeblink conditioning will be evaluated. We
      hypothesized that compared to placebo, DCS will speed up learning, i.e., it will facilitate
      extinction of fear conditioning and acquisition of eyeblink conditioning.

      Study 2: The rationale for testing nimodipine is highly similar to the rationale for testing
      DCS, and the procedure is very similar. Understanding the neurochemical bases of fear
      acquisition and fear extinction may provide insights into pathological anxiety and help
      develop more effective treatments. This study will be conducted over two experimental
      sessions (and a screening session). Nimodipine or placebo will be given during the 1st
      session prior to acquisition of fear conditioning and eyeblink conditioning. The 2nd session
      will be a test of retention of eyeblink conditioning. We hypothesized that nimodipine will
      impair fear conditioning and eyeblink conditioning.
    

Keywords: Classical Conditioning; Learning; NMDA; Startle; Eyeblink; Anxiety; Fear Conditioning; Fear Potentiated Startle; Extinction; D-cycloserine; Healthy Volunteer; HV; Normal Control