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.
