Serotonin reuptake inhibitors (SSRIs) are commonly used in the treatment of anxiety disorders, but their mechanism of action is poorly understood. Although the pharmacological effects of SSRIs are immediate, their therapeutic effects are delayed for weeks. In an effort to explore how these drugs work, we have begun a series of studies comparing the effects of acute vs. chronic treatment of the SSRI citalopram on the acquisition and expression of conditioned fear responses (freezing behavior) in rats. Fear conditioning involved 2 presentations of a tone (20 sec, 10 kHz) that co-terminated with a footshock (0.7 mA, 0.5 sec). A single systemic injection of citalopram (10mg/kg, i.p.) given one hour before training or testing increased conditioned freezing when tested 24 hr after training. In contrast, chronic systemic injections (21d) of citalopram (10mg/kg, i.p.) given before training led to a reduction in the amount of freezing that was expressed 24h after training. The effects of chronic injections (21d) given before testing will also be assessed. Our results are consistent with clinical findings showing that fear and anxiety increase after acute SSRI administration, but decrease with chronic treatment. Given this similarity and the detailed knowledge of the role of the amygdala in auditory fear conditioning, it is hoped that understanding how citalopram alters auditory fear conditioning will provide a tool for exploring the neural mechanisms by which SSRIs mediate their clinical effects on anxiety disorders.
Supported by: NIMH grants: 58911, 46516, 38774, and 00956.