Effect of a benzodiazepine receptor agonist and corticotropin-releasing hormone receptor antagonists on long-term foot-shock-induced increase in defensive withdrawal behavior

Rationale: Traumatic life events can induce long-term alterations in neuron al substrates, which may ultimately lead to the development of anxiety diso rders. It has been postulated that corticotropin-releasing hormone (CRH) pl ays an important role in anxiety-like behavior. Objectives: (1) To study th e long-term effects of a single foot-shock experience on defensive withdraw al (DW) behavior in rats. (2) To examine the effects of the benzodiazepine anxiolytic drug chlordiazepoxide on the behavior of preshocked and control rats in the DW test. (3) To study the role of endogenous CRH in the long-te rm stress-induced increase in DW behavior. Methods: (1) Rats were exposed t o a single session of foot shocks or exposed to the grid cage without recei ving any shocks. Two, six and ten weeks later, rats were tested in the DW t ests (2, 3). In subsequent experiments, rats were exposed to foot shocks or exposed to the grid cage without receiving any shocks, and 2 weeks later t he effect of pharmacological treatments on the behavioral response in the D W test was investigated. Chlordiazepoxide (1, 5, 10 mg/kg BW, i.p.) and the CRH antagonists D-Phe CRH(12-41) (0.2, 1, 5 mug per rat, i.c.v.) and alpha -helical CRH(9-41) (5 mug per rat, i.c.v.) were injected 30 min before the test. Results: A single session of foot shocks induced a long-term increas e in DW behavior, which persisted after repeated testing for at least 10 we eks. Chlordiazepoxide decreased the latency but did not affect time spent i n light, distance moved. or the number of entries in the open field. D-Phe CRH(12-41) had no behavioral effects. alpha -Helical CRH(9-41) increased th e time spent outside the box, primarily as a result of effects of alpha -he lical CRH(9-41) in controls. Conclusion: These data demonstrate that presho cked rats display long-term increased anxiety-like behavior in the DW test but that CRH is unlikely to be involved in its expression.