ELSEVIER NeuroscienceResearch 24 (1996) 151-158 Chlordiazepoxide discriminates between the neural circuits mediating neuroendocrine responsesto fear- and anxiety-producing stimuli in the rat Kinji Yagi*, Tatsushi Onaka Department of Physiology, Jichi Medical School, Minamikawachi-machi, Tochigi-ken 329-04. Japan Received3 October 1995; accepted 8 November 1995 Abstract Effects of a benzodiazepine, chlordiazepoxide (CDP), on neuroendocrine responses to emotionalstimuli werestudied in male rats. In the experiments with conditioned fear stimuli, rats received a pure tone pairedwith footshocks in the training session and weretested on the following day with the same environmental stimuli. CDP injected i.p. 30 min before training impaired the sup- pressive vasopressin and the augmentative oxytocin or adrenocorticotrophic hormone (ACTH) responses to the conditioned fear stimuli. However, the drug, administered 30 min after the training, did not significantly alter thehormonal responses to conditioned fearstimuli.CDPadministered 30min before testing also abolished thehormonal responses to conditioned fear stimuli. The stimuli which were identical to those used for training or unconditionedfear stimuli (intermittent footshocks)also produced the vasopressin, oxytocin and ACTH responses, and CDP prevented these hormonal responses. The drug, however,did not prevent the hormonal responses to novel environmental stimuli. Novel stimuli are known to produce a state of anxiety. Thus the present experiments demonstrate that CDP discriminates between the neural circuits mediating fear- and anxiety-producing stimuli in the rat. Keywords: Chlordiazepoxide; Benzodiazepine; Vasopressin; Oxytocin; ACTH; Fear; Novelty stress; Anxiety 1. Introduction Emotional stress has an impact upon a wide range of hypothalamo-hypophysial neuroendocrine functions. Among other things, emotional stress brings about seri- ous pathological conditions such as developmental retardation, immunosuppression or impairment of reproductive functions as a result of affected neuroen- docrine functions. The endocrine hypothalamus has heavy interconnenctions with the limbic brain areas which are believed to be responsible for inducing neuroendocrine as well as behavioral responses to emo- tional stimuli (Gray, 1987). The neuroendocrine responses can be produced by conditioned fear stimuli (Onaka et al., 1988; Yagi, 1992). When an animal is ex- posed to environmental stimuli which were originally neutral for the animal life but which have been previous- * Corresponding author, Tel.: +81 285 442111, ext. 3129; fax: +81 285 40 6016. ly experienced in spatial or temporal association with painful noxious stimuli such as mild electric footshocks, the environmental stimuli, thereafter, turn out to be the signal which predicts painful stimuli and as a result pro- duce a brain state of fear. In our model, whereas pain itself increases vasopressin secretion by the pituitary, ap- prehension of pain reduces vasopressin secretion (Yagi, 1992). Unconditioned as well as conditioned emotional stimuli also have been shown to suppress vasopressin se- cretion in the rat (Yagi, 1992). When rats received foot- shocks intermittently, for example, the animals began to exhibit ‘freezing behavior’ during intershock intervals and vasopressin secretion was suppressed (Onaka and Yagi, 1988). In contrast, continuously applied shocks enhanced vasopressin secretion (Onaka et al., 1986; Shibuki et al., 1987). In electrophysiological studies, noxious stimuli have been shown to excite hypothalamic magnocellular neurosecretory neurons in the anesthetiz- ed rat (Hamamura et al., 1984; Shibuki and Yagi, 1986). 0168-0102/9W$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI Ol68-0102(95)00988-6