The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

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Increasing evidence implicates the substance P (SP)͞neurokinin-1 receptor system in anxiety and depression. However, it is not known whether emotional stimulation alters endogenous extracellular SP levels in brain areas important for processing of anxiety and mood, a prerequisite for a contribution of this neuropeptide system in modulating these behaviors. Therefore, we examined in rats whether the release of SP is sensitive to emotional stressors in distinct subregions of the amygdala, a key area in processing of emotions. By using in vivo micropush-pull superfusion and microdialysis techniques, we found a pronounced and long-lasting increase (150%) in SP release in the medial nucleus of the amygdala (MeA), but not in the central nucleus of the amygdala, in response to immobilization stress. SP release in the MeA was transiently enhanced (40%) in response to elevated platform exposure, which is regarded as a mild emotional stressor. T he neuropeptide substance P (SP) and its preferred neurokinin-1 (NK 1 ) receptor have been proposed as possible targets for new antidepressant and anxiolytic therapies. Several preclinical studies have demonstrated a range of anxiety-related behaviors and defensive cardiovascular changes in response to central administration of SP agonists (1-6). Conversely, NK 1 receptor antagonists have been shown to produce anxiolytic-like effects after intracerebroventricular (4) or systemic administration (5,7,8). In addition, mice with selective deletion of the gene encoding the NK 1 receptor or the peptide itself also showed decreased anxiety-related behaviors (9-11). Thus, these findings suggest that SP acting as neurotransmitter͞neuromodulator (for review, see ref. 12) may be of relevance in the regulation of emotional states including anxiety-related behavior. Confirmation of this proposal was obtained by using a highly selective NK 1 receptor antagonist MK-0869, which relieved the symptoms of depression and anxiety in patients with major depressive disorder and a significant degree of anxiety (5). Although it has been shown that emotional and physical stressors modulate SP tissue levels or SP immunoreactivity in brain areas that are implicated in fear and anxiety (13-17), a change in extracellular SP levels, which is a direct and dynamic marker of SP neurotransmission, cannot be reliably predicted from these studies. Hence, at present it is not clear whether emotional stimuli actually do alter the in vivo release of SP, which is a prerequisite for a contribution of this neuropeptide system in modulating emotional states. Since stressful life experiences are thought to play a role in precipitating episodes of neuropsychiatric disorders including anxiety and depression (18,19), and laboratory stressors can produce behavioral and physiological changes resembling these mental disorders (20), it is of particular interest to examine the effect of emotional stressors on SP neurotransmission.The amygdala is critical for the processing of emotions including fear and anxiety (21, 22), and SP-cont...