Tachykinin receptors as therapeutic targets in stress-related disorders.

The first report demonstrating the therapeutic efficacy of an orally applied neurokinin-1 (NK1) receptor antagonist in depression was published 10 years ago. Although there were difficulties to reproduce this particular finding, a huge amount of data has been published since this time, supporting the potential therapeutic value of various tachykinin ligands as promising novel tools for the management of stress-related disorders including anxiety disorders, schizophrenia and depression. The present review summarizes evidence derived from anatomical, neurochemical, pharmacological and behavioral studies demonstrating the localization of tachykinin neuropeptides including substance P (SP), neurokinin A, neurokinin B and their receptors (NK1, NK2, NK3) in brain areas known to be implicated in stress-mechanisms, mood/anxiety regulation and emotion-processing; their role as neurotransmitters and/or neuromodulators within these structures and their interactions with other neurotransmitter systems including dopamine, noradrenaline and serotonin (5-hydroxytryptamine, 5-HT). Finally, there is clear functional evidence from animal and human studies that interference with tachykinin transmission can modulate emotional behavior. Based on these findings and on evidence of upregulated tachykinin transmission in individuals suffering from stress-related disorders, several diverse tachykinin receptor antagonists, as well as compounds with combined antagonist profile have been developed and are currently under clinical investigation revealing evidence for anxiolytic, antidepressant and antipsychotic efficacy, seemingly characterized by a low side effect profile. However, substantial work remains to be done to clarify the precise mechanism of action of these compounds, as well as the potential of combining them with established and experimental therapies in order to boost efficacy.

Neuroendocrine and behavioral response to social confrontation: residents versus intruders, active versus passive coping styles.

We investigated in the present study the neuroendocrine correlates in intruder and resident rats of a social confrontation. Adult male Wistar rats (intruders) were introduced into the home cage of a well-trained resident to induce characteristic agonistic interactions including physical attacks prior to separation by a wire mesh. The hypothalamic-pituitary-adrenal (HPA) axis activity and the intrahypothalamic release of arginine vasopressin (AVP) were monitored via chronically implanted jugular venous catheters and microdialysis probes aimed at the hypothalamic paraventricular nucleus (PVN), respectively. Based on the behavioral data collected during the 30-min confrontation, intruders and residents were additionally classified into two different subgroups: intruders which showed almost no freezing behavior (active copers) versus those showing pronounced freezing behavior (passive copers) and residents which were either predominantly aggressive or non-aggressive. The neuroendocrine data show that social confrontation caused a significantly increased secretion of the adrenocorticotropic hormone (ACTH) into plasma in both intruder subgroups, independently of their coping strategy. In contrast, plasma ACTH in residents was increased in response to social confrontation in non-aggressive animals only, whereas aggressive residents failed to mount an ACTH response. Interestingly, plasma AVP decreased in response to social confrontation in active intruders. As measured in microdialysates, the two groups of residents and passive intruders failed to show significant changes of intra-PVN release of AVP. In contrast, an increased release of this neuropeptide within the PVN could be monitored for active intruders. The data of the present study suggest that the different interpretation of an aversive encounter results in differences in the neuroendocrine response and intrahypothalamic vasopressinergic signaling in intruders versus residents.