Substance P system as therapeutic target in stress-related disorders

Antagonists of the substance P (SP) preferring neurokinin-1 (NK1) receptor have been shown to relieve the symptoms of depression and anxiety in preliminary clinical trials, offering a radical new approach to the management of stress-related disorders. These findings together with the observation that SP and its receptors is highly expressed in areas of the brain that have been implicated in mechanisms of stress, raise the exciting possibilities that there may be changes in the presynaptic SP transmission and/or expression of NK1 receptors in animals exposed to aversive stress, and that existing antidepressant drugs used in the treatment of stress-related disorders such as depression and anxiety mediate their therapeutic effect through decreasing the activity of brain SP pathways. The aim of the proposed project is twofold. Firstly to determine effects of stress on extracellular SP and SP receptor expression in an acute stress paradigm and an animal model based on stressful early life events. Stress early in life appears to have a profound impact on the shaping of the individual`s responsiveness and behavioural strategies later in life, both in animal and man and can predispose an individual to develop psychopathologies including depression and anxiety disorders. Secondly, to investigate the effects of acute and chronic antidepressant drug treatment on extracellular SP responses and expression of NK1 receptors with the specific hypothesis that there will be a decrease in the expression of these receptors correlating with the delayed onset of the therapeutic effect. We will use in vivo microdialysis/push-pull superfusion combined with a sensitive RIA to monitor extracellular SP, as well as a combination of in situ hybridisation, receptor autoradiography and immunocytochemistry to label NK1 receptor expression and binding in the rat brain. Our experiments will tell us how SP binding sites and/or extracellular release are influenced by stress and antidepressant treatment and this information will contribute to the evidence and understanding of the role of SP as a therapeutic target in stress- related disorders.

Stress-associated disorders such as depression and anxiety disorders which elicit a high degree of individual suffering are becoming leading causes of morbidity according to the World Health Organization and are expected to contribute dramatically to rises in economic burden for societies. Disadvantages of the existing drugs for treatment of these disorders include poor efficacy and the induction of adverse effects. Therefore it is important to search for new compounds possessing anxiolytic and/or antidepressant potential. Although antagonists of the substance P (SP) preferring neurokinin-1 (NK1) receptor have been shown to relieve the symptoms of depression and anxiety in preliminary clinical trials, offering a new approach to the management of stress-related disorders, the precise mechanisms mediating such effects are not clear. In this project we demonstrated for the first time that even mild emotional stressors triggers the release of the neuropeptid transmitter SP in specific limbic forebrain brain areas. Within the amygdala, the released SP was shown to elicit enhanced anxiety, which can be blocked by NK1 receptor antagonists, identifying the amygdala as a a critical brain area for a functional significant involvement of SP transmission in enhanced anxiety responses induced by stressors. We further observed that emotional stressors trigger a facilitated limbic SP outflow in animals with anhanced anxiety- and depression-related phenotype, as compared to low anxietydepression animals, indicating a hyperactive SP system in individuals with enhanced anxiety/depression. Finally, we demonstrated that markers of SP/NK1 receptor transmission are not influenced by a variety of classical antidepressant drugs, even if they are administered for long periods, suggesting that existing drugs do not act via the SP/NK1 receptor system and that NK1 receptor blockade indeed represents a radical new treatment principle.