Substance P receptor antagonists in psychiatry: Rationale for development and therapeutic potential

Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Freiburg, Germany.
CNS Drugs (Impact Factor: 5.11). 02/2005; 19(4):275-93.
Source: PubMed


Increasing evidence suggests that substance P (SP) and its receptor (neurokinin [NK]-1 receptor [NK1R]) might play an important role in the modulation of stress-related, affective and/or anxious behaviour. First, SP and NK1R are expressed in brain regions that are involved in stress, fear and affective response (e.g. amygdala, hippocampus, hypothalamus and frontal cortex). Second, the SP content in these areas changes upon application of stressful stimuli. Third, the central administration of SP produces a range of fear-related behaviours. In addition, the SP/NK1R system shows significant spatial overlap with neurotransmitters such as serotonin and noradrenaline (norepinephrine), which are known to be involved in the regulation of stress, mood and anxiety. Therefore, it was hypothesised that blockade of the NK1R might have anxiolytic as well as antidepressant effects. Preclinical studies investigating the effects of genetic or pharmacological NK1R inactivation on animal behaviour in assays relevant to depression and anxiety revealed that the behavioural changes resemble those seen with reference antidepressant or anxiolytic drugs. Furthermore, antagonism or genetic inactivation of the NK1R causes alterations in serotonin and norepinephrine neuronal transmission that are likely to contribute to the antidepressant/anxiolytic activity of NK1R antagonists but that are--at least partially--distinct from those produced by established antidepressant drugs. This underlines the conceivable unique mechanism of action of this new class of compounds. In three independent clinical trials with three different compounds (aprepitant [MK-869], L-759274 and CP-122721), an antidepressant effect of NK1R antagonists could be demonstrated. These results, however, have been challenged by recent failed studies with aprepitant. There are numerous indications from preclinical studies that, in addition to SP and NK1R, other neurokinins and/or neurokinin receptors might also be involved in the modulation of stress-related behaviour and that exclusive blockade of the NK1R might not be sufficient to produce consistent anxiolytic and antidepressant effects. One such candidate is the neurokinin-2 receptor (NK2R), and clinical trials to assess the antidepressant effects of NK2R antagonists are currently underway. Of special interest might also be substances that block more than one receptor type such as NK1/2R antagonists or NK1/2/3R antagonists. These compounds may be more efficacious in antagonising the effects of SP than compounds that only block the NK1R.

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    • "Neurokinin (NK)1 receptors as target for anxiety disorders (Ebner et al., 2009; Griebel and Holmes, 2013; Herpfer and Lieb, 2005; Kwako et al., 2015; Mathew et al., 2011; Tauscher et al., 2010). "
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    ABSTRACT: Psychopharmacology has had some bad publicity lately. Frankly, there have been some major problems along the way in developing new effective drugs for psychiatric disorders. After a prolonged period of high investments but low success rates, big pharmaceutical companies seem to retract their activities in the psychopharmacology field. Yet, the burden of mental disorders is likely to keep on growing in the next decades. In this position paper, we focus on drug development for depression and anxiety disorders, to narrow the scope of the assay. We describe the current situation of the psychopharmacology field, and analyse some of the methods and paradigms that have brought us here, but which should perhaps change to bring us even further. In addition, some of the factors contributing to the current stagnation in psychopharmacology are discussed. Finally, we suggest a number of changes that could lead to a more rational strategy for central nervous system drug development and which may circumvent some of the pitfalls leading to "me too" approaches. Central to the suggested changes, is the notion that mental disorders do not lead to several symptoms, but a network of causally related symptoms convolutes into a mental disorder. We call upon academia to put these changes in the early phases of drug development into effect. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.020 · 2.53 Impact Factor
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    • "Isolation-induced emotional stress and acute stress of foot shock both result in higher levels of SP in specific brain tissues (Mello et al., 2007; Ebner and Singewald, 2006; Hasenöhrl et al., 2000). In addition, the central administration of SP produces a range of fear-related behavior in rats (Herpfer and Lieb, 2005). In cerebrospinal fluid of the patients with depression, SP levels are significantly higher compared to healthy people (Geracioti et al., 2006). "
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    ABSTRACT: Substance P (SP) levels are closely related with the pathogenesis of depression. Recent work has focused on the antidepressive effect of substance P receptor antagonist (SPA), however, its action site and mechanism remain largely unresolved. Our previous results showed that the lateral habenula (LHb) plays a key role in the pathogenesis of depression. The current study investigates the effects of SPA microinjected into the LHb on the behavioral responses of two types of rats that exhibit depression-like behavior. To produce adult rats that exhibit depression-like behavior, rats were either exposed to chronic mild stress (CMS), or clomipramine (CLI), a tricyclic antidepressant, was chronically administered to the rats during the neonatal state of life. The forced-swimming test (FST) was used to evaluate the behavioral responses of the rats. Furthermore, we measured serotonin (5-HT) levels in the dorsal raphe nucleus (DRN) using microdialysis. The FST showed that the immobility time decreased and the climbing time increased after SPA injection into the LHb of depression-like behavior rats. In addition, the 5-HT levels in the DRN increased after SPA was microinjected into the LHb of rats that exhibited depression-like behavior. This study demonstrates that the LHb mediates the antidepressive effect of SPA by increasing the 5-HT levels in the DRN, suggesting that the LHb may be a potential target of antidepressant.
    Brain research bulletin 10/2013; 100. DOI:10.1016/j.brainresbull.2013.10.007 · 2.72 Impact Factor
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    • "Different forms of stress have been shown to affect substance P secretion [23]. Substance P levels were increased after chronic mild stress, an animal model of depression [58]. "
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    ABSTRACT: Early life trauma is an important risk factor for many psychiatric and somatic disorders in adulthood. As a growing body of evidence suggests that brain plasticity is disturbed in affective disorders, we examined the short-term and remote effects of early life stress on different forms of brain plasticity. Mice were subjected to early deprivation by individually separating pups from their dam in the first two weeks after birth. Distinct forms of brain plasticity were assessed in the hippocampus by longitudinal MR volumetry, immunohistochemistry of neurogenesis, and whole-cell patch-clamp measurements of synaptic plasticity. Depression-related behavior was assessed by the forced swimming test in adult animals. Neuropeptides and their receptors were determined by real-time PCR and immunoassay. Early maternal deprivation caused a loss of hippocampal volume, which returned to normal in adulthood. Adult neurogenesis was unaffected by early life stress. Long-term synaptic potentiation, however, was normal immediately after the end of the stress protocol but was impaired in adult animals. In the forced swimming test, adult animals that had been subjected to early life stress showed increased immobility time. Levels of substance P were increased both in young and adult animals after early deprivation. Hippocampal volume was affected by early life stress but recovered in adulthood which corresponded to normal adult neurogenesis. Synaptic plasticity, however, exhibited a delayed impairment. The modulation of synaptic plasticity by early life stress might contribute to affective dysfunction in adulthood.
    PLoS ONE 10/2012; 7(10):e46004. DOI:10.1371/journal.pone.0046004 · 3.23 Impact Factor
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