Do Substance P and the NK1 Receptor have a Role in Depression and Anxiety?

Abstract

Research on Substance P (SP) has, until recently, focused on its role in pain and inflammation. However, a report that NK(1) receptor antagonists have utility in the treatment of depression has stimulated research into the function of SP and the NK(1)receptor in anxiety and depression. The distribution of SP and the NK(1) receptor in brain areas implicated in anxiety and depression is initially reviewed. This is followed by evaluation of the preclinical data obtained for SP and NK(1) receptor antagonists in behavioral models of depression as well as the phenotype of genetically modified animals lacking the genes encoding for the NK(1) receptor or for SP. The weight of the evidence supports antidepressant and anxiolytic activity of NK(1) receptor antagonists. However, many of the studies do not control for nonspecific effects of the compounds, and when enantiomers that lack activity at the NK(1) receptor are included, the results, in some cases, suggest that blockade of NK(1) receptors does not account for the observed behavioral activity. Finally, clinical studies in depressed patients assessing SP levels in plasma and cerebrospinal fluid as well as the effect of NK(1) receptor antagonists are reviewed. The clinical studies are a mixture of positive, failed and negative studies on the antidepressant activity of NK(1) receptor antagonists, not unlike the early clinical results obtained with selective serotonin reuptake inhibitors.

Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

“…It seems that the observed effect is regionally very discrete, since no facilitatory effects of NK1R antagonist on 5-HT efflux could be demonstrated in other 5-HT target areas such as the frontal cortex and hippocampus (Froger et al, 2001;Millan et al, 2001;Lejeune et al, 2002;Zocchi et al, 2003;Guiard et al, 2004Guiard et al, , 2006. The now observed action may be of relevance for the clinical evidence that NK1R antagonists exert therapeutic effects also after acute or short-time treatment (McLean, 2005). Furthermore, by combining SSRIs with a NK1R antagonist, a faster onset in addition to the observed potentiation of neurochemical (Lejeune et al, 2003;Guiard et al, 2004Guiard et al, , 2005Guiard et al, , 2006 and behavioral (Chenu et al, 2006) effects of SSRIs may be expected, thus improving the existing therapeutic possibilities to modulate affective and behavioral responses to stress in stress-related disorders (Millan, 2006).…”

“…These findings could be confirmed by studies on mice with genetic disruption of NK1R function or of the peptide itself as these animals exhibit less anxiety-and depression-related behaviors in various behavioral tasks (Rupniak et al, 2001;Santarelli et al, 2001;Bilkei-Gorzo et al, 2002). On the basis of these findings, SP/NK1R pathways have been proposed to be involved in the etiopathology of a number of stressrelated diseases such as depression and anxiety disorders McLean, 2005). Confirmation of this proposal was obtained by clinical findings that selective NK1R antagonists have antidepressant as well as anxiolytic efficacy in patients with major depressive disorder and with moderately high anxiety levels (Kramer et al, 1998(Kramer et al, , 2004Furmark et al, 2005).…”

Roles of the hippocampal formation in pain information processing

“…NK-1 receptors and BDNF have previously been implicated in nociceptioninduced spinal central sensitization [185][186][187] ; however, the effects of painful stimuli on the expression of these two genes in the mood/affect and emotion-processing brain regions have not yet been characterized. In addition, their potential involvement in the neurobiology of stress-related mood disorders has also been demonstrated [188][189][190] , suggesting that the effects of pain and stress may converge and activate similar neuronal pathways in the higher brain centers. Moreover, overwhelming evidence has been presented to support that stress can have profound effects on the hippocampus, a cen-tral component of the limbic system involved in the regulation of mood or affect, including alteration in hippocampal structure [191] , neural genesis [192] , and synaptic plasticity [193,194] and so on.…”

Measurement of Plasma-Derived Substance P: Biological, Methodological, and Statistical Considerations

“…SP was subsequently characterized as a neurotransmitter (31,32,33). Elevation of serum or plasma SP and/or its cell-associated receptor (NK-1R) has been observed by our laboratory and others in a variety of disorders, including inflammatory bowel disease (25); sickle cell crisis (29); depression and anxiety (4,15,20,28,37); rheumatological diseases (1,26); and infectious diseases, such as AIDS and respiratory syncytial virus (12,39), as well as in cancer (34,38). More recently, the role of SP in neurotransmission has been expanded to include a major role in the regulation of the immune response (27, 40; reviewed by Ho and Douglas [17]).…”