Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function

Abstract

Alterations in serotonin (5-hydroxytriptamine, 5-HT), norepinephrine, and ␥-aminobutyric acid have been linked to the pathophysiology of anxiety and depression, and medications that modulate these neurotransmitters are widely used to treat mood disorders. Recently, the neuropeptide substance P (SP) and its receptor, the neurokinin 1 receptor (NK1R), have been proposed as possible targets for new antidepressant and anxiolytic therapies. However, animal and human studies have so far failed to provide a clear consensus on the role of SP in the modulation of emotional states. Here we show that both genetic disruption and acute pharmacological blockade of the NK1R in mice result in a marked reduction of anxiety and stress-related responses. These behavioral changes are paralleled by an increase in the firing rate of 5-HT neurons in the dorsal raphe nucleus, a major source of serotonergic input to the forebrain. NK1R disruption also results in a selective desensitization of 5-HT1A inhibitory autoreceptors, which resembles the effect of sustained antidepressant treatment. Together these results indicate that the SP system powerfully modulates anxiety and suggest that this effect is at least in part mediated by changes in the 5-HT system. S ubstance P (SP) and its receptor, the neurokinin 1 receptor (NK1R), participate in the neural processing of a range of noxious and stressful stimuli. In the spinal cord, SP contributes to nociception, and disruption of the NK1R decreases or ablates the late-phase response to peripheral injury (1-3). In the brainstem, SP modulates emesis, which can be decreased in animals and humans by NK1R antagonists (4). Peripheral inflammation in a variety of structures including gut, joints, and cutaneous tissue also partly depends on SP release and NK1R activation (5).Recently, SP also has been implicated in the modulation of stress responses, mood, and anxiety, but its exact role remains unclear. Localized administration of SP in the central nervous system may produce anxiogenic or anxiolytic responses, depending on the animal species and location of injection (6-8). Conflicting results also have been obtained from the use of NK1R antagonists, and issues of drug access and species specificity have further clouded the roles of SP in stress-related behaviors (9). Interestingly, in humans, an NK1R antagonist has been reported to be an effective antidepressant and anxiolytic, although this result has not been replicated (10). It has been proposed that the antidepressant activity of NK1R antagonism may be independent of serotonergic and noradrenergic pathways and thus may represent an alternative therapeutic strategy for the treatment of mood disorders (10).In the present study we used genetic disruption and pharmacological blockade of the NK1R to examine the roles of SP in the generation of anxiety-related behaviors in mice. Genetic disruption of NK1R function markedly reduced anxiety-related behaviors in the elevated plus maze (EPM), novelty suppressed feeding (NSF), and maternal separation paradi...

Behavioral and Pharmacological Validation of the Gerbil Forced-Swim Test: Effects of Neurokinin-1 Receptor Antagonists

“…Moreover, NK1 antagonists (eg MK-869, L-733060) have been shown preclinically to exhibit anxiolytic-like effects in gerbils in several different animal models including the elevated plus maze, fear conditioning, social interaction, and shock-induced foot tapping (Ballard et al, 2001;File et al, 2001;Gentsch et al, 2002;Rupniak et al, 2003;Varty et al, 2002b); and more recently, antidepressant-like effects in the tail suspension test (Varty et al, 2003). Consistent with these reports, genetic deletion of the NK1 receptor in mice resulted in anxiolytic and antidepressant effects in the elevated plus maze, novelty suppressed feeding model and the FST (Santarelli et al, 2001;Rupniak et al, 2001), providing additional support for the hypothesis that the NK1 receptor may be an important target for antidepressant/anxiolytic therapy.…”

Advances in the treatment of anxiety: Targeting glutamate

“…Importantly, we do not know many of the details about the frequently comorbid, intimate, and possibly related nature of de-pression and anxiety, either phenomenologically or psychobiologically. [27][28][29] …”

“…Many new theories and compounds have been proposed, including those based on 5-HT 1A agonists 10 and other specific serotonin-based compounds, 30,31 NK-1 antagonists and other Substance P-related species, 28 neuropeptides (NPY, NPS), 29,32 more specific GABA A agonists, 33,34 CRF antagonists, 35,36 glutamate modulators, and ␤-blockers, 37,38 among others.…”

The Gerbil Elevated Plus-Maze I Behavioral Characterization and Pharmacological Validation

“…Examples are NKP-608, which has been shown to have anxiolytic-like and antidepressant-like properties in social interaction and chronic mild stress models (File 2000;Papp et al 2000;Vassout et al 2000), and FK-888 and WIN51,708, which produced anxiolytic-like effects in mouse and rat elevated plus-mazes, respectively (Teixeira et al 1996;Nikolaus et al 1999). Furthermore, research using NK1 receptor knockout mice have shown that the deletion of the NK1 receptor results in a profile of reduced anxietylike behaviors in a number of models including elevated plus-maze, novelty suppressed feeding, and maternal separation-induced vocalizations (Rupniak et al 2000;Santarelli et al 2001). However, in general, preclinical research with NK1 antagonists has, by pharmacological necessity, focused on species such as guinea pig and gerbil.…”