Substance P: A neuropeptide involved in the psychopathology of anxiety disorders

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Substance P: A neuropeptide involved in the psychopathology of anxiety disorders ⁎

Kanwal Iftikhara,b, , Afshan Siddiqb, Sadia Ghousia Baigb, Sumbul Zehrac a

Hussain Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan Department of Pharmacology, Faculty of Pharmacy, University of Karachi, Karachi 75270, Pakistan c Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan b

A R T I C LE I N FO

A B S T R A C T

Keywords: Substance P Amygdala Anxiety Locus coeruleus Lateral septum Bed nucleus of stria terminalis Periaqueductal gray NK-1 receptor antagonist Hypothalamic pituitary-adrenal axis

Substance P (SP) is the most widely distributed neuropeptide in central nervous system (CNS) where it participates in numerous physiological and pathophysiological processes including stress and anxiety related behaviors. In line with this notion, brain areas that are thought to be involved in anxiety regulation contains SP and its specific NK1 receptors. SP concentration in different brain regions alters with the exposure of stressful stimulus and affected NK1 receptor binding is observed. SP is released in response to a stressor, which produces anxiogenic effects via activation of hypothalamic-pituitary-adrenal (HPA) axis, resulting in the liberation of cortisol. Moreover, SP is also involved in the activation of the sympathetic nervous system via stimulation of locus coeruleus (LC). This sympathetic surge initiates cortisol discharge by activation of HPA axis, representing the indirect anxiogenic effect of SP. Besides the aforementioned regions, SP also has an impact on other brain regions known to be involved in stress and anxiety mechanisms, including amygdala, lateral septum (LS), periaqueductal gray (PAG), ventromedial nucleus of the hypothalamus (VMH), and bed nucleus of stria terminalis (BNST). Thus, SP acts as an important neuromodulator in various brain regions in stress and anxiety response. Consistent with the above statement, SP makes a robust link in the psychopathology of anxiety disorders. As SP concentration is found elevated in stressed conditions, several studies have reported that the pharmacological antagonism or genetic depletion of NK-1 receptors results in the anxiolytic response making them a suitable therapeutic target for the treatment of stress and anxiety related disorders.

1. Introduction “Anxiety is an emotional response or anticipation of future threat and more often associated with muscle tension and vigilance in preparation for future danger and cautious or avoidant behaviors”, the statement is extracted from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). It can also be defined as an emotional phenomenon of nervousness and restlessness experienced by an individual who encounters the identified noxious stimuli causing changes in that individual's behavior and conscious state (American Psychiatric Association, 2013). There is high probability for the occurrence of an anxiety disorder when the individual is intertwined in any stressful situation that may cause them to experience threat and fear. Usually the symptoms of anxiety are resolved spontaneously after the cessation of the stressor but if a person continues to feel stress without any identified stressor then this will lead to the pathogenesis of

anxiety disorder. Anxiety disorders tend to emphasize on exaggerated distress resulting from unidentified potential threat and share the features of constant worries, intrusive thoughts, and cognitive impairment (American Psychiatric Association, 2013;Kessler et al., 2005). 1.1. Anxiety related disorders The dysregulation of neurotransmitters and neuropeptides signaling poses a great risk of developing anxiety disorders (Martin et al., 2009). Environment and genes are also widely acknowledged contributors for the development of stress and anxiety-related behaviors. The anxiety disorders include generalized anxiety disorder (GAD), separation anxiety disorder, panic disorder, social anxiety disorder (SAD) also named as social phobia, agoraphobia and other specific phobias. The diagnosis of Anxiety disorders has been explained in DSM-V in which the anxiety disorders are categorized on the basis of type of objects or situations

⁎ Corresponding author at: lab # 314, Hussain Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. E-mail address: [email protected] (K. Iftikhar).

https://doi.org/10.1016/j.npep.2019.101993 Received 4 April 2019; Received in revised form 7 November 2019; Accepted 10 November 2019 0143-4179/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Kanwal Iftikhar, et al., Neuropeptides, https://doi.org/10.1016/j.npep.2019.101993

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Chrousos, 2002) by various mechanisms which are discussed in detail in the subsequent sections. The purpose of this review is to elaborate the role of SP in the regulation of stress and anxiety. We also enlighted the mechanisms by which SP regulates stress and anxiety in distinct brain regions.

that causes stress and anxiety and analysis of associated beliefs, thoughts, and behaviors (American Psychiatric Association, 2013). DSM-V now categorizes obsessive-compulsive disorder and post-traumatic stress disorder (PTSD) under ‘obsessive-compulsive and related disorders’ and ‘trauma- and stress related disorders’, respectively (American Psychiatric Association, 2013; Kupfer, 2015).

2. Substance P 1.2. Neuropeptides in the regulation of anxiety response

Among all, SP is one of the chief neuropeptides found in nervous system (Burbach, 2011;Klavdieva, 1995). SP is an undeca-neuropeptide, a well-known member of the family of tachykinin peptides encoded by the gene called preprotachykinin. It was initially discovered in 1931 (Euler and Gaddum, 1931; Regoli et al., 1994) but its role of ‘acting as a neurotransmitter’ was found by the year 1950. It is considered a key player in regulating the psychopathological conditions revealed by various experiments. It also acts as a neuromodulator in brain where it co-exists with various classical neurotransmitters such as glutamate, dopamine, GABA, acetylcholine, serotonin and noradrenaline depending upon the region of brain involved (Nicholas et al., 1992; Dean et al., 1993).

Our nervous system hosts an enormous and diverse class of signaling molecules that comprises of neuropeptides as one of the major group, often labeled as neurotransmitters. Neuropeptides are manufactured and released by neurons in response to an appropriate stimulus (Burbach, 2011; Van Den Pol, 2012). They consists of small chains of aminoacids capable of producing long-lasting effects upon their release by neurons. These days, neuropeptides are considered as the modulators of various physiological and pathological processes in the central and peripheral nervous system (Burbach, 2011; Klavdieva, 1995). Recently, brain neuropeptides have received great attention in the field of neuroscience for the modulation and regulation of complex behavioral responses. In CNS, neuropeptides co-exist and co-release with classical neurotransmitters in regulating stress and anxiety response. Specific brain regions and neuropeptides participate in this regulation. The complete understanding of anxiety phenomenon is based on how neuropeptides regulate stress and anxiety response. So, the neuropeptides mediated regulation of stress and anxiety response is a key step in the modulation of anxiety response (Nemeroff, 1996; Ebner et al., 2004). The major neuropeptides involved in the psychopathology of anxiety are neuropeptide Y (NPY), cholecystokinin (CCK), SP, galanin, arginine vasopressin (AVP), oxytocin, and corticotropin-releasing hormone (CRH). NPY is the major neuropeptide known for its orexigenic function (White, 1993) It is highly concentrated in the area of arcuate nucleus of hypothalamus (Stanley et al., 1993) and shows anxiolytic effects via Y1 and Y5 receptors in amygdala (Heilig, 2004;Gehlert, 2004). CCK, a neuropeptide of gut, abundantly found in the brain (Moran and Schwartz, 1994). The anxiogenic effects of CCK are mediated by CCK-B receptors in the basolateral amygdala (Rotzinger and Vaccarino, 2003). Galanin is co-localized with CRH and vasopressin hormone in the regions of paraventricular nucleus (PVN) of hypothalamus (Mazzocchi et al., 1992). It reduces stress-induced HPA-axis activation in rats after intra-cerebral administration (Khoshbouei et al., 2002). Oxytocin influences reproduction, social interaction, and maternal behavior (Gimpl and Fahrenholz, 2001). Studies have reported the anxiolytic effects of oxytocin via ERK ½ activation (Blume et al., 2008; Neumann and Landgraf, 2012). CRH displays anxiogenic effects via activation of HPA-axis as well as increased levels of cortisol in blood stream (Hinz and Hirschelmann, 2000). CRH is also found in the LC, this region is involved in the noradrenergic pathway and hence associated with the regulation of anxiety (De Souza, 1995). AVP participates in the regulation of anxiety via activation of HPAaxis as its release increases in hypothalamic PVN in response to stress [see Table 1] (Neumann and Landgraf, 2012; Beurel and Nemeroff, 2014). SP shows anxiogenic activity (Ebner et al., 2004; Tsigos and

2.1. Receptors for substance p SP is designted as the most abundantly found neurokinin peptide that is extensively distributed all over the nervous system (Quartara and Maggi, 1998; Severini, 2002). Its activity is mediated by G-protein coupled neurokinin receptors i.e. neurokinin 1 (NK1), neurokin 2 (NK2) and neurokinin 3 (NK3) (Regoli et al., 1987). It shows high affinity towards G-protein coupled NK-1 receptor and exhibits various physiological and behavioral functions via NK-1 receptor (Regoli et al., 1987). The surplus quantity of these receptors are found in those areas of the brain that are extremely important for regulating stress mediated affective behaviour and neurochemical responces (Kramer et al., 1998). 2.1.1. Distribution of NK-1 receptors NK-1 receptors are abundantly found in hippocampus, cerebellum, central nucleus of amygdala (CeA), medulla oblongata, LS, the dorsal and ventral striatum, globus pallidus, basolateral nucleus of amygdala (BLA), dorsal raphe nucleus, and numerous cortical zones (Shults et al., 1984; Saffroy et al., 2003). These receptors are also located on the cholinergic neurons of the medial septum, substantia innominate, cholinergic interneurons of the dorsal striatum, ventral pallidum, and nucleus accumbens (Chen et al., 2001; Pickel et al., 2000). The distribution of these receptors in the CNS has been investigated by using autoradiography (Mantyh et al., 1989; Saffroy et al., 2003), immunohistochemistry (Nakaya et al., 1994) and in situ hybridization histochemistry (Caberlotto et al., 2003). Distinct brain regions that are involved in the regulation of stress and anxiety response, are also embedded with NK-1 receptors; for instance, hypothalamus, prefrontal cortex, LS, caudate putamen, LC and PAG (Nakaya et al., 1994; Shults et al., 1984). 2.1.2. Mechanism of substance P signaling SP displays its diverse biological actions by triggering the NK-1

Table 1 Summarized role of neuropeptides in psychopathology of anxiety. Neuropeptides

Role in psychopathology of anxiety

References

Cholecystokinin (CCK) Corticotropic Releasing Hormone (CRH) Galanin Neuropeptide Y (NPY) Oxytocin Substance P (SP) Vasopressin (AVP)

Anxiogenic Anxiogenic Anxiolytic Anxiolytic Anxiolytic Anxiogenic Anxiogenic

Rotzinger and Vaccarino, 2003. Tsigos and Chrousos, 2002;Davis, 1992. Khoshbouei et al., 2002. Heilig, 2004;Gehlert, 2004 Blume et al., 2008;Neumann and Landgraf, 2012 Ebner et al., 2004;Zhao et al., 2009 Neumann and Landgraf, 2012;Beurel and Nemeroff, 2014.

2

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with the aggravated plasma ACTH and corticosterone concentrations in PVN in unstressed rats (Larsen et al., 1993; Jessop et al., 2000). But the central administration of NK1 receptor antagonist did not end up in increasing the levels of ACTH and corticosterone but rather participated in maintenance of the stress hormones (Jessop et al., 2000). The plasma levels of corticosterone in NK1R−/− mice was equally consistent with the concentration of this hormone in wild type mice and its levels were decreased in response to the applied stress (Santarelli et al., 2001). Although these evidences suggest the role of SP as an inhibitory molecule for ACTH and glucocorticoid under basal conditions (Rupniak et al., 1993) but in stress conditions, further studies are required to explore the role of SP [see Table 2].

receptors, a G-protein coupled receptor (GPCR). So, there are two possible mechanisms underlying the actions of SP, mediated by the second messenger cascades. One is generation of cAMP and protein kinase A via stimulation of adenylate cyclase, and the other mechanism is stimulation of phospholipase C resulting in the elevation of free intracellular calcium levels and activation of protein kinase C (Quartara and Maggi, 1997; Nakajima et al., 1992;Garcia-Recio and Gascón, 2015). 2.2. Role of substance P in stress and anxiety response The evidences from various studies demonstrate the role of SP in the modulation of stress and anxiety, but the neuronal pathways adopted by SP in the regulation of stress and anxiety remains to be discovered (Zhao et al., 2009). Earlier, it was found that the endogenous SP releases in response to the stressors in brain areas that are considered to be involved in stress and anxiety mechanisms, for example, amygdala, LC, LS and nucleus accumbens (Ebner et al., 2008). One of the study showed that injecting SP into the dorsal area of PAG, medial nucleus of amygdala (MeA) and caudal pontine reticular nucleus induced anxiety (De Araújo et al., 1999; Ebner et al., 2004).

2.2.3.2. Amygdala. Amygdala is the main component or structure of the limbic system present in brain. This system is recognized for its role in emotions, memory, and survival instincts being considered as the key region in the modulation of emotional, stress and anxiety related behavior. Moreover, it plays a dynamic role in the establishment and retrieval of memories associated with fear and emotions (Phelps, 2004). The critical sub-regions of amygdala responsible for anxiety response are CeA, BLA and MeA (McDonald, 1982). These nuclei are interconnected with each other, the neuronal fibers from MeA and BLA are innervated as input projections into the CeA which is the main output zone of amygdala. The destination of CeA pathway leads to PVN of hypothalamus, crucial region in the neural circuitry of stress and anxiety response (Tsubouchi et al., 2007). Once the CeA is stimulated, it results in the activation of several neurocircuits involved in anxiety and stress axis which is also termed as the HPA axis (Martin et al., 2009). The presence of SP and its NK-1 receptors in the distinct sub-regions of amygdala has been widely reported. Sp gets activated once it is released in numerous areas of amygdala. In experimental model of immobilization stress, the high expression of this neuropeptide has been found in the MeA while the CeA contains lower expression (Ribeiro-da-Silva and Hökfelt, 2000; Sosulina et al., 2015., Ebner et al., 2004). The microinjected administration of NK-1 receptor antagonist into the MeA resulted in the cessation of the effects mediated by SP and produced anxiolysis, but SP did not produce any anxiolytic effect when administerd to an unstressed animal. After the administration of microinjected SP in the MeA, the NK-1 receptor antagonist showed significant anxiolytic effects (Ebner et al., 2004). According to previous studies, the ablation of MeA results in the anxiolytic response (Blanchard and Blanchard, 1972). On the contrary, the anxiogenic effect was produced when MeA was electrically stimulated (Adamec and Morgan, 1994; Adamec and Shallow, 2000). Likewise, GR 82334 (SP receptor antagonist) has been shown to disrupt fear-potentiated startle when administered into sub-regions of amygdala such as BLA and MeA (Zhao et al., 2009). Maternal separation-induced vocalizations in guinea-pig pups may possibly be blocked by the injection of NK-1 receptor antagonist (L760735) into the BLA (Boyce et al., 2001). In contrast, SP receptor antagonism did not modulate stress-induced expression of c-fos in the regions of BLA and MeA of rats amygdala under low stressed condition of EPM exposure (Ebner et al., 2008). The lesions in rats amygdala has been found to be linked with the attenuation of autonomic and neuroendocrine effects in response to numerous stressors (Feldman et al., 1994; Kopchia et al., 1992). In continuation to this, lesions in CeA produced very similar effects as observed in the lesions of whole amygdala, indicating that this nucleus has a major role in the regulation of stress and anxiety responses (Feldman et al., 1994; Kopchia et al., 1992).

2.2.1. Immuno-reactivity against SP High levels of SP immuno-reactivity that has been recognized in brain regions are known to be linked in the regulation of stress and anxiety response. These regions include amygdala, hypothalamus, hippocampus, nucleus accumbens, caudate putamen, LS, cingulate cortex, PAG, dorsal raphe nucleus, parabrachial nuclei, and nucleus of the tractus solitaries (Ebner and Singewald, 2006; Ebner et al., 2004). 2.2.2. CSF levels of SP Significantly elevated levels of SP are seen in cerebrospinal fluid of depressed patients, because anxiety has also been observed in these patients. Moreover, in patients of post-traumatic stress disorder, the levels of SP were found elevated due to exposure of traumatic stimulus (Geracioti Jr et al., 2006). 2.2.3. Role of substance P in brain regions involved in HPA axis regulation 2.2.3.1. HPA axis in anxiety regulation. HPA axis is the prime system implicated in the modulation of physiological and behavioral patterns in response to the physiological and psychological stressors (Sapolsky et al., 2000). It is a complex interactive system, composed of hypothalamus, pituitary gland, and adrenal gland. The main component of this system which regulates stress and anxiety is cortisol (Chrousos, 1992). Cortisol, a stress hormone that is released from adrenal gland in response to pituitary-derived hormone known as adrenocorticotropic hormone (ACTH). The release of ACTH is regulated by hypothalamus via corticotropin releasing hormone (CRH) (Hinz and Hirschelmann, 2000). The negative feed-back mechanism is regulated by cortisol itself at the level of anterior pituitary and hypothalamus (Evans et al., 2013; Hinz and Hirschelmann, 2000). This results in cessation of CRH and ACTH release and ultimately causes the termination of cortisol discharge, hence stress and anxiety response [see Fig. 1] (Tsigos and Chrousos, 2002; Davis, 1992). The supporting evidence has presented SP as a regulator of cortisol secretion via hypothalamus and adrenal gland. The presence of SP and NK1 receptors in various hypothalamic nuclei designate SP as a central molecule in regulating HPA axis (Larsen, 1992; Mantyh et al., 1989; Quartara and Maggi, 1998). By far, the HPA axis regulatory potential of SP is well investigated in basal conditions but less well explored in stressed conditions. The intracerebroventricular injection of SP in rats reported to inhibit the ACTH plasma levels in basal conditions (Chowdrey et al., 1990). This action was thought to be mediated through the inhibition of CRH from hypothalamus (Faria et al., 1991). Moreover, the NK1 receptor antagonist administration has been linked

2.2.3.3. Paraventricular nucleus (PVN) of hypothalamus. PVN of the hypothalamus is embedded with NK-1 receptors and highly innervated with neuronal projections containing SP which stimulates the synthesis of AVP (Jessop et al., 2000). It causes the release of CRH and synthesizes AVP when it is exposed to a stressor. After which, CRH 3

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Fig. 1. Schematic representation of HPA axis regulation. Environmental stress stimulates hypothalamus to secrete CRH, which prompts the release of ACTH into the blood stream via activation of pituitary gland. As a result of which adrenal gland is activated and releases cortisol hormone. Cortisol controls its own release through negative feedback mechanism by inhibiting CRH and ACTH from hypothalamus and pituitary gland, respectively. Abbreviations: CRH: Corticotropic Releasing Hormone, ACTH: Adrenocorticotropic Hormone, HPA: Hypothalamic pituitary-adrenal.

Table 2 Summary of role of substance P in the regulation of anxiety. Brain region

Sub-region

Substance P expression

Anxiety response

References

CeA

++

Emson et al., 1978;Roberts et al., 1982

MeA

+++

Roberts et al., 1982;Ribeiro-da-Silva and Hökfelt, 2000;Ebner et al., 2004

BLA

+

Boyce et al., 2001,Emson et al., 1978

Pons

LC

+++

Cheeseman et al., 1983;Ebner and Singewald, 2007

Hypothalamus

PVN

+++

Larsen, 1992;Ebner et al., 2008

Amygdala

VMH

++

Basal forebrain Septum

BNST LS

++ +++

Midbrain

PAG

++

Dornan et al., 1990;Petrovich et al., 2001;Zhao et al., 2009. −

Emson et al., 1978;Mayer and MacLeod, 1979;Gray and Magnuson, 1992;Ebner et al., 2008 Gavioli et al., 2002;Aguiar and Brandão, 1996;de Araújo et al., 1998. Dornan et al., 1990; Aguiar and Brandao,1996

Abbreviations: BLA: Basolateral Nucleus of Amygdala, CeA: Central Nucleus of Amygdala, MeA: Medial Nucleus of Amygdala, LC: Locus Coeruleus, PVN: Paraventricular Nucleus, VMH: Ventromedial Nucleus of Hypothalamus, BNST: Bed Nucleus of the Stria Terminalis, LS: Lateral Septum; PAG: Periaqueductal Gray. symbol refers to increase. +++ means ‘high’. ++ means ‘moderate’. + means ‘low’. – No response.

of NE, which in turn displays several stress-related symptoms by activating HPA axis. SP co-exists with NE in LC (Shults et al., 1984; Ziegler et al., 1999). SP excites LC via activation of NK-1 receptors present in this region and triggers noradrenergic discharge (Cheeseman et al., 1983). Sympathetic nervous system in turns causes the release of CRH and induces the stress related behavior. SP acts as an activator of HPA axis at the level of LC. Whereas, the SP effects are attenuated with the use of NK1 receptor antagonists (WARD et al., 1976). Furthermore, the noradrenergic projections from the PVN of hypothalamus innervate in the spinal cord and participate in the activation of autonomic nervous system (Holstege, 1987; Buijs et al., 2003) [see Fig. 2].

induces ACTH release from the activation of anterior pituatory gland (Tsigos and Chrousos, 2002; Davis, 1992). AVP then carries out the dispersion of ACTH into the circulatory system, which is then detected by the adrenal gland and hence the accumulation of cortisol in the blood stream is observed (Beurel and Nemeroff, 2014). It is critical for stress and anxiety mediated endocrine and behavioral responses (Vaughan et al., 1995). The EPM test was performed in the PVN of the hypothalamus using L822429 (SP receptor antagonist), which demonstrated the anxiolytic effect via antagonizing SP (Ebner et al., 2008). 2.2.3.4. Locus coeruleus (LC). The pontine nucleus LC is located in brain stem, which is rich in the neuronal projections of NE. It is activated in response to stress and then increases the release of NE, which is responsible for ‘Fight and Flight’ response (Atzori et al., 2016). LC shows a vital role in controlling autonomic functions by increasing the sympathetic activity with a concomitant reduction in parasympathetic activity (Samuels and Szabadi, 2008). The LC and NE system consists of a network that is projected throughout the nervous system and involved in the diverse range of behavioral actions including stress and anxiety like behavior (Berridge and Waterhouse, 2003). The efferent noradrenergic projections from LC are innervated into the BLA and promote anxiety response (McCall et al., 2017; Berridge and Waterhouse, 2003; Robertson et al., 2013). LC has been found to be involved in the stress regulation via release

2.2.3.5. Substance P and distinct brain regions. Apart from the role of SP in aforementioned brain regions, it also acts on other distinct brain areas that are implicated in the mechanisms of stress and anxiety regulation. 2.2.3.5.1. Lateral septum (LS). LS has been found to be involved in the regulation of numerous emotional and cognition processes including learning, memory, stress and anxiety responses. Evidences show that the LS is responsible for the modulation of the autonomic responses during stress and threatening situations (Sheehan et al., 2004; Kubo et al., 2002) and is innervated by massive fibers containing SP, known for inducing the anxiogenic response via NK-1 receptors (Szeidemann et al., 1995). Moreover, LS is also implicated in the regulation of the behavioral and neuroendocrine associated stress. For 4

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Fig. 2. Schematic representation of role of substance P in stress and anxiety. Stress is a contributing factor for the release of SP in the LC (nucleus of pons) and sub-regions of amygdala. In LC, SP is co-localized with NE, carrying out the activation of BLA (sub-region of amygdala) and PVN of hypothalamus as well. The activated PVN in turn causes the release of CRH and AVP. Both (CRH and AVP) are sensed by pituitary gland causing the release of ACTH. Then ACTH gets involved in the regulation of the endocrine response. Moreover, noradrenergic projections from PVN of hypothalamus innervate into the spinal cord and participate in the generation of autonomic response. Abbreviations: BLA: Basolateral Nucleus of Amygdala, CeA: Central Nucleus of Amygdala, MeA: Medial Nucleus of Amygdala, LC: Locus Coeruleus, NE: Norepinephrine, SP: Substance P, PVN: Para-ventricular Nucleus, AVP: Arginine Vasopressin, CRH: Corticotropic Releasing Hormone, ACTH: Adrenocorticotropic Hormone.

nuclei of BNST (Walter et al., 1991; Mayer and MacLeod, 1979). The cFos expression analysis was used as one of the parameter to check the NK1 receptor antagonistic effects in the region of BNST, and it was found that antagonizing NK-1 receptor has no influence on the stressinduced c-Fos expression. This indicated that inhibition of NK-1 receptor mediated anxiolysis is regardless of the c-Fos expression in this brain region (Ebner et al., 2008). 2.2.3.5.3. Periaqueductal gray (PAG). PAG, the gray matter situated around the cerebral aqueduct in the midbrain (Keay and Bandler, 2015) has widespread role in the modulation of stress and anxiety. It receives dense neuronal projections from VMH, in which approximately 30% projections are associated with the SP neurotransmission (Dornan et al., 1990). To analyze the contribution of PAG in anxiety response, SP was injected locally into the area of dorsal PAG, after which the anxiogenic and aversive effects were observed when tested through the EPM test (Aguiar and Brandao,1996). Whereas, the local infusions of SP antagonist in the PAG demonstrated the attenuation of fear potention-shock. The aforementioned observations establish the evidences for the involvement of SP and NK1 receptors in inducing anxiolytic effects (Zhao et al., 2009). 2.2.3.5.4. Ventromedial nucleus of hypothalamus (VMH). VMH also has a role in the modulation of stress and anxiety response (de Oliveira et al., 1997; Dielenberg et al., 2001; Han et al., 1996). It receives SP projections that are originating from MeA and making their way to PAG (Dornan et al., 1990; Petrovich et al., 2001). NK-1 receptor antagonism in VMH results in the diminution of anxiety induced responses which indicates that SP is involved in initiation of anxiety responses (Zhao et al., 2009).

the comparative analysis of SP anxiogenic response in different brain regions, SP was directly injected into the LS of rats and the effects were evaluated using elevated plus maze (EPM) test. The end result of the experiment showed that LS produced more pronounced anxiogenic response than other brain areas such as amygdala or dorsal PAG. Both regions are famous for producing the aversive response (Aguiar and Brandão, 1996; de Araújo et al., 1998). To demonstrate the NK-1 receptors mediated anxiogenic effects in the region of LS, NK-1 receptor antagonist was injected which showed anxiolytic effects upon the administration of exogenous SP (Gavioli et al., 2002). SP receptor antagonism has been observed by injecting L822429 in the EPM test in the region of LS (Ebner et al., 2008). The ablation of LS causes the increased plasma levels of ACTH and corticosterone in rats, which are responsible for long-term activation of HPA axis. The above observations establish the role of LS in the negative feedback regulation of the HPA axis, but the exact mechanism is still unclear (Singewald et al., 2011; Dobrakovová et al., 1982). 2.2.3.5.2. Bed nucleus of the stria terminalis (BNST). BNST serves as the key regulator in the control of behavioral and physiological activities via actions of various classical neurotransmitters in connection with other limbic structures like amygdala, hippocampus, hypothalamus, and brain stem (Dong and Swanson, 2004; Crestani et al., 2013). It is an important limbic forebrain component, also known as extended amygdala, plays significant role in the regulation of behavioral, neuroendocrine, and autonomic responses. This structure is an important area of interest because it projects into a set of targeted zones that are thought to be involved in the mediation of specific signs and symptoms related to anxiety which acts in co-ordination to produce an integrated anxiety response (Walker et al., 2003). BNST is intensely innervated with BLA neuronal projections, which further project into the brainstem (Hitchcock and Davis, 1991). These neuronal projections contain different neuropeptides especially, SP (Gray and Magnuson, 1992). SP takes part in the excitation of BNST (Mayer and MacLeod, 1979). Numerous radioimmunoassay and immuno-histochemichemistry techniques has been utilized to detect the presence of SP in sub-

2.3. Effects of antagonizing substance P and NK-1 receptors In animal studies, after central administration, SP produces various cardiovascular and behavioral responses similar to the stress related behavior in rats (Culman and Unger, 1995). These cardiovascular and behavioral responses can be terminated after the administration of NK5

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1 receptor antagonists (Culman et al., 1997). Reduced expression of stress induced c-Fos (marker of neuronal activity) is associated with SP receptor antagonism that has been shown in the areas of LS and PVN of hypothalamus (Ebner et al., 2008). The testing of NK-1 receptor antagonists has shown diminished neuronal excitation in vital brain regions and are reported to be involved in the stress pathways in numerous animal behavioral studies including social interaction test, EPM test, and transient maternal separation (Kramer et al., 1998; Rupniak et al., 2003). While the genetic depletion of NK-1 receptors in animal models attenuates the stress and anxiety related responses (Santarelli et al., 2002). Several studies have been carried out in patients of anxiety disorders to evaluate the efficacy of selective NK1 receptor antagonists. Whereas, some clinical studies showed negative results, for instance, NK-1 receptor antagonist L-759274 did not produce effective results in the treatment of GAD (Michelson et al., 2013). Likewise GR205171, another selective NK-1 receptor antagonist, failed to display efficacy in clinical trials in chronic PTSD patients (Mathew et al., 2011). The development of SP receptor antagonist LY686017 could not be considered effective in clinical trials in patients of SAD (Tauscher et al., 2010). With some exceptions, most of the investigations regarding SP signaling by NK-1 receptor demonstrate its role in stress and anxiety related behavior. So far, research has suggested NK-1 receptor antagonism as a possible mechanism for anxiolytic effects produced by drugs (McCabe et al., 2009). In clinical trials, NK-1 receptor antagonists display antidepressant or anxiolytic effects. They are thought to be well tolerated as their side effects profile lies in the safe range in pre-clinical trials (Kramer et al., 1998; Rupniak and Kramer, 1999). So, SP and its NK-1 receptors have become the proposed target for the development of novel anxiolytic drugs (Zhao et al., 2009). However, some SP receptor antagonists in clinical trials did not meet the desired efficacy endpoint. Therefore, further investigations are needed in the field of psychopathology of anxiety and anxiety related disorders to find out better and advanced therapeutic strategies for the prevention and treatment of these disorders, as the current treatment has limited efficacy and tolerability (Ebner et al., 2008).

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