Substance P NKi receptor antagonists

Panic Away

Panic Away End Anxiety and Panic Attacks

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Nadia M.J. Rupniak*

Clinical Neuroscience, Merck Research Laboratories, BL2-5, West Point, PA 19486, USA

Abstract: Stress responses involve changes in hormone secretion, respiration, cardiovascular, and gastrointestinal function, and behavior in order to prepare an organism to respond to perceived or actual danger. They are orchestrated by neural circuits including the amygdala, brainstem, and hypothalamus. Substance P is a peptide neurotransmitter that is expressed within these neural pathways and can activate various physiological systems in a manner consistent with an integrated stress response. Preliminary clinical trials using highly selective substance P (NK) receptor) antagonists (SPAs) have shown promising findings in patients with stress-related disorders (major depression, irritable bowel syndrome and social phobia). These observations suggest that substance P in the brain is involved in the pathophysiology of stress-related disorders and that SPAs may provide a novel approach to pharmacotherapy.

Stress disorders: pathophysiology and clinical manifestations

Stress responses are triggered when the brain interprets psychological or environmental stimuli as being dangerous or threatening. Responses to stress involve activation of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system in order to deal with the threat. These are part of the 'fight or flight' defense reaction that is critical for survival and have distinctive physiological counterparts: increased secretion of Cortisol, hyperventilation, increased blood pressure, and heart rate, increased blood flow to skeletal muscles, as well as vomiting, urination or defecation. Certain aversive situations, such as confrontation by a predator, are obvious life-threatening situations for which rapid, reflex escape responses have evolved that are not under voluntary control. A thalamic-amygdala "emergency hotline" activates the hypothalamus and brainstem to elicit an integrated fear or defense response (LeDoux, 1995; Fig. 1). Such hardwired protective mechanisms provide clear benefits for

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survival. The amygdala also activates neurones in the hippocampus and neocortex, where threatening stimuli are associated with fear and so that future behavior can be adapted to avoid danger. Fear responses can be readily conditioned to initially neutral stimuli (Mineka and Ohman, 2002). They are not clinically problematic unless the fear persists long beyond the immediate threat. A popular conception of stress-related disorders is that they are caused by inappropriate or overactivation of neural circuits that orchestrate defense mechanisms (LeDoux and Muller, 1997).

Human stress-related disorders are associated with dysfunction in many physiological systems: chronic pain, disturbances of mood and sleep, and with gastrointestinal, cardiovascular and respiratory symptoms. Several disorders are probably either caused or exacerbated by stress, including panic disorder, depression, fibromyalgia, post-traumatic stress disorder, tension headache, generalized anxiety disorder, irritable bowel syndrome, and stress-induced hypertension. Comorbidity between these conditions is high and pharmacotherapy with antidepressant and anxiolytic drugs is often beneficial, suggesting some commonality of pathophysiology.

Substance Headache

Stress hormones

Fig. 1. Neuroanatomical circuits mediating stress responses. Adapted from LeDoux (1995).

Stress hormones

Tachycardia Increased BP

Sweating Piloerection Pupil dilatation

Fig. 1. Neuroanatomical circuits mediating stress responses. Adapted from LeDoux (1995).

Recently, drugs that act by blocking the actions of substance P, a neuropeptide that is expressed in limbic brain regions that mediate stress responses, have been developed. Preclinical and clinical experience with substance P (NK, receptor) antagonists (SPAs) such as MK-0869 suggests that they may have therapeutic potential in the treatment of stress-related disorders, such as major depression (Kramer et al, 1998; Rupniak and Kramer, 1999). Preliminary clinical evaluations of SPAs in patients with irritable bowel syndrome and social phobia have also yielded promising findings.

Substance P as a stress neurotransmitter

Based on preclinical observations, substance P has been speculated to play important roles in nociception, emesis, emotion, diurnal rhythm as well as gastrointestinal, cardiovascular and respiratory function. A recurring theme that links these systems is that substance P is involved in preparing an organism to meet potentially fatal experiences, such as tissue damage, poisoning and other hazards present in the environment. Substance P and the NK, receptor are highly expressed in brain regions that regulate emotion and control the autonomic nervous system (e.g. amygdala, brainstem, hypothalamus; Mantyh et al, 1984; Arai and Emson, 1986). The content of substance P in these regions is altered by acute exposure to psychological stress (immobilization) and noxious stimuli (footshock) (Siegel et al, 1987; Rosen et al, 1992; Brodin et al, 1994). Direct activation of the pathways innervated by substance P by microinjection of agonists elicits a range of defensive cardiovascular, behavioral, and other physiological changes, suggesting that the release of endogenous substance P may contribute to the clinical manifestations of stress disorders. The relationship between substance P and the physiological systems that are alfected by stress is considered in the following sections, and provides a basis for conceptualizing a role for substance P in various stress-related responses.

Stress hormone secretion

Hypersecretion of the stress hormones adrenocorti-cotrophin (ACTH) and Cortisol is a common endocrine abnormality in major depression (Holsboer and Barden, 1996). There is growing

Fig. 2. Utilization of substance P in neural circuits that control blood pressure and other stress responses. Adapted from Li and Ku (2002).
Fig. 3. Distribution of substance P-like immunoreactive neurons in rat brain. Adapted from Hokfelt et al. (1987).

evidence that substance P regulates Cortisol secretion through actions in the hypothalamus and the adrenal glands, and its effects are dependent on its site of action.

There is a high density of substance P-containing nerve fibres in many hypothalamic nuclei including the ventrolateral, medial, paraventricular, preoptic and suprachiasmatic nuclei (Shaikh et al, 1993; Ricciardi and Blaustein, 1994; Reuss and Burger, 1994; Liu et al, 2002), and also in the median eminence and anterior pituitary (de Palatis et al, 1982). In anaesthetised rats, intracerebroventricular (i.c.v.) injection of substance P decreased plasma levels of ACTH (Chowdrey et al, 1990). This appears to be mediated via inhibition of the release of corticotrophin-releasing factor (CRF) from the hypothalamus (Faria et al, 1991; Larsen et al, 1993). Experiments using the SPA RP67580 are consistent with the interpretation that substance P exerts a central tonic inhibitory influence on ACTH

and glucocorticoid secretion. I.e.v. injection of RP67580 increased circulating levels of ACTH and corticosterone in conscious, unstressed rats, and increased the duration of a restraint stress-induced elevation of stress hormone secretion (Jessop et al, 2000). Hence, in the CNS, stress-induced release of substance P may serve to attenuate or brake the CRF-mediated secretion of ACTH and corticosterone.

However, experiments using genetically modified mice lacking NK, receptors (NK1R—/—) do not appear to be consistent with this proposal. Basal plasma levels of corticosterone in NK1R—/— mice were not different from those in wild type mice, and were lower in NK1R—/— mice subjected to the psychological stress of exposure to an elevated plus maze (Santaerelli et al, 2001). Reduced stress hormone secretion is consistent with the less anxious phenotype of NK1R-/- mice (Rupniak et al, 2001; Santarelli et al, 2001). It is not unusual to see a mismatch between findings obtained with acute receptor blockade versus genetic manipulation of mice. Often this is attributed to a putative developmental adaptation in mutant mice that is not mimicked pharmacologically. Other possible explanations are that the role of substance P is contingent on the type or severity of the stressor used, or that the central effects of substance P on glucocorticoid secretion may be masked by opposite effects in other brain regions that are less accessible to i.e.v. drug infusion, and/or the adrenal glands.

There are experimental findings supporting the latter interpretation. In addition to its central inhibitory effect on CRF production, substance P has a direct stimulatory effect on corticosterone secretion by the adrenal glands. Glucocorticoid secretion may be regulated via substance P-ergic fibres in the splanchnic innervation to the adrenal gland, or by circulating levels of the peptide. Substance P stimulated corticosterone secretion in an intact perfused rat adrenal preparation in situ (Hinson et al, 1994). Similar effects were observed in vitro (Neri et al, 1990). There is evidence that the release of endogenous substance P into the bloodstream may itself be triggered by stress. In a study using rats, substance P was secreted by the adrenal glands in response to noxious stimulation of the paw (Vaupel et al, 1998).

When injected intravenously (i.v.), substance P stimulated the secretion of corticosterone in normal human subjects (Coiro et al, 1992; Lieb et al, 2002). Whilst a direct stimulatory effect of substance P on the adrenal glands may increase secretion of Cortisol under these conditions, a long-loop mechanism involving the CNS is implicated by the concomitant elevation of ACTH seen by Coiro et al. (1992). Several studies have reported elevated serum levels of substance P associated with stress in humans. In one, plasma levels of substance P were elevated in civilians exposed to missile attacks during warfare (Weiss et al, 1996). In another, high levels of plasma substance P were associated with anxiety in inexperienced parachutists (Schedlowski et al, 1995). In a third study, there was a sustained increase in plasma substance P levels in volunteers undergoing a diagnostic medical procedure (Fehder et al, 1997). Recent evidence also suggests that circulating levels of substance P are elevated in patients with major depression, and that this may be normalized by antidepressant therapy (Bondy et al, 2003). Moreover, in a preliminary investigation using normal volunteers, i.v. infusion of substance P caused a worsening of mood, sleep disturbance and increased Cortisol secretion (Lieb et al, 2002). These findings suggest that high plasma levels of substance P may contribute to the symptoms of depression, although it is unlikely that this could be mediated by a direct action in the CNS as peptides are poorly brain penetrant. Indirect actions, such as induction of hypercortisolemia by high circulating levels of substance P, might provide a link with the clinical symptoms of depression and other stress disorders.

Cardiovascular function

Epidemiological studies strongly suggest that psychosocial factors contribute to the pathogenesis and expression of cardiovascular disease, notably hypertension and atherosclerosis. Risk factors for cardiovascular disease include depression, anxiety, social isolation, and chronic stress (Rozanski et al, 1999). The pathological process is thought to involve excessive sympathetic nervous system activation via a neural circuit controlling blood pressure that is activated by stress. Experiments in animals implicate the amygdala, locus coeruleus, hypothalamus, septum, and thalamus in this circuit. It is noteworthy that substance P is expressed in the pathways that connect these nuclei (Li and Ku, 2002; Fig. 1).

Substance P does not appear to regulate basal cardiovascular function since SPAs do not alter vascular tone or blood pressure in rats or humans (Couture et al, 1995; Newby et al, 1999). Rather, substance P is a central regulator of cardiovascular reflexes that activate the sympathoadrenal system, both at spinal and supraspinal levels. At supraspinal sites, substance P mediates an integrated response to noxious and stressful stimuli. The hypothalamus, which integrates neuroendocrine and autonomic processes, is rich in substance P-containing nerve endings and NK, receptors. Stimulation of periventricular or hypothalamic NK, receptors by central injection of substance P in conscious rats induces a cardiovascular defense response, characterized by increased sympathoadrenal activity, an increase in blood pressure and heart rate, mesenteric and renal vasoconstriction, and hind-limb vasodilatation (Unger et al, 1998). Microinjections of substance P into the central amygdala, thalamus, hypothalamus, periaqueductal gray, parabrachial nucleus, septum, locus coeruleus or medulla all evoke pressor responses (Itoi et al, 1994; Ku et al, 1998; Li and Ku, 2002). These pressor and vasoconstrictor responses serve to shunt blood to the skeletal muscles as part of the "fight or flight" reaction. Centrally acting SPAs block these effects of substance P on heart rate and blood pressure (Couture et al, 1995; Rupniak et al, 2003a). SPAs can also block a cardiovascular stress response elicited by a noxious stimulus (intraplantar injection of formalin), indicating that stressors cause release of endogenous substance P in the CNS (Culman et al, 1997).

Activation of the sympathetic nervous system also stimulates the renin-angiotensin system to produce angiotensin II, a powerful vasoconstrictor. Angiotensin converting enzyme (ACE) inhibitors are clinically effective antihypertensive drugs and this enzyme provides another potentially intriguing link between substance P, hypertension and depression, although interpretation of the available findings is complicated. ACE is a major metabolizing enzyme for substance P and there are reports of an association between a deletion polymorphism (DD) in the ACE gene in hypertension (O'Donnell et al, 1998) and major depression (Arinami et al, 1996; Baghai et al, 2002; Bondy et al, 2002). [However, the association with depression has not been observed by others (Pauls et al, 2000; Furlong et al, 2002)]. The DD genotype is believed to increase ACE activity (Tiret et al, 1992), and hence would be expected to cause a reduction in substance P levels. However, contrary to this interpretation, increased levels of substance P have been reported in patients with major depression, both in post mortem brain tissue (Baghai et al, 2002) and in blood plasma (Bondy et al, 2003). There have been no direct analyzes of ACE activity in major depression, and so the exact relationship between ACE genotype, substance P and depression awaits further exploration.

Respiratory function

Stimulation of respiration (hyperventilation) is a common event during panic attacks. A number of abnormalities in respiration, such as enhanced sensitivity to carbon dioxide, have been detected in patients with panic disorder. The ability to trigger panic attacks by the inhalation of carbon dioxide led Klein (1993) to speculate that panic disorder is a disturbance in a suffocation alarm system, in which a physiological misinterpretation of suffocative stimuli produces respiratory distress, hyperventilation and panic. Asthma is a risk factor for the development of panic disorder, reinforcing an important role of respiratory factors in panic disorder. However, respiratory physiology appears to be generally normal in most panic patients, and so it has been proposed that the pathophysiology may reflect a hypersensitive fear network, with impaired integration of information from cortical and brainstem centers by the amygdala (Gorman et al, 2000).

Substance P is widely expressed in the peripheral respiratory system and in brainstem centers that regulate respiratory drive. In the airways, SP acts as a potent bronchoconstrictor. In the brainstem, substance P is expressed in major nuclei that regulate respiratory rhythm, including the nucleus tractus solitarius (NTS; Chen et al, 1990), preBotzinger complex (the hypothesized site for respiratory rhythmogenesis in mammals; Guyenet and Wang, 2001), nucleus paragigantocellularis (Chen et al, 1990) and parabrachial nucleus (Li and Li, 2000). Local application of substance P in these regions generally stimulates respiratory frequency and tidal volume, so that putative release of endogenous substance P might stimulate respiration during a panic attack. The integrity of NR^ receptor-expressing neurones in the preBotzinger complex is essential for maintaining normal respiratory rhythm in conscious rats (Gray et al, 2001). Surprisingly few clinical studies have examined the effects of SPAs on respiratory dysfunction, attention having been directed exclusively at asthma, where no improvement in baseline pulmonary function has been reported to date (Joos et al, 1996).

Gastrointestinal function

Acute, traumatic stressors can cause marked perturbations of gut function, notably vomiting and defecation. Chronic stress is also associated with functional gastrointestinal disturbances, such as irritable bowel syndrome (IBS; Whitehead and Palsson, 1998). NK | receptors are highly expressed in the nucleus of the solitary tract (NTS), where primary visceral afferents terminate, and in the dorsal vagal complex and area postrema, where preganglionic motor neurones innervating the gastrointestinal tract are located. Through these pathways, substance P participates in the central autonomic regulation of gastrointestinal function.

Emesis

Centrally acting SPAs exhibit broad spectrum antiemetic activity in ferrets (Tattersall et al, 1994), and microinjection studies have confirmed that blockade of NK) receptors in the NTS is an important site for their anti-emetic actions (Tattersall et al, 1996). Injection of substance P into the dorsal motor nucleus has also been shown to cause relaxation of the stomach fundus, an essential prodromal component of emesis; this was blocked by the SPA GR203040, suggesting a second important central anti-emetic locus (Krowicki and Hornby, 2000). Clinical management of the emetic reflex is necessary during cancer chemotherapy since nausea and vomiting are serious adverse effects of cytotoxic drugs. Clinical trials with several SPAs have established that they are extremely effective in the prevention of emesis after cisplatin chemotherapy in humans (Kris et al, 1997; Navari et al, 1999), confirming an important role of substance P in human visceral function.

Gut motility and visceral pain

Stress also has marked effects on motility in the lower gut. In rats, psychological stress, such as immobilization or avoidance of immersion in water, markedly increases faecal output (Williams et al, 1988; Monnikes et al, 1993; Ikeda et al, 1995). These manipulations may be relevant to irritable bowel syndrome (IBS), a functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits (diarrhoea and/or constipation), whose symptoms may be triggered or exacerbated by stress (Mayer, 2000).

Substance P is present in enteric motorneurons that project to the longitudinal and circular muscle of the mammalian intestine. NKj receptor stimulation is usually associated with an increase in gut motility. Systemic administration of substance P and other agonists stimulates phasic contractions of the colon and increases the amplitude and frequency of spontaneous contractions in animal assays (Holtzer, 1982; Maggi et al, 1997). Consistent with an excitatory role for substance P, intraperitoneal administration of a peptide antagonist, [DPro2, DTrp7'9]-substance P, reduced gastric emptying and gastrointestinal transit in rats (Holtzer et al, 1986). Substance P agonists also increase the frequency of giant migrating contractions (GMCs) that cause diarrhoea and produce the sensation of abdominal cramping (Tsukamoto et al, 1997). Interestingly, the poorly brain penetrant NK, receptor antagonist SR140333 partially blocked GMCs associated with castor oil-induced diarrhoea in rats (Croci et al, 1997). Several studies using non-pep tide substance P antagonists have also shown potent inhibitory effects on restraint stress-induced increases in fecal output (Ikeda et al, 1995; Okano et al, 2001; Bradesi et al, 2002). Since the compounds used in these studies are poorly brain penetrant, their site of action is most likely in the gut itself. These findings indicate that SPAs may be useful to alleviate diarrhoea-predominant symptoms in patients with IBS via blockade of colonic NK] receptors.

In addition to altered bowel habits, abdominal pain and visceral hypersensitivity are key symptoms in IBS. Most IBS patients report heightened pain perception to mechanical distension of the colon with an intra-rectal balloon (Accarino et al, 1995). Mostly on anatomical grounds, there has been much speculation that substance P is involved in visceral pain as well as gut motility. Over 80% of primary afferent fibres in the splanchnic nerve contain substance P (Perry and Lawson, 1998), and laminae I and X of the spinal dorsal horn, which receive afferent inputs from the viscera, contain the highest density of NKi receptors found in the spinal cord (Li et al, 1998). These anatomical considerations have generated interest in the clinical potential of SPAs to treat visceral pain (Laird et al, 2000).

Preclinical studies indicate that SPAs may be able to reduce hyperalgesia of the colon, but are unlikely to be analgesic. Blockade or deletion of NKi receptors did not alter a nociceptive reflex response to colorectal distension (Julia et al, 1994; Laird et al, 2000). In contrast, hyperalgesia (measured by a cardiovascular reflex) to colonic distention following intracolonic instillation of acetic acid, a neurogenic inflammatory stimulus, was absent in NK1R—/— mice. Similarly, behavioral nociceptive responses (licking, stretching, arched posture) and referred hyperalgesia (response to abdominal stimulation with von Frey hairs) after intracolonic application of neurogenic inflammatory agents were abolished in NK1R—/— mice. However, nociceptive responses to intracolonic application of mustard oil, which did not cause neurogenic inflammation, were similar in NK1R—/— and wild type mice (Laird et al, 2000). Thus, the deficit in visceral nociception in NKI—/— mice was specific to stimuli causing neurogenic inflammation, and hence the ability of SPAs to alleviate abdominal pain in patients with IBS would be dependent on a significant neurogenic inflammatory component, which has not been described in this condition.

Consistent with these inferences from preclinical studies, data from a small scale clinical trial support the proposal that SPAs may be of benefit in IBS, although probably not primarily as analgesics. Lee et al. (2000) found that CJ-11,974 reduced feelings of anger induced by rectal distension and self-ratings of symptom intensity without affecting pain thresholds in IBS patients. Although encouraging, conclusions from this study are limited as it was terminated after only 7 days of treatment. Further trials of longer duration are awaited to characterize the clinical profile of SPAs in patients with IBS.

Stress-induced behaviors

Self defense, raising the alarm, and avoidance of aversive or unfamiliar environmental stimuli are reflexive or learned adaptations of behavior that are essential for survival. Various stressors have been used to elicit these behaviors in laboratory animals in order to model human anxiety disorders. The neural pathways that regulate the expression of these behaviors involve the amygdala and its associated output pathways, including the hypothalamus and periaqueductal gray, and there is accumulating evidence they utilize substance P as a neurotransmitter.

Aggression

The ability of benzodiazepines such as diazepam to calm aggressive behavior in animals was one of the earliest indications of the powerful psychotropic effects of these compounds (da Vanzo et al, 1966). Similarly, the ability of antidepressant drugs to reduce rage elicited by electrical stimulation of the hypothalamus in cats was an observable behavioral effect of these compounds (Dubinsky and Goldberg, 1971). Subsequently, the muricide test, in which the ability of drugs to increase the latency for rats to kill mice, was developed into a screening assay for antidepressants (Horovitz, 1965). This has been superceded by the resident-intruder test (Sanchez et al, 1993; Payne et al, 1994), in which a conspecific is introduced into the home cage of another animal, and the latency to initiate an attack is recorded.

In cats, a monosynaptic substance P-ergic pathway from the amygdala to the hypothalamus has been described that regulates the expression of defensive rage. Electrical stimulation of the medial hypothalamus elicits a defensive rage syndrome in this species that is facilitated by simultaneous stimulation of the medial amygdala (that is, the behavior is elicited at lower stimulation thresholds). The SPA CP-96,345 was able to inhibit amygdaloid facilitation of defensive rage when administered systemically or directly into the medial hypothalamus (Shaikh et al, 1993). Like anxiolytic and antidepressant drugs, acute administration of SPAs increased the latency to attack in hamsters subjected to the resident-intruder test (Rupniak et al, 2001), an effect on behavior that resembled the phenotype of NK1R-/- mice (de Felipe et al, 1998). Therefore it appears that substance P is released in the hypothalamus in preparation for fight as part of the defense response.

Alarm responses

The first clues to the psychotropic properties of SPAs came from observation of the effects of central injection of the substance P agonist GR73632 on the behavior of guinea-pigs and gerbils. In guinea-pigs, i.e.v. injection of GR73632 elicits escape-like behavior accompanied by vocalization that was blocked by SPAs and by antidepressant drugs (Kramer et al, 1998; Rupniak et al, 2000). Vocalization is a common stress response in infants and adults separated from their mothers and conspecifics, and can be inhibited by acute administration of anxiolytic and antidepressant drugs (Miczek et al, 1995; Molewijk et al, 1996). In guinea-pig pups subjected to maternal separation, SPAs completely inhibited distress vocalizations. Similarly, separation-induced vocalizations were almost absent in NK1R—/— mouse pups (Kramer et al, 1998; Rupniak et al, 2000). The amygdala is a likely site of action of SPAs in regulating this behavior since substance P is released in this region during maternal separation, and intra-amygdala injection of an SPA was able to attenuate the vocalization response (Kramer et al, 1998; Boyce et al, 2001).

In parallel experiments using gerbils, several laboratories reported that i.e.v. injection of substance P agonists elicited a profound behavioral response of vigorous hindfoot drumming or tapping (Graham et al, 1993; Vassout et al, 1994; Bristow and Young,

1994; Rupniak and Williams, 1994), a behavior recognised as an alarm signal in desert rodents. In feral gerbils and kangaroo rats, foot drumming has been observed when animals are startled (Daly and Daly, 1975), confronted by snakes (Randall and Stevens, 1987), defending their territory (Randall, 1984) and during agonistic encounters (Daly and Daly, 1975). In gerbils studied under laboratory conditions, foot drumming has also been elicited by aversive stimuli, including termination of rewarding brain stimulation, foot shock (Routtenberg and Kramis, 1967; Kramis and Routtenberg, 1968) and threatening environmental stimuli (Clark and Galef, 1977). Thus, the ability of substance P agonists to elicit this behavior is consistent with other evidence for an involvement of this neuropeptide in stress responses. Recently, it has been reported that foot drumming can be elicited by fear conditioning in gerbils, and that this was inhibited by SPAs and by diazepam, consistent with an anxiolytic-like effect (Ballard et al, 2001; Rupniak et al, 2003b). Foot drumming elicited by fear conditioning was also abolished by amygdala lesions, providing further evidence that this is a potential site of action of SPAs (Rupniak et al, 2003b).

Avoidance behavior

Anxiety is often assessed in rodents by measuring the time they spend avoiding aversive environments such as the exposed, open arms of an elevated plus maze. Benzodiazepine anxiolytics such as diazepam markedly increase the time spent by animals in exploration of the aversive open arms (Pellow et al, 1985). Focal injection of substance P into the periaqueductal gray, which receives a major substance P-ergic projection from the amygdala (Gray and Magnusson, 1992), reduces the time spent on the open arms of a plus maze, consistent with an anxiogenic effect (Aguiar and Brandao, 1996; Teixeira et al, 1996). The evidence that blockade or deletion of NKi receptors is anxiolytic (that is, increases time on the open arms) is less clear, with two negative studies (Murtra et al, 2000; Rupniak et al, 2001), and two positive (Santarelli et al, 2001; Varty et al, 2002). The failure to detect anxiolysis may reflect methodological differences between the studies, such as the dimensions of the maze, lighting conditions, and the species and strain of animals, all of which can markedly influence behavior in this apparatus.

Another assay in which avoidance behavior is inferred to correlate with anxiety is the social interaction test, in which unfamiliar animals are placed in a novel, brightly lit arena, and the time spent in social interaction (sniffing, social investigation) is determined. Like the benzodiazepine anxiolytic diazepam, several SPAs have been shown to increase social interaction in rats (File, 1997; File, 2000; Vassout et al., 2000) and gerbils (Cheeta et al, 2001; Gentsch et al, 2002). These observations prompted a clinical investigation of NKP-608 in patients with social phobia (Ameringen et al, 2000); however, the outcome of these studies has not yet been published.

Potential of substance P antagonists to treat stress disorders

It is over 70 years since substance P was first discovered by von Euler and Gaddum (1931). Since that time, there has been much speculation about the physiological role of this neuropeptide, particularly concerning its role in pain transmission, but it is only recently, since selective antagonists of the NK, receptor have been available, that these hypotheses could be tested. The picture that is currently emerging from preclinical studies is that substance P may serve a broader role in protecting the body from potentially harmful stimuli, including poisons, predators and perceived threats. Preclinical studies establish substance P as a transmitter in the neural circuits that mediate physiological stress responses involving changes in endocrine, cardiovascular, respiratory and gastrointestinal function, and also behavior. The clinical implications of these findings have yet to be elucidated, but preliminary clinical data suggest that SPAs may alleviate symptoms of depression and anxiety in patients with major depression, and that there may be promising results in patients with IBS. The therapeutically active dose range has been established for several compounds, and they have been well tolerated in the patient populations studied to date. Publication of the outcome of studies conducted with SPAs in other patient populations, such as social phobia, is awaited with interest.

Further clinical studies will be needed to define the scope of clinical benefits of SPAs in stress-related disorders in humans.

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T. Sleekier, N.H. Kaiin and J.M.H.M. Reul (Eds.) Handbook of Stress and the Brain, Vol. 15 ISBN 0-444-51823-1

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