A possible role of neuropeptide Y in depression and stress

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Research Report

A possible role of neuropeptide Y in depression and stress Julio César Morales-Medina a,b , Yvan Dumont b , Rémi Quirion b,c,⁎ a

Department of Neurology & Neurosurgery, McGill University, Montréal, QC, Canada H4H 1R3 Douglas Mental Health University Institute, McGill University, Montréal, QC, Canada H4H 1R3 c Department of Psychiatry, McGill University, Montréal, QC, Canada H4H 1R3 b

A R T I C LE I N FO

AB S T R A C T

Article history:

Neuropeptide Y (NPY) mediates its physiological effects through at least four receptors

Accepted 19 September 2009

known as Y1, Y2, Y4, and Y5. This peptide is one of the most abundant peptides in the central

Available online 25 September 2009

nervous system and is highly conserved throughout evolution. The most abundant receptors of the NPY family, the Y1 and Y2 receptors, are densely expressed in the cortex,

Keywords:

hippocampus, and amygdala. These brain regions are particularly associated with mood

Animal model

disorders, stress responses, and memory processing. With this in mind, researchers

Antidepressant

suggested the involvement of NPY as well as the Y1 and Y2 receptors in affective disorders.

Depression

Earlier studies showed that NPY and the Y1 and Y2 receptors mediate some aspects of

Neuropeptide Y

depression-like disorders and stress responses in rodents. Recent research also suggests the

Stress

involvement of the Y4 and Y5 receptors in emotion-related processes in rodents. In addition,

Mood disorder

human studies have consistently suggested a role for NPY in stress responses, whereas conflicting data have been obtained in relation to the role of NPY in depression-related illnesses. However, novel evidence from polymorphisms in the prepro-NPY gene has shed new light on the potential clinical relevance of NPY in depression. In this article, we review the literature from both animal and human studies regarding the contribution of NPY and its receptors in depression and stress. © 2009 Elsevier B.V. All rights reserved.

1.

Introduction

Mood disorders comprise a wide array of disabilities, including major depressive disorder (unipolar depression), bipolar disorders, mood disorder due to a general medical condition as well as substance-induced with different subclassifications (DSM IV) (APA, 1994). Among these disabilities, depression-

related disorders are the most prevalent and are predicted to be the second leading cause of disability worldwide by year 2020 (Murray and Lopez, 1996; Ustun et al., 2004). Depression is a heterogenous, multifactorial condition in which neurobiological mechanisms are not fully elucidated (D'Sa and Duman, 2002). Several hypotheses including chronic stress, failure of adulthood neurogenesis, altered neuroplasticity, dysfunction

⁎ Corresponding author. Douglas Mental Health University Institute, McGill University, 6875 La Salle Boulevard Montréal, QC, Canada H4H 1R3. Fax: +1 514 888 4060. E-mail address: [email protected] (R. Quirion). URL: http://www.douglasrecherche.qc.ca/groups/quirionlab/ (R. Quirion). Abbreviations: ACTH, adrenocorticotropin hormone; BLA, basolateral amygdala; BBB, blood–brain barrier; CSF, cerebrospinal fluid; CORT, corticosterone; CRF, corticotrophin-releasing factor; DβH, dopamine-β-hydroxylase; ECT, electroconvulsive therapy; EPM, elevated plus maze; FSL, flinders sensitive line; FST, forced swim test; HPA, hypothalamus–pituitary–adrenal; ICV, intracerebroventricular; KO, knockout; NPY, neuropeptide Y; OBX, olfactory bulbectomy; PPs, pancreatic polypeptides; PYY, peptide YY; SNRI, selective noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor 0006-8993/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2009.09.077

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of monoaminergic systems, and genetic factors have been studied to elucidate depressive-related behaviors (Duman, 2004; Manji et al., 2001; Nestler et al., 2002; Sahay and Hen, 2007). However, none of these hypotheses fully explain all the symptomatology observed in the human condition. Furthermore, for a considerable number of patients, current therapies provide only rather limited efficacy with side effects and delays in treatment effectiveness (Berlim et al., 2008; Nestler et al., 2002). For these reasons, elucidations of the etiology of depression and related disorders as well as the search for novel antidepressants are two of the foremost challenges in health research today. Stress produces a broad cascade of hormonal and neuroendocrine responses. Acute stress is beneficial and necessary for the organism to cope with short-term imaginary or real threats. However, chronic stress maintained for long periods, results in a disrupted immune response, neuronal dendritic remodeling, and memory deficits which resembles some of the symptomatology observed in depressed subjects (de Kloet et al., 2008; Erickson et al., 2003; Morales-Medina et al., 2009b; Sapolsky, 2000). Stress activates the hypothalamus–pituitary–adrenal (HPA) axis (Lupien et al., 2009) and hypothalamic cells release corticotrophin-releasing factor (CRF), which in turn induces the secretion of the adrenocorticotropin hormone (ACTH) from the anterior pituitary. In addition, the adrenal glands release glucocorticoids [cortisol in humans and corticosterone (CORT) in rodents] into the circulatory system (Mesotten et al., 2008). Also, recent evidence suggest that HPA-independent CRF system mediates stress-related behaviors (Heinrichs and Koob, 2004). For example, Zobel et al. (2000) showed that blockade of CRF1 receptor ameliorates depression scores after long-term treatment with no alteration in plasma CRF and cortisol in humans. Moreover, administration of CRF in the dorsal raphe nucleus decreases serotonergic transmission in the lateral septum similar to a physical model of stress (Price et al., 2002). Intracerebroventricular (ICV) but not subcutaneous administration of CRF produced aversive effects in the place preference paradigm (Cador et al., 1992). Neuropeptides including CRF, VGF, cholecystokinin, substance P, and neuropeptide Y (NPY) have been shown to function as neuromodulators of emotional processing (Dumont et al., 2009; Thakker-Varia and Alder, 2009). Interestingly, NPY, a 36-amino acid peptide (Tatemoto, 1982; Tatemoto et al., 1982), is highly conserved among species and widely distributed in the central nervous system (Dumont and Quirion, 2006; Larhammar and Salaneck, 2004) with dense levels in the hippocampal formation and cortex, two areas involved in affective disorders. These findings suggest that NPY could be implicated in depression-related disorders. The synthesis of NPY is depicted in Fig. 1A. NPY belongs to a tripartite family of peptides, including the pancreatic polypeptides (PPs) and peptide YY (PYY). The effects of NPY are transduced by at least four G proteincoupled receptors known as Y1, Y2, Y4, and Y5 in mammals (Michel et al., 1998). In contrast to all known NPY receptor subtypes, the y6 receptor subtype has been identified in mice and rabbit but is absent in rat while in human and other primates the cDNA contains a single base deletion resulting in the expression of a non-functional receptor protein which is truncated from the sixth transmembrane domain (Larham-

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mar and Salaneck, 2004). The Y1 and Y2 receptors protein and mRNA are widely distributed in high amounts in the central nervous system, especially in frontal cortex, hippocampus, and amygdala (Dumont et al., 1998), brain regions associated with mood-related disorders (Kask et al., 2002). The Y4 and Y5 receptors protein are found in discrete brain regions while their mRNA expressions are more widely distributed (Dumont et al., 2000). For example, the Y4 receptor protein is expressed in thalamic and hypothalamic nuclei, area postrema, and nucleus tractus solitarious of the rat brain (Dumont et al., 2000). Meanwhile, significant amount of the Y5 receptor protein is observed in the dentate gyrus, septum, area postrema, and nucleus tractus solitarius while low to very low levels are found in the piriform cortex, hypothalamus, and caudate putamen (Dumont et al., 2000). Animal studies have shown that increasing levels of NPY, activation of NPY Y1 receptor subtype as well as deletion or blockade of Y2 receptor subtype possess antidepressant-like activity in acute models of depression or in NPY knockout (KO), Y1 KO and Y2 KO receptor animals (Bannon et al., 2000; Heilig et al., 1989; Painsipp et al., in press; Redrobe et al., 2002; Widerlov et al., 1988a). Recent results suggested that the Y4 and Y5 receptors are also involved in depression-like behaviors in rodents (Painsipp et al., 2008b; Sorensen et al., 2004). Preclinical studies have suggested that NPY levels are disrupted in depression in humans; however, the results are rather inconclusive (Gjerris et al., 1992; Heilig et al., 2004; Widerlov et al., 1988a). Finally, the role of NPY in the stress response has been investigated in both clinical and preclinical studies (Morgan et al., 2000; Zukowska-Grojec et al., 1988; Zukowska-Grojec and Vaz, 1988). Together, these results reveal that NPY counteracts the deleterious effects of CRF. In this review, we summarize the current literature regarding the role of NPY in depression and stress in animal and human studies.

2.

Animal studies

Multiple studies using pharmacological tools as well as genetically modified animals have been carried out to dissect the role of NPY and its receptors in emotional and stress responses. Earlier studies focused on NPY and its most abundant receptors in the brain, the Y1 and Y2 subtypes. More recent studies also have investigated the role of Y4 and Y5 receptors.

2.1.

The role of NPY in depression-related behaviors

The modulation of NPY levels in various animal models has produced robust data suggesting that NPY is implicated in depression-like behaviors and may produce antidepressantlike effects. For example, in the forced swim test (FST), a screening tool for antidepressants, the acute intracerebroventricular (ICV) administration of NPY produces an antidepressant effect in naive rodents (Redrobe et al., 2005; Stogner and Holmes, 2000) as well as an anxiolytic effect in the elevated plus make (EPM) in naive rats (Heilig et al., 1989). In the olfactory bulbectomized (OBX) rat model of depression-like behavior, subchronic ICV infusion of NPY reduces vertical

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Fig. 1 – Synthesis and processing of NPY under normal conditions and after stress. (A) Showing the steps involved in the synthesis of NPY. (B) Role of different polymorphisms after the stress cascade is activated. Leu7/Leu7 may result on low levels of NPY, meanwhile, Leu7/Pro7 may produce high levels of NPY.

hyperactivity, a trait associated with anxiogenic responses (Song et al., 1996). In addition, in the “learned helplessness” rat model, acute infusion of NPY in the CA3 region of the hippocampal formation produced an antidepressant-like effect (Ishida et al., 2007). In accordance with these results, Bannon et al. (2000) reported a mild anxiogenic effect in the open field but not in the EPM in NPY KO mice. The NPYtransgenic mice [in which NPY is overexpressed under the dopamine-β-hydroxylase promoter (DBH)] have a tendency toward an anxiolytic phenotype (Ruohonen et al., 2009), whereas NPY-transgenic rats behave like wild type animals in the EPM under basal conditions (Thorsell et al., 2000). In the Flinders Sensitive Line (FSL) rats (a genetic-based model of depression-like behavior), NPY-like immunoreactivity is augmented after chronic administration of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Caberlotto et al., 1999). Some studies have found that NPY levels are disrupted in key brain regions involved in affective disorders (Caberlotto et al., 1999; Jimenez-Vasquez et al., 2001). Maternally separated rats, a model of depression-related behavior, showed significantly lower levels of NPY in the dorsal hippocampus, and increased levels of NPY in the hypothalamus later in adulthood (Jimenez-Vasquez et al., 2001). Similarly, NPY levels

are decreased in the dorsal hippocampus of FSL rats (Caberlotto et al., 1999). In addition, discrepancies in the behavioral effect of NPY may be caused by the differences in receptor expression in various animal models. For example, NPY-deficient mice show higher levels of Y1 receptor subtype in numerous brain regions and localized increases of Y2 receptor subtype (Trivedi et al., 2001). Gehlert and Shaw (2007) replicated this finding for Y1 receptor subtype and found increased binding in different brain regions for Y2 receptors as well. However, differences in receptor expression were not translated into increased functional receptor coupling (Gehlert and Shaw, 2007). In addition, NPY Y1 receptor binding was significantly increased in the hippocampal region in FSL rats, and thus, these differences were hypothesized to occur as a compensatory mechanism due to the reduced levels of NPY (Caberlotto et al., 1999). In line with previous findings, NPY transgenic rats showed decreased Y1 receptor binding in the hippocampal region (Thorsell et al., 2000). This reduction in Y1 receptor expression may account, at least partially, for the lack of effect of the endogenous high levels of NPY in this transgenic rat in the EPM during basal conditions. Further studies evaluating the expression of various NPY receptors in a variety of models are warranted.

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Several studies also have investigated the possible mechanisms of NPY antidepressant actions. Stogner and Holmes (2000) found that rats treated with NPY show improved swimming time without signs of struggle in FST. SSRIs improve swimming time, whereas selective noradrenaline reuptake inhibitors (SNRIs) increase struggling in the FST (Cryan et al., 2005; Page et al., 1999). These findings suggest that NPY may mediate its antidepressant-like effects by increasing serotonin levels. In support of this hypothesis, Redrobe et al. (2005) suggested that the antidepressant action of NPY may be mediated via a serotonergic-dependent pathway. Indeed, the co-administration of NPY with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (to deplete serotonin), significantly attenuated the antidepressant-like effects of NPY in the FST (Redrobe et al., 2005). Attention deficits, poor concentration, and memory loss have been consistently reported in depressed subjects (Castaneda et al., 2008). Interestingly, NPY has also been proposed to be involved in memory processing in rodents. For example, the acute administration of NPY in the third ventricle of rats resulted in an improvement in memory in two well-known models of amnesia, anisomycin and scopolamine (Flood et al., 1987). In contrast, memory deficits were observed in young (Thorsell et al., 2000) but not in old (Carvajal et al., 2004) NPYoverexpressing rats. NPY KO mice display a similar profile as to wild type mice in learning tests (Bannon et al., 2000). NPY has been investigated with respect to the behavioral response to stress in rodents (Heilig, 2004). For example, after naive rats were exposed to stressful events such as cold water, novel environments, and intermittent footshocks, their plasma NPY levels were increased (Zukowska-Grojec et al., 1988; Zukowska-Grojec and Vaz, 1988). Further studies with rats also suggested that acute and repeated physical stress significantly increase NPY (protein and mRNA) levels in the amygdala (de Lange et al., 2008; Thorsell et al., 1998; Thorsell et al., 1999). In addition, after restraint (a paradigm of physical stress), NPY levels were increased four times in female NPYDBH overexpressing mice but not in male mice (Ruohonen et al., 2009). Moreover, exogenous administration of NPY in the basolateral amygdala reduced anxiety-like behaviors produced by physical stress (Sajdyk et al., 2008). NPY infusion in the basolateral amygdala blocked anxiogenic effects of urocortin 1, a CRF agonist (Sajdyk et al., 2006). After being maternally separated, NPY KO pups also showed an aberrant CORT response compared to wild type mice (Schmidt et al., 2008). In that context, when tested for the first time, young NPY transgenic rats also show a similar behavior to a wild type counterpart in the EPM (Thorsell et al., 2000). However, after 10 days or after acute physical stress, NPY overexpression protected both young (Thorsell et al., 2000) and old rats (Carvajal et al., 2004) from the anxiogenic-like behavior produced by these stressors. Recently, Mitra and Sapolsky (2008) showed that the activation of the HPA axis by a single dose of CORT produced an anxiogenic response and amygdalar hyperactivity 12 days after treatment but not the day following the administration of CORT. Therefore, results obtained in NPY transgenic rats suggest that the exposure to EPM may activate the HPA axis, while the overexpression of NPY may counterbalance deleterious behavioral effects. Thus, the activation of the NPY system (especially in the amygdala)

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after stress hormones are released could contribute to the reduction of the anxiogenic effects of stress. Taken together, these results strongly support a role for NPY in depression-like states and stress response. Subsequent studies should investigate other potential mechanisms of action (e.g., neurogenesis in dentate gyrus) and the downstream cascade of the serotonin-dependent pathway.

2.2.

The NPY Y1 receptor in depression-related behaviors

Recent studies have attempted to dissect how NPY modulates its effects. The Y1 receptor subtype is densely expressed in brain regions associated with emotionality and memory processing. In addition, this receptor has high affinity for NPY and analogs including [Leu31, Pro34]NPY and [Leu31, Pro34] PYY (Dumont et al., 2000). In the FST with naive mice, acute ICV administration of the Y1-like agonist [Leu31Pro34]PYY produced an antidepressant-like effect (Redrobe et al., 2002). In addition, in the “learned helplessness” rat model of depression, the acute infusion of [Leu31Pro34]PYY in the CA3 region of the hippocampal formation produced an antidepressant effect (Ishida et al., 2007). Moreover, the antidepressant effect produced after the administration of NPY was blocked by the co-administration of the selective Y1 receptor antagonist BIBO3304 in the learned helplessness (Ishida et al., 2007) and naive rats (Redrobe et al., 2002). Interestingly, when tested in the FST apparatus for the first time, female Y1 KO mice showed regular activity in the FST but a reduced immobility in the tail suspension test, a depressionrelated paradigm, compared to wild type mice (Painsipp et al., in press). In contrast, Karlsson et al. (2008) found that Y1 KO mice (male and female) display a depressive-like state in the mice show a mild anxiety-like behavior in the FST. Male Y−/− 1 EPM, although locomotor activity is increased (Karl et al., 2006), an effect probably caused by the novel, mildly stressful condition of the paradigm, given the fact that male and female Y1-deficient mice present home cage hypolocomotion relative to wild type animals (Pedrazzini et al., 1998). Therefore, the observed hyperlocomotion in the EPM may compromise the interpretation of results (Schorscher-Petcu et al., 2009). Conversely, Karlsson et al. (2008) found that Y1 KO mice have a basal, normal phenotype in the EPM and open field. However, in an object recognition test, male Y1-deficient mice show cognitive deficits (Costoli et al., 2005). Studies with Y1 KO mice showed that these animals seem to have a mild anxiolytic effect depending on the behavioral test used. Novel approaches are needed to evaluate further the role of the Y1 receptor in cognitive processes. Previously mentioned strategies have limitations regarding the interpretation of the results especially between exogenous administration of NPY Y1 agonists and NPY-deficient mice. Since germ line Y1 KO animals show compensatory mechanisms and to avoid these adaptational changes, novel conditional KO animal models need to be developed. For example, Y1 KO animals showed reduced NPY binding sites (Pedrazzini et al., 1998) and also displayed increase in Y2 mRNA in all major brain regions related to emotional processes (Wittmann et al., 2005). Additionally, the possible antidepressant-like effect of Y1-like agonists following an acute administration in naive animals could be misinterpreted since the NPYergic system may

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produce different effects under normal compared to pathological conditions. Moreover, the effectiveness of antidepressants in humans is observed only after long-term administration of at least three weeks. By using a repeated ICV infusion of the Y1-like agonist, [Leu31Pro34]PYY, for 14 days, we evaluated the behavioral effect of the Y1 receptor activation in the open field, the FST, and the social interaction paradigms in the OBX model of depression-like behaviors. Our study shows that [Leu31Pro34] PYY reversed the depressive- and anxiolytic-like behaviors displayed in the OBX rats (Morales-Medina et al., 2009a). Interestingly, recent studies using Y1 KO mice have suggested that Y1 receptors may play a role in the stress response. For example, Karl et al. (2006) reported that male Y1 KO mice display an important anxiolytic-like phenotype only after physical restraint while female Y1 KO mice show augmented antidepressant-related activity in both the FST and the tail suspension test after being tested in the EPM 1 week earlier (Painsipp et al., in press). In both cases, the HPA axis was previously activated. These Y1 KO mice also show normal activity in the EPM when tested for the first time. However, enhanced locomotion occurs in the EPM when animals are tested 1 week after the FST (Painsipp et al., in press). These data are in agreement with previous results using similar paradigms and suggest that NPY is activated to “buffer” the anxiogenic effects of stress (Carvajal et al., 2004; Thorsell et al., 2000). In summary, the Y1 receptor seems to be involved in the stress response and to mediate antidepressant-like properties of NPY. By using animal models, new approaches should investigate the possible mechanisms of action associated with the activation of this receptor and more precisely determine its role in the behavioral response to stress. The development of selective Y1 agonists that can cross the blood–brain barrier (BBB) is also warranted.

2.3.

The NPY Y2 receptor in depression-like behaviors

The Y2 receptor modulates the release of NPY and some classical neurotransmitters, including monoamines and excitatory amino acids (King et al., 1999, 2000; Qian et al., 1997). Since antidepressant-related activity has been associated with elevated levels of NPY, the inhibition or deletion of Y2 receptors has been hypothesized as an indirect way to increase NPY and produce antidepressant- and anxiolytic-like behaviors (Redrobe et al., 2003a; Weiser et al., 2000). A reduced anxiety mice and depressive profile is consistently observed in Y−/− 2 independent of sex and age (Carvajal et al., 2006; Painsipp et al., 2008a; Redrobe et al., 2003b; Tschenett et al., 2003). In addition, the acute ICV administration of the Y2 receptor antagonist BIIE0246 to naive mice induces antidepressant-related effects (Redrobe et al., 2002). In the “learned helplessness” rat model of depression, the acute infusion of BIIE0246 in the CA3 region of the hippocampal formation produces an antidepressant-like effect (Ishida et al., 2007). However, the Y2 agonist, NPY13-36, has little effect in these behavioral tests (Ishida et al., 2007). Recently, we suggested that chronic administration of BIIE0246 produced antidepressant-like behaviors during the FST with little effect in anxiety-related paradigms (Morales-Medina et al., 2009a). Moreover, the long-term administration (14 days) of the Y2 receptor agonist PYY3-36 enhanced the depression-like state of the OBX rats (Morales-Medina et al., 2009a). The fact

that PYY3-36 is a more potent Y2 agonist than NPY13-36 may account for discrepancies observed in the two animal models. In contrast to NPY and Y1 KO mice, Y2-deficient mice showed no apparent compensatory changes in the expression of other NPY receptor subtypes (Wittmann et al., 2005) as revealed by reproducible behavioral antidepressant- and anxiolytic-like effect in these animals. Moreover, a caveat with respect to the efficacy of Y2 receptors relates to their memory-reducing effects as observed in Y2 KO mice (Greco and Carli, 2006; Redrobe et al., 2003a). The role of the Y2 receptor in the stress response is not well established. Defecation is known to be enhanced after stress and is diminished in Y2 KO mice following an immune challenge using lipopolysaccharide (Painsipp et al., 2008a). Additionally, Sainsbury et al. (2002) have shown a massive reduction in CRF levels in germ line Y2 KO mice. Both reports may suggest the involvement of the Y2 receptors in the stress response. However, further investigations are required to clarify this specific contribution of this receptor subtype in stress using selective molecules and inducible KO mouse models.

2.4.

The NPY Y4 receptor in depression-related behaviors

The Y4 receptor is known for its high affinity for PPs relative to NPY. This receptor also regulates gastrointestinal motility and decreases food intake (Tasan et al., 2009; Ueno et al., 2007). Recent evidence, using Y4 KO or transgenic PP mice, has suggested a possible role for the Y4 receptor and its preferred ligands in emotional processes. Y4 KO mice display an antidepressant phenotype in male (Tasan et al., 2009) and female (Painsipp et al., 2008a,b) mice. Furthermore, female Y4 KO mice do not demonstrate memory deficits as compared to those observed in Y2 KO mice (Painsipp et al., 2008b). In addition, Y2/Y4 double KO mice showed augmented reduction in immobility time in the FST, compared to Y2-deficient male mice (Tasan et al., 2009). In line with these results, mice overexpressing PPs possess an anxiogenic phenotype (Ueno et al., 2007). Moreover, chronic intraperitoneal administration of PPs induced anxiety in a murine model of obesity (Asakawa et al., 2003). However, ICV administration of PPs failed to modulate emotional behaviors in mice (Asakawa et al., 1999). Finally, repeated administration of PPs diminished CRF mRNA levels in the hypothalamus of obese mice (Asakawa et al., 2003), suggesting an inhibitory effect on the stress response. Accordingly, the Y4 receptor subtype is a promising target toward the development of novel antidepressants. However, major limitations currently exist regarding the study of this receptor subtype. Pharmacological approaches are restricted due to the lack of selective antagonists. Furthermore, the role of the Y4 receptor and its preferential ligands should also be investigated in more appropriate models of anxiety- and depression-related behaviors.

2.5.

The NPY Y5 receptor in depression-like behaviors

The Y5 receptor subtype has been known as the “feeding receptor” (Marsh et al., 1998). Anorexic properties have been associated with Y5 antagonists, such as CGP71683A, in naive as well as in obese animals (Kask et al., 2001) and MK-0557, after a long-term treatment in humans (Erondu et al., 2006). In

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contrast, food intake is enhanced after the administration of the NPY Y5 agonist [cPP1-7, NPY19-23, Ala31, Aib32, Gln34]hPP in rat (Cabrele et al., 2000) as well as in Y5-deficient mice (Higuchi et al., 2008). Interestingly, the Y5 receptor subtype is expressed in low levels in hypothalamic nuclei, lateral septum, locus coeruleus, brainstem, and amygdala of the rat brain (Dumont et al., 2000). Recent data also suggested that this receptor may be involved in mood-related behaviors in animal models (Kask et al., 2001; Sajdyk et al., 2002; Sorensen et al., 2004; Walker et al., 2009). For example, the acute administration of the NPY Y5 receptor agonist, [cPP1-7, NPY19-23, Ala31, Aib32, Gln34]hPP administered in the lateral ventricle (Sorensen et al., 2004) as well as basolateral amygdala (Sajdyk et al., 2002) induced anxiolyticlike activity in naive rats. In contrast, Novartis 1, a Y5 antagonist, reversed the anxiolytic-related effects of the basolateral infusion of NPY3-36 (Sajdyk et al., 2002) suggesting a main role in the modulation of anxiety by Y5 receptors in the amygdala. Meanwhile, the Y5 antagonist, CGP71683A, when administered acutely in naive rats, had limited effect in the open field but modified vertical and horizontal activity in the EPM (Kask et al., 2001). In accordance with these data, Novartis 1, failed to modulate the time spent in social contacts when administered alone (Sajdyk et al., 2002). Recently, the repeated administration of a novel Y5 receptor antagonist, Lu AA33810, produced robust antidepressant-related behaviors in two animal models of depression-like behaviors in rat (Walker et al., 2009). Although both Lu AA33810 as well as CGP71683A displayed anorexic properties, their emotion-related behaviors were in the opposite direction. These apparent discrepancies could be due to the fact that CGP71683A possess nanomolar affinity for muscarinic receptors and serotonin uptake sites while Lu AA33810 seemed to be more selective for the Y5 receptor subtype. Decrease in Y5 receptors in lactating dams induce lower maternal care and diminished body weight in rat offsprings (Ladyman and Woodside, 2009). Therefore, Y5 receptors may mediate some aspects of maternal care in early life which might reduce the risk of developing mood-related disorders later in adulthood. Marsh et al. (1998) and Higuchi et al. (2008) studied the role of Y5 receptor in feeding behaviors in Y5 KO mice. However, there is a lack of literature regarding the importance of Y5 KO mice in emotional processes. Interestingly, some Y5 antagonists can cross the BBB in contrast to currently available Y1 and Y2 receptor antagonists. Accordingly, studies using specific Y5 receptor ligands in well-established animal models of depression- and anxiety-like behaviors and Y5 receptor KO mice are certainly warranted.

3.

1996; Westrin et al., 1999a; Widerlov et al., 1988a,b). NPY mRNA levels are decreased in bipolar patients as well (Kuromitsu et al., 2001). However, other studies failed to observe any significant differences in NPY levels (Czermak et al., 2008; Gjerris et al., 1992; Ordway et al., 1995; Roy, 1993). These apparent discrepancies could be due to methodological differences or more likely to the heterogeneous nature of the disease. Recent findings using genetic approaches (see Section 3.5) may help to clarify these data. Additionally, NPY levels vary among species. For example, plasma NPY levels are in picomoles per milliliter range in rat (Zukowska-Grojec et al., 1988) while NPY being femtomoles per milliliter range in human (Pernow et al., 1986). The difference in order of magnitude of NPY levels may also have contributed to find more reproducible results obtained in depression-related behaviors in animal models. Interestingly, postmortem brain study of epileptic patients with depressive symptomatology revealed higher number of NPY-positive cells in the basolateral amygdala (BLA) (Frisch et al., 2009). However, the authors did not measure NPY levels in BLA limiting possible interpretations as to release and relevance to the process of disease.

3.2.

Clinical studies involving the use of antidepressants

Human subjects treated with antidepressants have been shown to present with augmented levels of NPY. For example, Nikisch et al. (2005) reported a positive correlation between long-term treatment with the SSRI, citalopram, and increased CSF NPY levels. In addition, Nikisch and Mathe (2008) found a significant increase in CSF NPY levels in refractory depressed patients following electroconvulsive therapy (ECT). However, data relative to antidepressant effectiveness and NPY levels have not been consistent. For example, the administration of the selective monoamine oxidase A inhibitor, amiflamine, failed to modulate NPY levels in depressed patients (Widerlov et al., 1988a). Olsson et al. (2004) measured NPY levels before antidepressant treatment as well as 3–4 months posttreatment in depressed patients who attempted suicide. Reduced CSF NPY levels were noted between the second and third measure, a period during which depressed patients received drug treatment. In that study, patients received diverse antidepressants at different doses during monitoring time which makes it difficult to make definite conclusions. Additionally, it is known that a considerable number of depressed subjects do not respond well to antidepressant therapy (Berlim et al., 2008). Accordingly, the absence of change in NPY levels could be particularly seen in non-responders. Further studies will be required to investigate this hypothesis.

Human studies 3.3.

A summary of clinical data on the role of NPY in depression is presented in Table 1 with details discussed below.

3.1.

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Clinical studies related to depression

Investigations on the level of NPY in plasma or cerebrospinal fluid (CSF) have shown that those are decreased in patients suffering from major depression (Hashimoto et al., 1996; Heilig et al., 2004; Hou et al., 2006; Irwin et al., 1991; Nilsson et al.,

Studies in other mental illnesses

NPY has been associated with other psychiatric illnesses including schizophrenia (Karl and Herzog, 2007). A few studies have evaluated the level of NPY and of its receptors following the administration of antipsychotics. Treatment with typical and atypical antipsychotics including haloperidol and clozapine did not alter NPY levels in schizophrenic patients who had never received any medication or had a wash out for at least 2 weeks prior to treatment (Widerlov et al., 1988b).

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Table 1 – Summary of clinical studies, suggesting a role of neuropeptide Y (NPY) in depression. Model

Effect

Cerebrospinal fluid

Brain tissue Plasma levels

Plasma levels Platelets Platelet-poor plasma Brain tissue Antidepressant treatment mRNA level

Condition

↓ NPY levels

Major depression

=NPY levels

Major depression

↓ NPY levels ↓ NPY immunoreactivity frontal cortex and caudate putamen ↑ NPY levels ↓ NPY levels =NPY levels Positive correlation between NPY levels and psychiastenia and irritability ↓ NPY levels ↑ NPY immunoreactivity ↓ NPY levels

Suicide attempters Postmortem suicide brains

(Widerlov et al., 1988a; Widerlov et al., 1988b; Heilig et al., 2004; Hou et al., 2006) (Gjerris et al., 1992; Roy, 1993; Ordway et al., 1995; Nikisch and Mathe, 2008) (Westrin et al., 1999a,b; Olsson et al., 2004) (Widdowson et al., 1992)

Major depression Major depression Major depression Suicide attempters

(Irwin et al., 1991) (Hashimoto et al., 1996) (Czermak et al., 2008) (Westrin et al., 1998)

Suicide attempters Major depression Major depression

(Westrin et al., 1999a,b; Westrin et al., 1999) (Nilsson et al., 1996) (Nilsson et al., 1996)

↓ NPY-positive cells in amygdala ↑ NPY levels =NPY levels ↓ NPY levels ↓ NPY mRNA =NPY levels =Y1 receptor

Depression and epilepsy Major depression Major depression Major depression Bipolar disorder Suicide victim Major depression and bipolar disorder Suicide victim

(Frisch et al., 2009) (Nikisch et al., 2005; Nikisch and Mathe, 2008) (Widerlov et al., 1988a) (Olsson et al., 2004) (Kuromitsu et al., 2001) (Caberlotto and Hurd, 1999) (Caberlotto and Hurd, 2001)

↑ Y2 receptor in frontal cortex

Similarly, additional studies showed that fluphenazine has little effect on the expression of Y1 and Y2 receptors in schizophrenic subjects (Caberlotto and Hurd 1999, 2001). Accordingly, changes in NPY-related markers seen in depression may not apply to other mental illnesses.

3.4.

Reference

Suicide-related studies in depressed patients

Suicide is an extreme consequence of psychiatric disorders with up to 60% of co-morbidity with mood disorders (Mann et al., 1999; Mann, 2003) and up to 15% of suicide cases occurring in depressed patients (Mann et al., 1999). Hence, another approach to better establish the relationship between NPY and depression is the postmortem examination of NPY markers in the brain of depressed suicide victims compared to those of accidental death controls as well as CSF and plasma levels of NPY in suicide attempters. Westrin et al. (1998) reported a positive correlation between NPY levels and both psychasthenia and irritability in a battery of personality scores in suicide attempters with a mood-related disorder. Widdowson et al. (1992) observed decreased levels of NPY in brain tissues of suicide victims. However, in a subsequent study, the same group reported unaltered NPY levels in brains of suicide victims (Ordway et al., 1995). Methodological differences likely explain these apparent discrepancies. Suicide attempters with a depression-related diagnosis displayed diminished CSF NPY levels (Olsson et al., 2004; Westrin et al., 1999b). In contrast, Roy (1993) did not find a significant difference in CSF NPY levels of depressed patients following a recent suicide attempt. Moreover, Caberlotto and Hurd (1999) failed to observe a reduced NPY mRNA levels in the brains of suicide victims.

(Caberlotto and Hurd, 2001)

Caberlotto and Hurd (2001) also investigated the mRNA levels of Y1 and Y2 receptors in the cortex of patients with different psychiatric conditions (major depression, bipolar disorder, and schizophrenia). Y1 receptor mRNA levels were unaltered in any of the conditions studied. In a small percentage of brains, Y2 receptors mRNA levels in the prefrontal cortex were increased in suicide victims (Caberlotto and Hurd, 2001). Further studies should investigate NPY receptor subtype changes in these disorders.

3.5.

Genetic studies in depression-related illnesses

New gene-related technologies are helpful for dissecting specific contribution of a given gene under normal physiological conditions and in disease states (Merikangas et al., 2002). Initial studies have suggested the possible involvement of NPY polymorphisms in mood and anxiety related disorders. Recently, a polymorphism in the prepro-NPY gene (SNP rs16147, Leu7Pro) has been linked to higher and faster processing of NPY as shown in Figs. 1B and C (Kallio et al., 2001). Since low levels of NPY have been observed in depressed patients, subjects with this polymorphism may present with a decreased susceptibility to depression-related disorders. In a preliminary study with Swedish participants, Heilig et al. (2004) observed that the frequency of this polymorphism is reduced in depressed patients as compared to healthy controls and this result is being replicated in a larger sample (Sjoholm et al., 2009). The outcome of this study also suggests that the Leu7Pro polymorphism may have a protective effect in subjects who have depression with no concurrent anxiety disorder. However, a Danish population-based study failed to replicate these findings (Lindberg et al., 2006). These negative

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results may be related to the fact that critical clinical information, such as age, sex, and presence of a psychiatric illness, was not available for the first control group (Lindberg et al., 2006). The control group in the later part of the study was selected based only on questionnaires to exclude moodrelated disorders. Another polymorphism-related study in small sample (SNP rs16147, − 399C/T promoter) carried out to evaluate the response of this polymorphism (three haplotypes H1, H2, and H3) to stress suggested that the difference in haplotype predicts a robust stress response and variability in emotion processing in humans (Zhou et al., 2008). But recently, differences in these haplotypes were not correlated to anxiety trait in a larger sample study (Cotton et al., 2009). Finally, Detera-Wadleigh et al. (1987) failed to find association between NPY variants and unipolar or bipolar depression using restriction fragment length polymorphisms. Further genetic association studies are thus clearly warranted.

3.6.

Relationship between stress and NPY in humans

Long-term stress has been found to be inductive and concomitant in a considerable proportion of depressed subjects (Cabib and Puglisi-Allegra, 1996). Antonijevic et al. (2000) showed that repeated administration of NPY reduces cortisol secretion during night hours in healthy subjects. This was the first study demonstrating a relationship between NPY and cortisol in humans. In addition, a series of experiments demonstrated that acute, uncontrollable psychological stress increased plasma cortisol as well as augmented NPY levels in healthy subjects (Morgan et al., 2000, 2001, 2002). These studies used a model of psychological stress which mimics captivity experience in a training laboratory of the United States Army. These results demonstrate increased NPY levels following stressful events, with elevated levels generally returning to baseline 24 hours later. In addition, higher levels of NPY have been observed in soldiers who either present reduced psychological distress (Morgan et al., 2002) or belong to special forces (Morgan et al., 2000). Interestingly, for special force soldiers, increased NPY levels returned to baseline level faster than in non-special forces soldiers (Morgan et al., 2000). Usually, special force soldiers experienced longer training time and thus are apparently more capable of controlling unpredictable and stressful conditions. Therefore, this extended training time may explain why higher levels of NPY are released faster to “buffer” the effects of stress in these subjects. In addition, the more rapid return to baseline values might suggest that training of special force soldiers is associated with dangers of threat being interpreted as ending more rapidly relative to conventionally trained forces. Although studies carried out by Morgan et al. (2000, 2001, 2002) are in agreement on the role of NPY in response to stressful stimuli, measurements were carried out only using plasma levels. Hence, these measures most likely only account for changes in NPY levels related to sympathetic nervous system activation but not to those occurring in the central nervous system. It would be of interest to perform similar studies on the level of NPY in the cerebrospinal fluid in other groups experiencing chronic stressful conditions at work, such as

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emergency room triage nurses or trauma surgeons compared to other practitioners.

4.

Conclusion

For nearly two decades, scientists have studied the role of NPY and of its receptors in affective disorders and stress. Behavioral results on NPY, Y1 and Y2 receptors in animals have provided robust data as to their role in emotional responses and stress. By using relevant animal models of depression-like behaviors, novel approaches should reveal possible mechanism of action as well as opportunities for long-term clinical treatment using Y1 agonists and Y2 antagonists. The possible role of Y4 and Y5 receptors needs further investigation to establish their contribution in depression-like behaviors. Human studies have revealed a role for NPY in “buffering” the deleterious effects of stress. However, its involvement in depression remains rather controversial. Further studies are thus required using subjects that are better genotyped and phenotyped into subgroups. It would then be clearer as to the role of NPY in depression-related illnesses and possible NPYrelated therapies.

Acknowledgments This study was supported by grants from the Canadian Institutes of Health Research (RQ). J.C.M.M. is a PhD student with fellowship from CONACyT-Mexico. Thanks to Mira Thakur for editing the English-language text.

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