Angiotensin as stress mediator: Role of its receptor and interrelationships among other stress mediators and receptors

Pharmacological Research 76 (2013) 49–57

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Review

Angiotensin as stress mediator: Role of its receptor and interrelationships among other stress mediators and receptors Anjana Bali, Amteshwar Singh Jaggi ∗ Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, 147002, India

a r t i c l e

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Article history: Received 11 July 2013 Accepted 15 July 2013 Keywords: Stress Angiotensin Corticotrophin releasing hormone Hypothalamus–adrenal–pituitary axis AT2 receptors

a b s t r a c t The involvement of renin-angiotensin system (RAS) and its active peptides, particularly angiotensin II (Ang II), has been described not only in hypertension, but also in stress-associated anxiety disorders. Ang II and its two subtypes of receptors, viz. AT1 and AT2 , are localized on stress-responsive brain areas including the hypothalamus–adrenal–pituitary (HPA) axis. The different types of stressors increase the levels of Ang II and change the expression of its receptors. Transgenic animals with a centrally inactivated angiotensin system demonstrate increased anxiety-related behavior describing the anxiolytic effects of basal Ang II. However, studies showing the anxiolytic potential of AT1 receptor antagonists have described the anxiogenic effects of endogenously released Ang II. It suggests that the basal Ang II (in low amount) may attenuate anxiety, while stress-released Ang II (in high amount) may produce anxiety. By employing AT2 -deficient mice, the functional role of AT2 receptors in attenuating stress-associated anxiety has been described. Moreover, AT1 receptor antagonists-induced anti-anxiety effects are associated with up-regulation of AT2 receptors in the brain suggesting that the centrally acting AT2 receptor agonists may serve as potential anxiolytic agents. The present review discusses the dual role of Ang II and its receptors in the development of stress-associated anxiety along with its interrelationship with benzodiazepines (BZD) receptors, and other stress mediators including corticotrophin releasing hormone (CRH) and serotonin (5-HT). © 2013 Elsevier Ltd. All rights reserved.

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AT1 and AT2 receptors in stress-responsive brain areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. AT1 receptors and stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. AT2 receptor and stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Anxiolytic/anxiogenic effects of centrally administered Ang II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Anxiogenic phenotype in transgenic rats with centrally inactivated angiotensin system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Hypothesis for the contradictory results of Ang II in stress-based studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Role of other angiotensin neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interrelationship among different endogenous stress modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. CRH, Ang II and stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. 5-HT, Ang II and stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Benzodiazepine (BZD), Ang II and stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, Patiala 147002, India. Tel.: +91 9501016036; fax: +91 0175 2283073. E-mail address: [email protected] (A.S. Jaggi). 1043-6618/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.phrs.2013.07.004

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1. Introduction Stress is a state of threatened homeostasis, which mobilizes a composite spectrum of adaptive physiological and behavioral responses with the aim of restoring and maintaining challenged homeostasis [1]. Every change in the internal or external environment that disturbs or threatens to disturb the homeostasis evokes a spectrum of adaptive physiologic responses, including activation of the hypothalamic–pituitary–adrenal (HPA) axis and autonomic system [2]. The body responds to acute stress by releasing endogenous mediators to cope with stressors [3,4]; while the same endogenous mediators may trigger maladaptive signaling to produce pathophysiological changes during repeated stress exposures [5,6]. Accordingly, the term allostasis (achieving stability through change) is used and refers to an active process by which the body responds to daily events and maintains homeostasis. However, allostatic load/overload either due to too much of stress or from inefficient management of allostasis (not turning off the response, when it is not needed) leads to pathophysiological changes such as anxiety and depression [2,3]. Stress is an antecedent and is a causative factor for the development of anxiety and depression. Furthermore, anxiety disorders generally precede the development of depression suggesting a continuum between these disorders with common pathophysiological features. Both anxiety and depression are the result of an inappropriate adaptation to stress and have been termed as stress-related disorders, with a causal role of HPA axis [7]. In contrast to acute and chronic stress, anxiety disorders are considered as diagnosable mental illnesses. The DSM-IV-TR recognizes the following diagnosable anxiety disorders: generalized anxiety disorder, panic disorder, panic disorder with agoraphobia, phobias, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), separation anxiety, and childhood anxiety disorders. Generalized anxiety disorder is mainly characterized by an excessive anxiety and worries for at least 6 months, in addition to restlessness, fatigue, irritability and sleep disturbance. Angiotensin II (Ang II) synthesized in the brain by the local renin-angiotensin system acts as a neuropeptide, neuromodulator, neurotransmitter and neurohormone [8,9]. As a neuromodulator, Ang II facilitates neurotransmission by enhancing the release of norepinephrine (NE) from the catecholaminergic nerve terminals and inhibiting its reuptake [10]. Ang II is also a classical neurohormone and regulates blood pressure, thirst, water and electrolyte balance. Moreover, it modulates the neuroendocrine system to influence the behavioral functions, and is regarded as an important “stress hormone” [11,12]. Ang II produces different actions by acting on its two sub-types of receptors (AT1 and AT2 ). The well-known physiological actions of Ang II are mediated through AT1 receptors, while the role of AT2 receptors in mediating homeostatic functions is controversial [13,14]. The binding of Ang II induces a conformational change in the G protein coupled AT1 receptors to trigger the signal transduction via several plasma membrane localized effector systems. These include enzymes such as phospholipase A2 , C, D; adenylyl cyclase; NADPH oxidase and ion channels such as Land T-type voltage-sensitive calcium channels [15,16]. The AT2 receptors are clearly distinct from the AT1 receptors with respect to molecular weight, diversity in tissue-specific expression and signaling mechanisms. These receptors are also G-protein coupled (mostly of Gi type), and the signal transduction pathway involves the activation of protein serine/threonine phosphatase PPA2 and phosphotyrosine phosphatases (PTPases), nitric oxide, and cyclic guanosine monophosphate [14,17]. The different types of stressors (isolation, immobilization/restraint, cold restraint and immunological) influence the release of Ang II and expression of its receptors in the brain as well as in the peripheral tissues [18,19]. The stimulation of AT1

receptors of paraventricular nucleus (PVN) of the hypothalamus increases the secretion of corticotrophin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and adrenal glucocorticoids [20,21]. The literature reports the critical role of AT1 receptors in modulating stress-associated anxiety [22,23]. The evidences suggest that the central AT2 receptors control the stress response by modulating catecholamine synthesis/release in the locus coeruleus (LC) region [24,25]. A variety of preclinical and clinical studies have shown the usefulness of renin-angiotensin modulating drugs in attenuating stress-associated anxiety and improving mood in depressed patients [26,27]. AT1 receptors have received greater attention so far, and scientists have employed the selective AT1 receptor antagonists to demonstrate their anxiolytic potential [26]. However, recent studies have shown that stress decreases the expression of AT2 receptors in the brain, and animals lacking the AT2 receptors tend to develop anxious behavior [28,29]. These findings suggest that activation of central AT2 receptors may attenuate stress-associated anxiety and hence, central AT2 receptor agonists may be potential anti-stress and anxiolytic agents. Furthermore, an anxiogenic phenotype of transgenic rats lacking the central angiotensin system suggests the anxiolytic effects of basal Ang II [30]. The beneficial actions of Ang II are supported by studies showing that its acute central administration produces anxiolytic effects [31]. Therefore, it is proposed that novel centrally acting Ang II analogs may serve as effective adaptogenic agents to attenuate stress-associated anxiety and other behavioral changes. The present review discusses the dual role of Ang II and its receptors (AT1 and AT2 ) in the development of stress-associated anxiety and its interrelationship with benzodiazepines (BZD receptors, and other stress mediators such as corticotrophin releasing hormone (CRH) and serotonin (5-HT).

2. AT1 and AT2 receptors in stress-responsive brain areas The AT1 receptors are distributed throughout the brain, including the key areas regulating stress response such as the HPA axis [16,32]. The medial, basomedial, lateral, and basolateral nuclei of amygdala (located deep within the medial temporal lobes and part of the limbic system) control the emotional responses such as fear conditioning and adaptation to danger, and these nuclei are enriched with AT1 receptors [33–35]. The other stress responsive brain regions include the cortex, hippocampus, LC, median eminence (ME), subfornical organ (SFO), dorsomedial hypothalamus (DMH) and nucleus tractus solitarius (NTS), and are also enriched with Ang II and its receptors. The different sections of cortex such as the prefrontal cortex, entorhinal, piriform cortex and neocortex control cognition and emotional behavior [16,36]. The hippocampus (located deep within the medial temporal lobes of the brain, lateral to the amygdala, and a part of the limbic system) is an important structure for storing memory processes during stress. The preformed memories have an important influence on enhancing, suppressing or independently generating stress response. The LC region is located in the pons (a part of the brainstem) and is actively involved in controlling the physiological response to stress and panic. It is a site of origin of sympathetic innervation to the cortex and is involved in stress-induced central sympathetic stimulation. The DMH is a nucleus of the hypothalamus that regulates paniclike responses [37,38]. The paraventricular nucleus (PVN) of the hypothalamus is another important stress-sensitive brain region (located adjacent to the third ventricle of the forebrain), which is activated by a variety of stressful and/or physiological changes. The SFO is a sensory circumventricular organ (situated on the ventral surface of the fornix, at the interventricular foramina outside the blood–brain barrier in lamina terminalis) and is also involved in

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regulating the stress response. NTS is a group of cells in the brainstem (on each side of the upper medulla and dorsal nucleus of the vagus reticular) that receive viscerosensory information and transmits to the basal forebrain, which is actively involved in regulating cortical processing of anxiogenic stimuli. Furthermore, additional nerve projections from the NTS to the LC, the bed nucleus of stria terminalis and the amygdaloid structures, influence the processing of anxiogenic stimuli. The ME is an integral part of the hypophyseal portal system, which connects the hypothalamus to the pituitary gland. The projections of neurons from median preoptic nucleus (a region of the hypothalamus) to ME regulate the stress response by controlling the release of stress hormones [18,39,40]. The two homologous isoforms of AT1 receptor, i.e., AT1A and AT1B may produce differential actions within the same brain region. The AT1A receptors in the mouse SFO region are involved in blood pressure regulation, while the AT1B receptors mediate the water drinking response [41]. Functional and anatomical studies have shown the abundant presence of AT2 receptors in neonates, where these are involved in the development of central nervous structures [11,16]. However, their number is significantly reduced in the adult tissues, including the brain [42] and is restricted to the inferior olivary complex, thalamic nuclei and LC to control sensory, motor and behavioral functions [16]. Although it has been proposed that the AT2 receptors exhibit their functional role only after their up-regulation under pathologic conditions [32], their physiological role has also been demonstrated in AT2 −/− mice suggesting that these receptors are also functional during normal non-pathological conditions [30,31]. 2.1. AT1 receptors and stress The different types of non-immunological (isolation, immobilization/restraint and cold restraint) and immunological stressors increase the expression of the AT1 receptors in the stressresponsive brain areas both inside and outside the blood–brain barrier [18,43]. The evidences suggest that stress increases the release of Ang II within the brain and also increases the expression of AT1 receptors, both inside the brain as well as in the peripheral tissues. This suggests the involvement of Ang II/AT1 receptor system in stress-mediated changes [11,18,19,44]. In particular, the significant rise in AT1 receptor expression in the parvocellular PVN of the hypothalamus (cell bodies forming CRH are present) in response to stress has been demonstrated [20,21]. Furthermore, it is also reported that these receptors are transported from the PVN to the ME through the axons co-expressing CRH [45]. The changes in AT1 receptor density are related to changes in the hormonal and the sympathoadrenal system in response to stress. Stress-induced activation of the HPA axis increases the levels of adrenal glucocorticoids that in turn regulate the expression

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Fig. 1. Dual role of AT2 receptor in the brain and periphery in stress-induced anxiety and its modulation by AT1 receptor antagonists.

of Ang II receptors on the PVN region [20,21] through stimulation of glucocorticoid response elements in the AT1 receptor promoter region [46]. Interestingly, these receptors are also present on the HPA axis [15] and the different stressors that vary in intensity increase their expression on this axis [20,26,47]. Therefore, it may be proposed that stress activates the HPA axis to activate the Ang II/AT1 receptor system, which in turn may also activate the HPA axis to induce a vicious cycle and exaggerate the stress response (Fig. 1). The literature suggests that the AT1 receptor antagonists attenuate stress-mediated deleterious effects (Table 1). Administration of candesartan (AT1 receptor antagonist) has been shown to prevent the isolation stress-induced changes in the hormonal and sympathoadrenal system by inhibiting peripheral and brain AT1 receptors [25]. In addition, pretreatment with candesartan has also been shown to prevent cold-restraint and isolation-induced gastric ulceration in rats [48]. These gastro-protective effects have been attributed to attenuation of Ang II-mediated inflammation (neutrophil infiltration and increased expression of ICAM-1 and TNF-␣) in the gastric mucosa [48]. Peripheral administration of losartan (a selective AT1 receptor antagonist) has also been shown to attenuate anxiety in experimental renal hypertensive as well as in normotensive rats. Furthermore, administration of enalapril

Table 1 The summarized preclinical and clinical pharmacological effects of ACE inhibitors, AT1 receptor antagonists in stress-associated anxiety and other behavioral changes. Sr. no.

Intervention

ACE inhibitors and AT1 receptor antagonists Candesartan 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Candesartan Candesartan Candesartan Candesartan and Ramipril ACE inhibitor/ARB Losartan Enalapril Captopril and enalapril Lisinopril ACE inhibitors/ARB

Comments

References

Normalization of hormonal and sympathoadrenal response to isolation stress and cold restraint stress Attenuation of gastric ulceration produced by isolation and cold restraint stress Decrease in tyrosine hydroxylase mRNA in LC and adrenal medulla leads to decrease in central sympathetic outflow and adrenaline release, respectively Prevents acute inflammatory and restraint stress-induced BZD receptor changes Decreases stress sensitivity of HPA axis Decreases the incidences of post-traumatic stress disorder (PTSD) in patients Attenuates i.c.v Ang II-induced anxiety Attenuates anxiogenic behavior in experimental renal hypertension Improves cognition and depressed mood in hypertensive patients Augments the therapeutic response of antidepressants Lower rate of anti-depressant usage

[18,26] [48] [59] [89] [50] [64] [60] [49] [22] [53] [27]

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(angiotensin-converting enzyme inhibitor) selectively attenuates anxiety in hypertensive rats [49]. Intracerebroventricular (icv) administration of losartan has been shown to attenuate Ang II-induced anxiety and motor impairment [22]. Raasch et al. demonstrated that the administration of candesartan and ramipril (angiotensin-converting enzyme inhibitor) decreases the stress-sensitivity of the HPA axis in spontaneously hypertensive rats, independent of their anti-hypertensive effects. Chronic treatment with angiotensin antagonists was shown to attenuate CRH-stimulated ACTH and corticosterone release in the plasma without affecting their baseline levels [50]. Bregonzio et al. demonstrated that the administration of candesartan abolishes cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the LC and adrenal medulla of spontaneously hypertensive rats [18] suggesting that the decreased sympathetic outflow from the brain, and reduced release of adrenaline from the periphery may be responsible for the anti-stress effects of AT1 receptor antagonists. The same study also demonstrated the reduction in AT1 receptor binding in the different brain regions, including ME and basolateral amygdala in response to the cold restraint stress. The reduced AT1 receptor binding may be due to fast internalization of these receptors in response to stress-induced Ang II release [18,44]. The reduced AT1 receptor binding serves as an endogenous protective mechanism to prevent the deleterious effects of Ang II in stress-subjected animals. The contention that increased levels of Ang II-induces anxiety has been supported by studies showing the development of an anxiety-like behavior in transgenic rats with the up-regulated RAS system [TGR (mREN2)27] [51]. Renin-angiotensin system modulating drugs have been shown to exert beneficial effects in patients with behavioral alterations. Zubenko and Nixon reported an improvement in mood and attenuation of depressive symptoms in three hypertensive patients [52]. These results were supported by studies showing that captopril and enalapril improved the cognition and depressed mood in hypertensive patients [22]. Hertzman et al. demonstrated that administration of lisinopril may augment the anti-depressant response [53]. A more recent study has shown that the administration of renin-angiotensin-aldosterone system modifying medications lowers the rate of anti-depressant usage [27]. A recent cross-sectional and observational clinical study has also suggested a significant association between ACE inhibitor/ARB (angiotensin receptor blocker) medications and decreased posttraumatic stress disorder (PTSD) symptoms [54]. Thus, both preclinical and clinical reports suggest that the AT1 receptor antagonists are of therapeutic relevance in controlling stress-associated deleterious effects (Fig. 1).

2.2. AT2 receptor and stress The distribution of AT2 receptors in the brain is age-dependent and in the young rats, these are widely distributed in the anterior pretectal nucleus, nucleus of the optic tract, ventral tegmental area, posterodorsal tegmental nucleus, hypoglossal nucleus, central medial and paracentral thalamic nuclei, laterodorsal thalamic nucleus, and oculomotor nucleus of the brain [15]. A major role of these receptors has been defined in the development of visual, motor, sensory, and limbic functions. However in the adult brain, the distribution of these receptors is limited to certain brain regions related to sensory, motor and behavioral function, such as the inferior olivary complex (particularly medial sub-nuclei A and B), thalamic nuclei and LC. The expression of these receptors within the LC area is highly species-dependent. In rats, the LC region expresses only the AT2 receptors (does not express the AT1 receptors), while these have not been detected in the mouse LC region [15].

Apart from the role of these AT2 receptors in the development of brain, there are evidences of reduced exploratory behavior and spontaneous movements in AT2 gene-disrupted (AT2 −/− ) mice suggesting the key role of these receptors in behavioral control [28,29]. Furthermore, these reports also suggest that these AT2 receptors are functional in normal (basal) physiological conditions. On the other hand, there have been reports proposing that these receptors exert their modulatory actions only after their up-regulation under certain pathological conditions [55]. Watanabe et al. demonstrated that central administration of AT2 receptor antagonist (CGP42112A), not AT1 antagonist, attenuates interleukin-1 (IL-1)induced hyperthermia in rats [56]. The same group of scientists also demonstrated that AT2 -deficient mice exhibit lower hyperthermia in response to immunologic stress (administration of IL-1␤) [57]. In these studies, it was shown that the disruption or pharmacological blockade of AT2 receptors attenuates early stages of hyperthermia suggesting that the activation of AT2 receptors is an important factor in contributing to the development of immunological stress-induced hyperthermia [56,57]. In contrast, a greater increase in body temperature in response to non-immunological cage-switch stress (psychological stress of a new environment) was demonstrated in AT2 receptor-deficient mice suggesting the dual role of these receptors in controlling hyperthermia depending on a type of stressor, i.e., immunological or non-immunological [57]. Okuyama et al. demonstrated the development of anxiety-like behavior in AT2 -receptor deficient mice suggesting the basal anxiolytic effect of these receptors in wild-type mice. Furthermore in these AT2 receptor-deficient mice, a significant reduction in the number of [3H] prazosin, but not [125I] CRF, binding sites in the amygdala was demonstrated. The administration of prazosin (␣1 antagonist), but not the CRF receptor antagonist, was also shown to reverse anxiety-like behavior suggesting the involvement of noradrenergic system in producing anxiety in AT2 -deficient mice [58]. Peng and Phillips demonstrated the decreased AT2 receptor density/binding in the LC and inferior olive regions in response to chronic cold stress-induced hypertension in rats [24]. Other studies have also shown the decreased AT2 receptor binding in the LC region in response to isolation-induced stress [43] suggesting that the decreased AT2 receptor density/binding may be responsible for stress-related deleterious changes. On the other hand, Bregonzio et al. demonstrated the differential changes in the AT2 receptor binding in the different brain regions in response to acute cold stress. The authors demonstrated an increase in AT2 receptor binding in the medial sub-nucleus of the inferior olive region, and a decrease in AT2 binding in the ventrolateral thalamic nucleus of rats [18]. These finding suggest that more studies are warranted to precisely state the changes regarding the density and binding of AT2 receptors in the brain stem in stress-subjected animals. Pharmacological research has demonstrated the participation of these receptors in Ang II-mediated behavioral changes as i.c.v. administration of AT2 receptor antagonist (PD 123319) has been shown to attenuate Ang II-induced anxiety and motor impairment [22]. Furthermore, the relationship between AT1 receptor blockade and changes in the AT2 receptor binding within the different brain regions and periphery is also explored. Pretreatment with AT1 receptor antagonists increases the AT2 receptor binding in the LC, inferior olive, and adrenal cortex; and decreases in the adrenal medulla [59]. Administration of candesartan has also been shown to selectively enhance the expression of AT2 receptors in the brain and abolish cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the LC region and adrenal medulla of spontaneously hypertensive rats [22]. The up-regulation of AT2 receptors in the LC, due to AT1 receptor blockade, may decrease the central sympathetic outflow; while their decreased expression in the adrenal medulla may decrease the adrenaline release. Therefore, the indirect participation of AT2 receptors may

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administration of Ang II was shown to produce anxiety with an increase in pro-oxidant status, and these effects were attenuated in the presence of Ang II antagonists [64]. A recent study has also reported that chronic infusion of Ang II (1900 ng/kg/min) for three weeks produces anxiety along with learning and spatial memory deficits in the elevated plus maze and open field tests [65]. 2.4. Anxiogenic phenotype in transgenic rats with centrally inactivated angiotensin system

Fig. 2. The differential action of AT1 receptor antagonists and central inactivation of angiotensinogen on stress-induced anxiety with possible mechanism and interrelationship among angiotensin and other endogenous stress modulators.

be crucial for the documented anti-stress effects of AT1 receptor antagonists. A critical role of peripheral AT2 receptors in stressmodulating effects has been supported by the findings of Muller et al. The latter demonstrated the up-regulation of these receptors in the adrenal gland of TGR(ASrAOGEN)680 in response to CRH or ACTH challenge, thereby suggesting that the up-regulation of AT2 receptors on the adrenal gland may be involved in increasing the stress-sensitivity. TGR(ASrAOGEN)680 rats are characterized by specific down-regulation of the angiotensinogen protein synthesis (by more than 90%) due to brain-specific expression of anti-sense RNA against angiotensinogen mRNA [60] (Fig. 2). Based on these studies, it may be proposed that the basal AT2 receptors localized on the brain stem (particularly on the LC) exhibit anxiolytic phenotype and their up-regulation produces anti-stress effects due to a decrease in tyrosine hydroxylase and central sympathetic derive from the brain. Furthermore, the peripherally-located AT2 receptors on the adrenal gland also modulate stress-responsiveness in a significant manner and in contrast to the central system; up-regulation of these receptors in the periphery exhibits an anxiogenic phenotype. The up-regulation of AT2 receptors on the adrenal cortex may enhance the corticosterone release, whereas their up-regulation in the adrenal medulla may increase the adrenaline release to produce anxiety. 2.3. Anxiolytic/anxiogenic effects of centrally administered Ang II There have been conflicting reports regarding the anxiolytic/anxiogenic actions of centrally administered angiotensin. ICV administration of Ang II has been shown to exert significantly less defensive burying behavior (conditioned fear-related behavior) in a dose-dependent manner suggesting that Ang II may modulate the central neurotransmitter system to exert the anxiolytic effects [54]. The bilateral microinjections of Ang II (0.1, 0.5 and 1.0 ␮g) into the hippocampal CA1 area has also been shown to exert the anxiolytic effects [31,62]. Research has demonstrated the anxiolytic effects of icv administered Ang II (1 nmol) in Wistar rats [63]. On the contrary, Ciobica et al. demonstrated the development of anxiety in response to icv Ang II (0.1 mg/kg for seven consecutive days) in the elevated plus maze model. Chronic central

Scientists have employed transgenic rats TGR(ASrAOGEN)680 for studying the endogenous role of angiotensin in stress and anxiety [30,66,67]. In these transgenic rats, the AT1 receptor binding is significantly increased in most of the regions inside the blood–brain barrier, including the paraventricular nucleus, piriform cortex, lateral olfactory tract, and lateral preoptic area. Furthermore, the functional response of Ang II is increased in these rats suggesting that these up-regulated AT1 receptors in the brain are functional. However in the subfornical organ and area postrema regions of circumventricular organs, the AT1 receptor binding is significantly lower in these rats. Furthermore, no changes in the AT2 receptor binding have been observed in the inferior olive region of brain [68]. Voigt et al. demonstrated that these transgenic rats exhibit more signs of anxiety as compared to normal Sprague-Dawley rats in the elevated plus maze and light/dark box tests [30]. The same group of scientists also demonstrated the development of anxiety in these rats in the canopy test of anxiety-related behavior [67]. Müller et al. demonstrated that TGR(ASrAOGEN)680 exhibit higher stress-sensitivity as compared to corresponding normal control rats. In response to CRH or ACTH challenge, the corticosterone release is more distinct in these transgenic rats and is independent of concurrent ACTH enhancement. The ACTH independence of enhanced corticosterone release during CRH and ACTH challenge test indicates the possible involvement of adrenal mechanisms in corticosterone release in the stress challenge tests. Furthermore, these scientists demonstrated that the AT2 receptors are up-regulated in the adrenal gland, thereby, proposing that an increased stress-sensitivity and excessive corticosterone release may be possibly mediated through up-regulation of AT2 receptors on the adrenal gland [69] (Fig. 1). 2.5. Hypothesis for the contradictory results of Ang II in stress-based studies Transgenic animals with a centrally inactivated angiotensin system (about 90%) exhibit anxiety-related behavior similar to the anti-stress/anxiolytic effects of physiological (basal) Ang II. On the other hand, studies showing the anxiolytic effects of peripheral and central AT1 receptor antagonists suggest the anxiogenic effects of stress-released Ang II [49,50]. A significant rise in the Ang II levels (1174 ± 112.0 pg/ml) in the plasma of rats subjected to acute stress (compulsive cold water swimming test) has been demonstrated as compared to the corresponding basal plasma (130 ± 9.7 pg/ml) levels. Similarly, the rise in Ang II levels in the hypothalamus (246 ± 24.1 pg/mg) and medulla oblongata (320 ± 58.3 pg/mg) has also been shown in the chronic stress model (cold environment test) as compared to the corresponding basal levels in the brain (134 ± 33.7 pg/mg in the hypothalamus and 200 ± 50.4 pg/mg in the medulla) [44]. From the results of these studies, it may be tentatively proposed that the basal Ang II (low amount) produces the anxiolytic effects, while the stress-released Ang II (large amount) produces anxiety and depression. The literature suggests the dual role of Ang II on the behavioral functions including memory and learning [70,71]. The reports from our own laboratory have described the important role of Ang II in mild stress-induced

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cognitive enhancement in mice [72] and streptozotocin (STZ)induced dementia in rats [73]. However, there has not been any direct study looking for the dual aspects of angiotensin in stress and anxiety. Apart from the above proposed hypothesis regarding the dual role of Ang II, changes in the expression of AT1 and AT2 receptors may also contribute to different results in transgenic rats based- and pharmacological antagonists-based studies. In TGR (ASrAOGEN) 680, the increased density of AT2 receptors in the adrenal gland leading to enhanced corticosterone release [69], and up-regulation of AT1 receptors in the different brain areas, may contribute to increased stress-sensitivity to stress stimuli/CRH challenge. On the contrary, the AT1 receptor antagonists indirectly up-regulates the AT2 receptors in LC region of the brain and downregulates these receptors in the periphery, i.e., adrenal gland. The up-regulation of AT2 receptors in the brain and down-regulation in the periphery may also contribute significantly to the stressalleviating functions of AT1 receptor antagonists. Research has demonstrated the contradictory results of centrally administered Ang II in anxiety alleviation/development [63,64]. Chronic central administration of Ang II has been shown to produce anxiety [64,65]; whereas its acute central administration is described to exert anxiolytic effects [61–63]. Again, there is no direct study to describe the differential role of centrally administered Ang II in the development or alleviation of anxiety. An earlier proposed hypothesis that Ang II exerts different actions depending on its amount may also be extended to explain the differential role of centrally administered Ang II. During chronic (repeated) administration, the total amount of Ang II delivered may be much higher at which it induces anxiogenic effect. On the other hand during single administration, relatively small amount of Ang II is delivered in the brain at which it may produce anxiolytic effects. Alternatively during chronic administration of Ang II, unexplored compensatory alterations in the expression of AT2 receptors (or some other proteins) may also contribute significantly to the documented anxiogenic actions of Ang II. However, direct experimental studies are warranted to precisely define the dual role of Ang II and its receptors in the development or attenuation of stress-associated behavioral disorders. 2.6. Role of other angiotensin neuropeptides Besides the very well-known central functions of Ang II, the role of other Ang peptides in modulating central functions including anxiety has also been reported [9,74]. Ang IV (Ang 3–8) binds to constitutively active metallopeptidase AT4 receptor (or oxytocinase/insulin-regulated membrane aminopeptidase). In vitro studies have shown that Ang IV inhibits the peptidase activity of AT4 receptors to increase the concentrations of oxytocin. Accordingly, it has been hypothesized that Ang IV may exhibit anxiolytic effects by increasing the brain levels of various peptides, including oxytocin. This hypothesis was supported by Beyer et al. by showing that systemic and intra-amygdalar injection of Nle-Ang IV, a metabolically stable derivative of Ang IV, elevates the extracellular levels of oxytocin in rat amygdala to exert anxiolytic effect (assessed in terms of significant increase in the number of punished crossings). Nle-Ang IV-mediated anxiolytic effects were comparable to oxytocin and standard anxiolytic agent, chlordiazepoxide. Furthermore, administration of AT4 receptor antagonist (divalinal) or the selective oxytocin receptor antagonist (WAY-162720) reversed the anxiolytic effects of Nle-Ang IV. Interestingly, combined administration of ineffective doses of NleAng IV and oxytocin exerted anxiolytic effects suggesting that both interventions are complimentary to each other [75]. Ang (1-7) is an endogenous ligand for Mas receptors (G protein-coupled receptors) and modulates the cardiac, renal and cerebral functions [76].

Recently, Bild and Ciobica demonstrated that i.c.v. administration of Ang-(1-7) produces anxiolytic effects (assessed using elevated plus maze) by decreasing oxidative stress in the amygdala [77]. Nevertheless, more studies are warranted to identify the role and possible mechanisms of these Ang neuropeptides in stress-associated anxiety. 3. Interrelationship among different endogenous stress modulators 3.1. CRH, Ang II and stress CRH and its two sub-types of receptors viz.; CRH-R1 and CRHR2 have been identified in the various regions of brain including the prefrontal cortex (PFC), parvocellular paraventricular nucleus of hypothalamus (PVNp), central nucleus of amygdala (CeA), oval nucleus of the bed nucleus of the stria terminalis (BNSTov), hippocampus and LC [20,78,79]. In response to stress exposure, CRH is mainly produced by the PVNp of the hypothalamus and is released at the ME from the neurosecretory terminals of these neurons into the primary capillary plexus of the hypothalamic-hypophyseal portal system [80]. There have been a number of preclinical studies documenting the increased expression of CRH mRNA and CRHR1 in the PFC, PVN and CeA nuclei in response to acute restraint stress and chronic unpredictable stress suggesting the key role of CRH/CRH-R1 in the development of anxiety [79,81,82]. Other studies have also demonstrated the anxiogenic effects of exogenous CRH [83,58] and anxiolytic actions of selective CRH-R1 antagonists [84,85]. On the other hand, the important contribution of CRH-R2 dependent signaling in shutting down the stress response has been documented suggesting the anxiolytic profile of CRH/CRH-R2 [86] (Fig. 1). Research studies have shown the presence of Ang II receptors on the same brain regions in which CRH and its receptors are localized [18,37]. Moreover, studies have reported an increase in AT1 receptor expression in the parvocellular PVN (the brain region where the cell bodies forming the CRH are predominantly present) in response to different stressors [21,37]. It has also been demonstrated that these receptors are transported from the PVN region to the ME through the axons co-expressing CRH [55]. Furthermore, it is well documented that the stimulation of AT1 receptors of the PVN region increases the release of CRH and ACTH [87]. The AT1 receptor antagonists decrease the isolation stress-induced CRH production/release in the PVN region suggesting that activation of AT1 receptors is involved in stress-induced CRH release in the PVN region [26,88]. Furthermore, the AT1 receptor antagonists have been shown to attenuate stress-induced decrease in cortical CRH-R1 again suggesting an important co-ordination between the Ang II/AT1 receptors and CRH/CRH-R1 in orchestrating stresstriggered plethora of deleterious events [41,89]. However, Saavedra et al. demonstrated that administration of candesartan does not modulate the isolation stress-induced changes in CRH-R1 /CRH-R2 receptor expression in the subcortical limbic structures, including the amygdala, septum, and hippocampus regions indicating that the effects of Ang II on CRH receptors may be restricted only to the cortical areas [43]. 3.2. 5-HT, Ang II and stress There have been reports suggesting the interactions between Ang II and 5-HT, and it has been proposed that Ang II modulates stress-associated behavior by affecting 5-HT neurotransmission. The increased levels of 5-HIAA has been demonstrated in the brain following Ang II infusion into the striatum suggesting that Ang II increases the 5-HT levels [90]. Voigt and coworkers demonstrated

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the reduced contents of 5-HT and its metabolite 5-hydroxyindolic acid (5-HIAA) in the hippocampus, frontal and parietal cortices in TGR (ASrAOGEN) 680 (rats with the disrupted central RAS system and anxiogenic phenotype) [30]. Furthermore, the AT1 receptor antagonist including losartan decreases the 5-HT synthesis outside the blood–brain barrier area [91]. These findings support the notion that brain Ang II mediates its stress modulatory effects by increasing the 5-HT content in the different brain regions. However, the increased 5-HT levels in the brain (inside the blood–brain barrier) in the presence of candesartan has also been reported [92], suggesting the biphasic response of Ang II on 5-HT synthesis [93]. At higher concentrations, Ang II is shown to stimulate the tryptophan hydroxylase enzyme to increase the 5-HT synthesis; while at low concentration, Ang II inhibits the enzyme to reduce its levels [93]. Furthermore, Voigt et al. demonstrated the development of more pronounced anxiogenic effect of mCPP (5-HT2C/1B receptor agonist) in TGR(ASrAOGEN)680 suggesting that the development of anxiety with low brain angiotensinogen is possibly linked to secondary dysfunctions of the brain serotonergic system [30,67]. Nevertheless, further research is needed to precisely define the correlation between Ang II and 5-HT in the development of anxiety-related behavior in stress-subjected rats. 3.3. Benzodiazepine (BZD), Ang II and stress During periods of stress, Ang II-induced behavioral changes may be mediated through BZD receptors, a part of GABAA receptor complex [43,89,94]. It has been reported that the different stressors (isolation, foot shock and forced swimming) decrease the BZD receptor binding in the frontal cortex [43,95]. The reduction in BZD binding decreases GABA-mediated inhibitory system and may lead to development of anxiety [96]. Saavedra et al. demonstrated that pretreatment with candesartan completely prevents the isolation stress-induced decrease in cortical BZD receptor binding, particularly in the cingulate cortex and in layer IV corresponding to granular layer of the parietal cortex [43]. These reports are supported by other findings demonstrating that pretreatment with candesartan attenuates the isolation stress-induced decrease in cortical BZD expression [94]. A recent report has shown that coadministration of inflammatory stressor (in the form of LPS) and physical stressor (restraint and foot shock) also reduces the mRNA expression of ␥(2) subunits of the GABAA receptor in the cingulate cortex leading to decreased BZD binding. Furthermore, candesartan also prevents stress-induced changes in the expression of BZD receptors suggesting that stress-induced changes in BZD receptor expression are under the control of AT1 receptors [89]. It may be proposed that stress-induced increases in Ang II levels produces anxiety and associated behavioral changes by decreasing the BZD receptor binding and subsequently, reducing inhibitory influence of the GABAA receptor complex. Accordingly, restoration of the BZD receptor binding and inhibitory influence of the GABAA receptor complex may be responsible for the anxiolytic effects of ATI receptor antagonists [43,94] (Fig. 1). 4. Conclusion The studies have demonstrated the beneficial role of reninangiotensin modulating drugs in attenuating stress-associated anxiety. In most of these studies, the development of anxiety has been associated with activation of AT1 receptors and major attention has been paid to selective AT1 receptor antagonists. However, recent literature has shown the crucial role of central AT2 receptor activation in attenuating stress-associated anxiety. Therefore, it may be proposed that the novel centrally acting Ang II analogs may serve as effective adaptogenic agents to attenuate stress-associated

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anxiety and other behavioral changes. It also appears that the physiological brain Ang II (low amount) produces the anti-anxiety effects; however, stress-released Ang II (large amount) may produce anxiety and depression. However, more experimental studies are needed to establish the beneficial role of AT2 receptor activation and the dual role of Ang II in stress-associated anxiety disorders. Acknowledgements The authors are grateful to Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India for supporting this study and providing technical facilities for the work. We are also thankful to Ms Kiran Bali, Clinical Psychologist, University of Birmingham, UK for editing the manuscript. References [1] Kyrou I, Tsigos C. Stress hormones: physiological stress and regulation of metabolism. Curr Opin Pharmacol 2009;9:787–93. [2] McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav 2003;43:2–15. [3] McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med 1998;338:171–9. [4] Masood A, Banerjee B, Vijayan VK, Ray A. Modulation of stress-induced neurobehavioral changes by nitric oxide in rats. Eur J Pharmacol 2003;458:135–9. [5] Chrousos GP, Kino T. Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress 2000;10:213–9. [6] Adzic M, Djordjevic J, Djordjevic A, Niciforovic A, Demonacos C, Radojcic M, et al. Acute or chronic stress-induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain. J Endocrinol 2009;202:87–97. [7] Erhardt A, Ising M, Unschuld PG, Kern N, Lucae S, Pütz B, et al. Regulation of the hypothalamic–pituitary–adrenocortical system in patients with panic disorder. Neuropsychopharmacology 2006;31:2515–22. [8] Ferguson AV, Washburn DL, Latchford KJ. Hormonal and neurotransmitter roles for angiotensin in the regulation of central autonomic function. Exp Biol Med (Maywood) 2001;226:85–96. [9] McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol 2003;35:901–18. [10] Fabiani ME, Sourial M, Thomas WG, Johnston CI, Johnston CI, Frauman AG, et al. enhances noradrenaline release from sympathetic nerves of the rat prostate via a novel angiotensin receptor: implications for the pathophysiology of benign prostatic hyperplasia. J Endocrinol 2001;171(October (1)):97–108. [11] Saavedra JM. Brain and pituitary angiotensin. Endocr Rev 1992;18:21–53. [12] Phillips MI. Functions of angiotensin in the central nervous system. Annu Rev Physiol 1997;3:103–26. [13] Saavedra JM. Emerging features of brain angiotensin receptors. Regul Pept 1999;85:31. [14] De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology XXIII. The angiotensin II receptors. Pharmacol Rev 2000;52:415–72. [15] Nguyen Dinh Cat A, Touyz RM. Cell signaling of angiotensin II on vascular tone: novel mechanisms. Curr Hypertens Rep 2011;13:122–8. [16] Tsutsumi K, Saavedra JM. Characterization and deve-lopment of angiotensin II receptor subtypes (AT1 and AT2)in rat brain. Am J Physiol 1991;26:209–16. [17] Huang XC, Richards EM, Sumners C. Mitogen activated protein kinases in rat brain neuronal cultures are activated by angiotensin II type 1 receptors and inhibited by angiotensin II type 2 receptors. J Biol Chem 1996;271: 15635–41. [18] Bregonzio C, Seltzer A, Armando I, Pavel J, Saavedra JM. Angiotensin II AT(1) receptor blockade selectively enhances brain AT(2) receptor expression, and abolishes the cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the locus coeruleus of spontaneously hypertensive rats. Stress 2008;6:457–66. [19] Yang G, Wan Y, Zhu Y. Angiotensin IIFan important stress hormone. Biol Signals 1996;5:1–8. [20] Castrén E, Saavedra JM. Repeated stress increases the density of angiotensin II binding sites in the rat paraventricular nucleus and subfornical organ. Endocrinology 1988;122:370–2. [21] Aguilera G, Kiss A, Luo X. Increased expression of type 1 angiotensin II receptors in the hypothalamic paraventricular nucleus following stress and glucocorticoid administration. J Neuroendocrinol 1995;7:775–83. [22] Braszko JJ, Kułakowska A, Winnicka MM. Effects of angiotensin II and its receptor antagonists on motor activity and anxiety in rats. J Physiol Pharmacol 2003;2:271–81. [23] López LH, Caif F, García S, Fraile M, Landa AI, Baiardi G, et al. Anxiolytic-like effect of losartan injected into amygdala of the acutely stressed rats. Pharmacol Rep 2012;64:54–63. [24] Peng JF, Phillips MI. Opposite regulation of brain angiotensin type1 and type 2 receptors in cold-induced hypertension. Regul Pept 2001;97:91–102.

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