1096 Current Drug Targets, 2009, 10, 1096-1108 The -Endorphin Role in Stress-Related Psychiatric Disorders

Avia Merenlender-Wagner, Yahav Dikshtein and Gal Yadid*

Neuropharmacology Section, The Mina and Everard Goodman Faculty of Life Sciences and The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel

Abstract: Long known for its anti-nociceptive effects, the -endorphin is also reported to have rewarding and rein- forcing properties and to be involved in stress response. In this manuscript we summarize the present neurobiological and behavioral evidence regarding the role of -endorphin in stress-related psychiatric disorders, depression and PTSD. There is existing data that support the importance of -endorphin neurotransmission in mediating depression. As for PTSD, however, the data is thus far circumstantial. The studies described herein used diverse techniques, such as biochemical measurements of -endorphin in various brain sites and behavioral monitoring, in two animal models of depression and PTSD. We suggest that the pathways for stress-related psychiatric disorders, depression and PTSD, converge to a com- mon pathway in which -endorphin is a modulating element of distress. This may occur its interaction with the mesolim- bic monoaminergic system and also by its interesting effects on learning and memory. The possible involvement of - endorphin in the process of stress-related psychiatric disorders, depression and PTSD, is discussed. Keywords: Anxiety, depression, post-traumatic stress disorder (PTSD), .

INTRODUCTION involve posttranslational processing as in the case of POMC, to produce several opioid , including -LPH and - The involvement of the opioid system in depression and endorphin [12]. PTSD (post traumatic stress disorder) has been previously studied by several groups. Most of these studies employed pharmacological means, and examined the involvement of The Opioid - Endorphin the different opioid receptors in these psychiatric diseases. -lipotrophin is a fat-mobilizing pituitary [5] However, an exclusive role for a specific opioid in these which contains an N-terminal fragment known as Met- diseases had not been thoroughly assessed. Long known for and a C-terminal fragment known as -endor- its anti-nociceptive effects, the opioid -endorphin is now phin. The cleavage of POMC generates -lipotrophin, whi- known to induce reinforcing properties and to decrease feel- ch is later cleaved to produce -endorphin [9]. The cleavage ings of distress. In this manuscript we provide new data, us- enzyme L-cathepsin has been recently linked with the pro- ing animal models, which support the involvement of - duction of -endorphin through a protease gene knockout endorphin in stress-related psychiatric disorders, depression and expression study [13]. and PTSD. -endorphin is an endogenous opioid consisting of 31 amino acids which has been demonstrated to be in- THE OPIOID SYSTEM volved in stress-related disorders as well as in other disor- Opioid Peptides and their Biosynthesis ders such as obesity, diabetes, and altered immune responses [14-16]. The first endogenous opioids were discovered in the mid- 80s [1]. Later, researchers succeeded in isolating and charac- -endorphin can act as a in the central terizing the [2], [3, 4] and also - nervous system and in the brain that synthesize and endorphin [5]. The behavioral and physiological effects of release -endorphin are located mainly in the arcuate nucleus these opiods, such as rewarding and sedative sensations, are of the (ArN), the anterior and neurointermedi- similar to those displayed by as they all interact ate lobes of the pituitary gland and the nucleus tractus solitar- with post-synaptic opiod receptors [6-8]. Most of the en- ies, and these neurons’ extensions terminate in diverse brain dogenous opioids are enzymatically generated from three regions [17, 18]. In both humans and rodents, injection of precursor proteins, (POMC) [9]; pro- exogenous -endorphin into the intracerebrospinal fluid (PDYN) [10] and (PENK) [11]; causes a stronger effect than that of morphine [19- which undergo specific cleavage by proteolytic enzymes to 22]. Since it is produced in some regions in the brain that are give opiod as well other as non-opiod peptides. The final associated with stress response its role was suggested in the product is dependent on the enzymes present and can also manifestation of some psychiatric diseases [23-25].

Interaction of -Endorphin with the Monoaminergic Sys- *Address correspondence to this author at the Leslie and Susan Gonda tems (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan Univer- sity, Ramat-Gan 52900, ISRAEL; Tel: 972-3-531-8123; Fax: 972-3- Several studies show that activation of the opioid system 6354965; E-mail: [email protected] can alter release. Ventricular infusions of -

1389-4501/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. -endorphin and strees-related psychiatric disorders Current Drug Targets, 2009, Vol. 10, No. 11 1097 endorphin were shown to increase dopamine release in the -Endorphin, Opioid Receptors and their Knockout nucleus accumbens via - and -opioid receptors [26]. - Models endorphin inhibits the GABA-blocking dopaminergic neu- There are 3 major types of opioid receptors: (mu), rons and lead to increase in dopamine release [27]. Further- (delta) and (kappa) and they were originally described by more, -endorphin at doses that stimulate dopamine release in-vivo and in-vitro pharmacology [38]. Several different in the nucleus accumbens is rewarding, as tested by the con- neural systems are modulated by the receptors. ditioned place preference paradigm [28]. Interestingly, ac- cumbal -endorphin has a reinforcing effect [24, 29, 30], The mu- gene, OprM, is alternatively spliced into many variants and distributed in the Raphe nu- which suggests that -endorphin is an endogenous mediator of reinforcement, which is a measure of reward feelings us- cleus and different limbic regions. Studies provide evidence for the region- and -specific processing of the OprM ing opertant conditioning, and can increase mesolimbic do- gene and support the possibility of functional differences paminergic neurotransmission as a secondary target. These among the variants [39]. -endorphin has the highest affinity findings indicate an opioid-dopamine interaction wherein to mu-Opioids receptor. mu-Opioids inhibit GABAergic and opioid receptor agonists act at a site upstream from the do- the glutamatergic afferents, thereby indirectly affect 5-HT pamine synapse in the nucleus accumbens. The dopamine- efflux in the dorsal raphe nucleus. In contrast, kappa-opioids opioid interaction is the evidence of enhanced locomotor inhibit 5-HT efflux independent of their effects on glutama- response and reward sensitivity to opioid receptor agonists, tergic and GABAergic afferents [40]. given systemically or intra-accumbal, following mesolimbic dopaminergic lesions or chronic treatment with dopamine Mutant mouse strains lacking the genes encoding opioid receptors have been generated utilizing homologous recom- blockers [31, 32]. Our demonstration of a decrease (to ~35% bination technology. Theses have aided in obtaining evi- of controls) in -endorphin basal levels in 6-hydroxydo- dence suggesting that mu and delta receptors are responsible pamine-treated rats may be relevant for the understanding of for reinforcement and that stimulation of kappa receptors this dopamine-opioid interaction [33]. This result indicates triggers aversive effects [41-43]. A -endorphin knockout that the basal opioid tone in the nucleus accumbens is under mouse model has also been generated [44] and these mice dopaminergic control. demonstrate a selective reward deficit [45]. The examination The relevance of the dopaminergic system to depression of this mouse model in stress-related disorders is warranted. was previously suggested (for review see [34]). Therefore, if -endorphin is modulated by dopamine, it may be a relevant STRESS- RELATED PSHYCIATRIC DISORDERS chain in the cascade that affects the manifes- Depression, anxiety and PTSD are the most prevalent tation of depressive like behavior. Other data [35], as well as psychiatric disorders in the general population. Whereas those presented herein, demonstrate that extracellular - stressful events are the etiological trigger to develop PTSD, endorphin levels in NAcc (nucleus accumbens) and ArN they were also suggested as a concept to explain the etiologi- were altered in response to 5-HT (5-hydroxytryptamine). cal and pathophysiological mechanisms of anxiety and major 5-HT1A is the most widespread receptor. It is pre- depression. Moreover, vulnerability to depression has been sent in both the central and peripheral nervous systems, and linked to the interaction of genetic predisposition with stress- controls a variety of different biological and neurological ful life events [46-51]. During stress, the synthesis of central functions. Activation of 5-HT1A receptors has been shown to corticotropin-releasing hormone (CRF) in the paraventricular increase plasma -endorphin levels in animal studies and in (PVN) increases and is released into the hypothalamo– healthy humans. In depressed patients who were treated with hypophysial portal vascular system [52]. When the peptide citalopram for 8 weeks, a reduction was shown in the - reaches the gland, it binds to CRF- recep- tors and causes a cascade of intracellular steps that increases endorphin response to a 5HT1A agonist. Moreover, the reduc- tion was parallel to the improvement in the patient's condi- POMC gene expression. POMC is a large gene that is trans- tion. Since 5-HT is involved in many psychiatric diseases it lated into many POMC-derived peptides such as ACTH (adrenocorticotropic hormone) and -endorphin (Fig. 1). is hypothesized that -endorphin might mediate the devel- Thus, activation of the stress system by CRH stimulates the opment of these diseases. There are additional studies that secretion of hypothalamic -endorphin and other POMC- indicate an interaction between -endorphin and 5HT. Treat- derived peptides, which reciprocally inhibit the activity of the ing pregnant rats with -endorphin caused a long- lasting stress system [15, 53]. reduction of 5-HT levels in the frontal cortex, hypothalamus and brain stem in the offspring [37]. Depression The evidence of an interaction between -endorphin and Depression is a mental illness which poses a major public monoamines may facilitate the understanding of the role that health problem. Major depression usually develops early in -endorphin plays in hedonia and motivation, since mono- life and can last for a lifetime, during which it will impair the amines were established as key players in both hedonia and overall function (with regard to occupation and social roles), motivation. Decreased motivation and anhedonia are core and affect the quality of life [54, 55] of the affected individ- symptoms in depression and are also involved with other ual. Lifetime prevalence rates of up to 20% for depression psychiatric diseases. have been reported for the mild form of the illness, and

1098 Current Drug Targets, 2009, Vol. 10, No. 11 Yadid et al.

Fig. (1). The Opioid's Precursor Proopiomelanocortin and its Cleavage Products. The gene that codes for the precursor proopiomelano- cortin (POMC) is transcribed into mRNA which is then translated to a pro-hormone of 241 amino acids. Post translational processing of the large precursor peptide produces several smaller opioid peptides, including -, -endorphin and non opioid peptides such as adrenocorticotropic hormone (ACTH), corticotrophin-like intermediate peptide (CLIP) and -, - and - melanocyte-stimulating hormone (MSH).

2%–5% of the U.S. population will suffer from the severe medications, usually in combination with psychotherapy form of major depression [56]. Major depression is defined involving cognitive and behavioral therapies, which together as a chronic state (at least 2 weeks) of a patient suffering can exert a synergistic effect [68, 69]. The antidepressants from at least one core symptom and at least four of the fol- are classified into three classes or three generations. The first lowing secondary symptoms. The core symptoms are: (i) generation is divided to two main groups: 1. The tricyclic lack of motivation and loss of interest in practically every- antidepressants that are generally thought to treat depression thing, and (ii) inability to experience pleasure (anhedonia). by inhibiting the synaptic re-uptake of the The secondary symptoms are: (i) loss of appetite, (ii) insom- and serotonin. 2. The monoamine oxidase nia [increased amount and decreased latency of rapid eye inhibitors (MAOI) that inhibit the activity of monoamine movement (REM) sleep, as deter-mined by EEG measure- oxidase. Thus, preventing the breakdown of monoamine ments], (iii) motor retardation or agitation, (iv) feelings of neurotransmitters and thereby increasing their bioavailabil- worthlessness or guilt, (v) continues fatigue, (vi) cognitive ity. The agents of these classes were discovered by accident. difficulties, and (vii) suicidal thoughts [57]. The following However, the fact that agents that undoubtedly change the physiological and biochemical characteristics are often ob- chemical balance in the brain can benefit the patients, paved served in depressed patients: (i) chronic pain [50% of the the way to the assumption that there may be chemical depressed patients suffer from chronic pain [58, 59], (ii) high changes in the brain that regulate depressive symptoms to levels of plasma [60, 61], (iii) resistance in the dex- begin with. Further research has lead to the development of amethasone suppression test [62], (iv) supersensitivity to the second generation of agents, the serotonin-selective reup- cholinergic agonists [63-66], and (v) first degree relatives take inhibitors (SSRIs) which are widely used today. SSRIs that also suffer from depressive disorders, i.e, a genetic com- act by inhibiting the reuptake of serotonin after being re- ponent [67]. leased into the synapse [70] . The SSRIs are the most com- monly used drugs to treat depression [71]. One of the main There are several available treatments for depression, reasons that the SSRIs are widely used is due to their minor- which seem to benefit about 50% of patients. These patients ity of side effects compared to the first generation drugs. show some improvement after receiving antidepressant -endorphin and strees-related psychiatric disorders Current Drug Targets, 2009, Vol. 10, No. 11 1099

Later, a combination of neurotransmitters was suggested to So far the following 18 animal models for depression in express faster onset on behavior [72]. It has been suggested humans have been developed: (i) predatory behavior [95, 96], that dual-action antidepressants acting on both serotonin and (ii) yohimbine I potentiation [97, 98], (iii) kindling [99-101], noradrenaline pathways in the brain may offer superior (iv) dopa potentiation [102, 103], (v) 5-HTP-induced behavioral therapeutic benefit over classical antidepressants, particu- depression [104, 105], (vi) olfactory bulbectomy [106-108], larly in severe depression. This third generation includes (vii) isolation-induced hyperactivity [109-111], (viii) exhaustion agents such as venlafaxine, reboxetine, nefazodone and mir- stress [112], (ix) circadian rhythms [113], (x) behavioral despair tazapine. Studies showed no convincing differences between [114-117], (xi) chronic unpredictable stress [118-121], (xii) third-generation agents and comparators in terms of overall separation models [118, 122-124], (xiii) incentive disengage- efficacy, relapse prevention and speed of onset [73-76]. ment [125], (xiv) intra-cranial self-stimulation [126-130], (xv) The precise mechanism of action of antidepressant medi- learned helplessness [131, 132], (xvi) chronic mild stress (CMS) cations is yet unknown. Altering neurotransmission should [133], (xvii) Swim Low-Active (SwLo) line rat [134], and be expected to have an immediate effect on mood. However, (xviii) FSL rats [135]. all available antidepressants exert their mood-elevating ef- The behavior of the FSL rats (Flinders Sensitive Line) fects only after prolonged administration (several weeks), resembles that observed in many depressed patients [136], which means that the mechanism probably involves some thus the model has face validity. Both FSL rats and de- sort of drug-induced neuroplasticity. This is consistent with pressed individuals are sensitive to cholinergic agonists the ability of these agents to benefit a wide range of syn- (cholinergic supersensitivity; [65, 137] and have serotoner- dromes besides depression, such as anxiety disorders [77] gic and dopaminergic abnormalities [182,136], thus the and PTSD [78]. model has construct validity. Both FSL rats and depressed individuals respond positively to chronic treatment with an- Post Traumatic Stress Disorder (PTSD) tidepressants, thus the model has predictive validity. Since the FSL rat has fulfilled all three major criteria for determin- PTSD is a chronic and disabling anxiety disorder that ing the validity of an animal model of depression (face, con- may develop in survivors of a traumatic event [79]. About struct, and predictive validities), it appears to be a suitable Twenty percent out of those that were exposed to a traumatic animal model for studying the neurochemical basis of de- event will develop PTSD. PTSD is currently defined by the pression and the neurochemical consequences of antidepres- coexistence of three clusters of different stress paradigms sant agents. (re-experiencing, social avoidance and hyperarousal) persist- ing for at least one month [80]. Previous studies indicated Unlike most other mental disorders, the diagnostic crite- that there are several risk factors for developing PTSD [81, ria for PTSD in DSM IV specify an etiological factor, which 82]: (i) genetic background in monozygotic twines studies is an exposure to a life-threatening traumatic event [138]. that were exposed to a traumatic event there was 48% corre- A number of animal models have been developed, mim- lation in PTSD symptoms. (ii) gender-females have higher icking many of the behavioral and physiological changes risk to develop PTSD as a result of a traumatic event (ii) seen in PTSD-like behavior. These models use an electric personal history background (child abuse etc) (iii) Family shock [139-142], underwater trauma [143] and restraint history of psychopathology (depression, bipolar disorder) stress [144, 145], are the most widely used method of apply- (iv) The impact of the traumatic event (v) socioeconomic ing a stressor to laboratory animals. Nevertheless, the use of status (vi) environmental assistance dealing with the trauma. exogenous stimuli that closely mimic those seen in the wild The most common and effective of current treatments are such as exposure to a live predator [146-148], a predatory SSRI [83]. Research has pointed out that during the last dec- cue [149-152] or psychological stress [153, 154] might have ade, SSRIs have proven to be effective in reducing PTSD greater ethological relevance, thereby leading to improved symptoms with the most effective ones being sertraline, modeling and analysis of fear and anxiety states. fluoxetine, paroxetine and citalopram [83-86]. Other studies do not agree with this statement [87, 88]. The has Stressed rats tend to show PTSD-like behavior such as been postulated as a crucial site in expression of PTSD increased immobility, decreased grooming and rearing [152], pathophysiology. This assumption was further demonstrated decreased exploratory behavior and decreased food con- in several Positron Emission Tomography (PET) studies. sumption [155]. The 'freezing' response has been used as a Researchers have shown that the amygdala of PTSD patients behavioral measure of anxiety or fear [156]. Amongst all the is activated during presentation of traumatic stimuli or hid- unconditioned stressors, the predator stress seems to be the den traumatic stimuli [89-91] and the destruction of this re- most potent stressor, since its effects on fear/anxiety poten- gion prevent expression of PTSD [92]. tiation can last for 3 weeks [147]. Most studies in animal models for PTSD-like behavior Animal Models for Depression and PTSD refer to the maladapted group as a uniform population. Oth- ers developed an animal model that categorizes PTSD-like Animal models, although limited in their ability to com- prehend human complexities, are an invaluable tool in the behavior individually and in addition they applied it to fur- ther monitor the animal over a month in order to determine research of markers for psychiatric disorders in general. A whether it had PTSD-like behavior. This adapted model in- good animal model of clinical conditions should fulfill 4 cludes re-exposure to the traumatic cue in a time-course criteria [93, 94]: Etiological validity, Face validity Construct manner, and showed high face-, contract- and predictive- validity and Predictive validity. validities [157]. 1100 Current Drug Targets, 2009, Vol. 10, No. 11 Yadid et al.

Opioids and Stress-Related Disorders inconsistent [66, 175-179]. Later, using microdialysis, it was enabled to determine of the local release of -endorphin in Endogenous opioid peptides and their receptors are rep- specific brain regions in vivo. This may lead to a more accu- resented throughout corticolimbic structures [158, 159] and rate understanding of the neurophysiological basis of behav- their high sensitivity to acute and prolonged aversive stimuli ioral abnormalities in depression, and the mode of action of has been documented [160-164]. Herein we will summarize drugs used for treating them. The neuronal mechanisms that their possible role in depression, anxiety and PTSD. mediate the beneficial effect of several antidepressants on (+/-)-, an - monoaminergic agent, depressive behavior [180] are not known, but may involve conceivably displays antidepressant actions in a variety of the 5-HT--endorphin interaction in NAcc and ArN, since rodent models [165-169], although the precise contribution some findings [35] demonstrate that extracellular - of monoaminergic as compared to opioidergic mechanisms endorphin levels in these areas are altered in response to 5- to its antidepressant properties remains unclear. Since it has HT. Antidepressants, such as tricyclics and SSRIs, increase a dual mechanism of action by which analgesia may be 5-HT neurotransmission in the brain [181]. Therefore, this achieved via -opioid receptor activation, and enhancement increase in 5-HT neurotransmission should facilitate the re- of serotonin and norepinephrine transmission may conceiva- lease of -endorphin in brain regions, such as the abovemen- bly exert a degree of antidepressant effect and it was sug- tioned, where this opiate can mediate hedonia or motivation gested to be of particular value in patients with chronic pain [19, 22, 35]. Extracellular levels of -endorphin in the NAcc, who also suffer from depression [170]. as well as behavioral deficiencies associated with depressive behavior, were assessed in and animal model of depression Recent literature supports a potent role of , and control rats, before and after chronic antidepressant , tramadol, morphine, and other opioids as treatment. Using microdialysis, [35] it was demonstrated that effective, durable and rapid therapeutic agents for anxiety extracellular -endorphin levels were dose dependently in- and depression [171]. Some studies showed that produced an antidepressant-like effect when administered creased when artificial cerebrospinal fluid (aCSF) containing 5-HT was applied to the NAcc (Fig. 2). This response was alone and even an accentuated anti- like effect attenuated in FSL rats showing a shift to the right in the when administrated at subeffective doses in combination dose-response curve [208](Fig. 3). In FSL rats exposed to with selective serotonin reuptake inhibitors (fluoxetine or the same 5-HT treatment, the -endorphin levels increased citalopram). In contrast, when codeine was combined with a only slightly, but not significantly. Chronic treatment (18 noradrenaline reuptake inhibitor () or with a noradrenaline/serotonin reuptake inhibitor (duloxetine), no days) with desipramine or paroxetine did not significantly affect the basal levels of -endorphin in the dialysates ob- such effect was observed. The anti- depressant like effect tained from the NAcc of FSL or control Sprague-Dawley also remained unchanged with the combination of subeffec- rats. However, in FSL rats treated with desipramine or par- tive doses of codeine and (+/-)-tramadol (the weak -opioid oxetine, exogenous administration of 5-HT via the agonist with serotonin/noradrenaline reuptake inhibitor microdialysis probe induces increases in extracellular levels properties) or (-)-tramadol (noradrenaline reuptake inhibitor properties only). Conversely, the combination with (+)- of -endorphin, similar to those observed in controls (Fig. 4). In FSL rats chronically injected with saline, exogenous tramadol ( -opioid agonist with serotonin reuptake inhibitor application of 5-HT appeared to slightly affect -endorphin properties) produced an increase of the anti-depressant like release. However, this 5-HT-mediated effect was minimal effect [172]. compared to that observed in the FSL rats treated with the The existing information indicating the possibility of antidepressants. 5-HT-mediated release of -endorphin in the opioids' neurotransmission in controlling PTSD is mostly control Sprague-Dawley rats was not significantly affected circumstantial. Only recently a direct examination of central by chronic administration of saline or the antidepressants nervous system opioid function in PTSD was reported, using [208]. The basic characteristic symptoms of depressed positron emission tomography (PET) and the selective - patients are anhedonia and a lack of motivation, both of opioid receptor radiotracer [173] . The study sepa- which are expressed in the absence of an immediate response rated trauma exposed combat veterans who developed PTSD to environmental stimuli [182]. Responses to environmental after combat experience, from trauma exposed combat veter- stimuli that activate specific neuronal circuits in the brain ans without PTSD, as well as non-exposed controls indicat- involved in mediation of motivation or hedonia (and are ing changes in -opioid receptor occupancy in limbic fore- likely to involve release of -endorphin) are probably brain and cortical regions involved in emotional regulation. impaired in depressive patients [183]. Chronic, but not acute, These alterations are likely to reflect adaptive responses to treatment with antidepressant drugs, which is necessary for trauma or stress, or alternatively potential adaptation failures effective treatment of depressive behavior [136] normalizes that may be related to PTSD pathophysiology [173]. Another the 5-HT-- endorphin interaction, probably by affecting study of acute administration of morphine reported limited neuronal plasticity [184]. fear conditioning in the aftermath of traumatic injury and Injection of -endorphin into the brain has also rewarding may serve as a secondary prevention strategy to reduce effects [24, 29] and impairment of the reward system was PTSD development [174]. suggested to occur in depression [185]. Therefore a comple- mentary way to address -endorphin role in depression is by Involvement of -Endorphin in Depression its modulating the reward system. The results obtained from depressive patients not receiv- ing drug therapy on plasma or CSF -endorphin levels, were -endorphin and strees-related psychiatric disorders Current Drug Targets, 2009, Vol. 10, No. 11 1101

Fig. (2). Increments of -endorphin levels in extracellular fluid of nucleus accumbens in response to exogenous serotonin. Rats were implanted with a microdialysis probe (2 mm length, 20 kDa cutoff value, CMA/10; Carnegie Medicine; Stockholm, Sweden) in their nucleo- lus accumbens using the Paxinos & Watson the rat brain in stereotaxic coordinates [207]. Artificial cerebrospinal fluid (aCSF; 145 mM NaCl, 1.2 mM CaCl2, 2.7 mM KCl, 1.0 mM MgCl2, pH 7.4) was pumped continuously (1.5 l/min) through the dialysis probe using a microinjec- tion pump (CMA/400, Carnegie Medicine). Experiments were initiated 24 h after surgery in awake, freely moving rats. After collecting base- line, various concentrations of 5-HT were applied locally via the probe for 30 min. Data are mean ± SEM values from six rats. Two-way ANOVA with repeated measurements was conducted. *p<0.001 compared with basal levels by Student–Newman–Keuls post hoc test [35].

Fig. (3). Attenuated effect of exogenously added 5-HT on the extracellular levels of -endorphin in the nucleus accumbens of an ani- mal model of depression (FSL) rats. FSL and Sprague–Dawley (control) rats were implanted with a microdialysis probe in their nucleolus accumbens. The microdialysis probe was perfused with aCSF before and after a 30 min perfusion with aCSF containing 5-HT (bar). (A) A dose–response curve when the peak of the response to each 5-HT concentration (mean±S.E.M. values of five rats in each group) was plotted. ANOVA with repeated measure over time applied to each 5-HT dose separately revealed that only at the 5 M 5-HT (B) a significant strain– sample interaction was obtained (control group: F(4,8)=7.78, P<0.001); FSL group: F(4,8)=1.22, P=0.31), strain x treatment interaction (F(1,8)=2.34, P=0.028). *P<0.05 [208]. 1102 Current Drug Targets, 2009, Vol. 10, No. 11 Yadid et al.

Fig. (4). Effect 5-HT-induced release of -endorphin in the nucleus accumbens of FSL and Sprague–Dawley (control) rats. FSL and Sprague–Dawley (control) rats were treated with saline or antidepressants (paroxetine or desipramine) for two weeks. Thereafter they were implanted with a microdialysis probe in their nucleolus accumbens. The microdialysis probe was perfused with aCSF before and after a 30 min perfusion with aCSF containing 5 M 5-HT. The pick of the stimulation in the various groups after 5HT administration is demonstrated. Mean±S.E.M. values of five or six rats in each group are presented [208].

It is worth to mention that Tramadol, an opioidergic ety behavior measured using the elevated plus maze, sug- monoaminergic (NA and 5-HT re-uptake inhibitor) agent gesting that this peptide normally inhibits anxious behavior. displays antidepressant actions in a variety of rodent models However, mice lacking -endorphin demonstrated an exag- [165-169], although the precise contribution of mono- gerated anxiolytic response to alcohol in this assay [189]. aminergic as compared to opioidergic mechanisms to the Together, these studies suggest that lowered -endorphin antidepressant properties of tramadol remains unclear. may contribute to anxiety-related behaviors. We suggest that impaired 5-HT-induced release of - endorphin may be involved in the etiology of depression, and Involvement of -Endorphin in PTSD that normalization of this induction by chronic antidepres- In animals exposed to a scent of predators, a prolonged sant treatments mediate, at least in part, the therapeutic ac- 25% increase in of -endorphin in the ArcN was observed tion of antidepressant drugs. [190]. Exposure to stress enhances release of the endogenous opioid receptor, dynorphin, in several cerebral structures, Involvement of -Endorphin in Anxiety including the and nucleus accumbens [162, 163, 191-193]. An earlier report found lower plasma - The role of in general and -endorphin in in PTSD patients [194], however later findings particular in anxiety-related disorders is largely unknown. In [195, 196] suggested higher levels of immunoreactive - humans, acute stress, which is associated with higher anxiety endorphins. Treatment with the opioid antagonists levels, had increased plasma levels of -endorphin [186]. In and has reduced PTSD symptoms like flashbacks animal studies, mice with selective deletion of -endorphin and dissociations, intrusions, and hyperarousal [89, 197, demonstrated lower anxiety levels in the zero-maze, a model 198], whereas activation of opioid receptors by morphine for a mildly stressful situation [187]. Several others studies reduced the risk of subsequent development of PTSD symp- address the issue of alcohol-withdrawal induced anxiety and toms [199]. Only one study directly examined the role of the its possible connection to -endorphin in both humans and opioid function in PTSD [173]. mice. -endorphin plasma levels were significantly lowered on day 1 and day 14 of alcohol withdrawal relative to control However, a direct evidence for a specific opiate involve- subjects and levels of -endorphin were inversely correlated ment in PTSD was only recently available by the use of mi- with anxiety levels [188]. In mice, a direct inverse relation- crodialysis and a unique animal model of PTSD. A recent ship was noted between -endorphin plasma levels and anxi- study has measured -endorphin levels both in tissue and in -endorphin and strees-related psychiatric disorders Current Drug Targets, 2009, Vol. 10, No. 11 1103 the extra cellular fluid in the amygdala. Table 1 demonstrates Table 1: -endorphin content in the amygdala PTSD rats. Rats the basal levels of tissue content. PTSD rats demonstrated a were prepared as described in Fig 5 [157]. After separating mal- significant lower concentration of -endorphin then the non- adapted (PTSD) from non- maladapted (non- PTSD) rats, their PTSD rats and the naive rats. When extracellular fluid was brains were removed and -endorphin was assayed [35] in their sampled by microdialysis in freely moving rat during re- amygdala. A marked decrease was measured in the PTSD group exposure the traumatic remainder only (without cat scent), that exceeded the decrement indicated of non- PTSD group. the PTSD rat had increased the extraßcellular -endorphin (*p<0.01 vs naive, **p<0.0 vs non-PTSD, ANOVA) which remained high for two hours post re-exposure to the cue associated with the traumatic event (Fig 5). This may Naive non-PTSD PTSD indicate that the mechanism underlying heighten behavioral -endorphin reaction to the traumatic cue involve inability to maintain a (g/ml) 157.06±38.71 * 75.86±20.7 **15.32±4.9 threshold of basal -endorphin release. Hence, -endorphin levels may increase in order to moderate the distress reac- tion. Massive extracellular release of the -endorphin may endorphin in post-operative memory in the amygdala was further lead to depletion of its cellular storage. Despite the suggested [200, 201]. Additionally, retrieval of avoidance increase in the extracellular fluid -endorphin levels in the learning is modulated by -endorphin and enhanced by amygdala, they did not reach the basal levels of control rats, [202]. In humans, opioid receptor blockade, using but they approximate the basal extra cellular fluid - a single oral dose of naltrexone, may specifically improve endorphin level of non-PTSD rats. These findings support incidental recognition memory following physiological Grisel et al. finding that -endorphin have a significant role arousal [206]. These findings demonstrate that opioid pep- in moderating anxiety. Inability to increase -endorphin lev- tides in general, and -endorphin in particular, mediate al- els in PTSD might explain the behavioral symptoms of terations in specific aspects of human memory during trauma re-experiencing. heightened emotional states and that learning-based interven- tions can create new memories that may modify existing -Endorphin and Memory ones [203]. These studies support a role for -endorphin in learning and memory that may be associated with memory- The process of learning and memory is obviously in- related stress disorders. volved is stress-related disorders. An involvement of -

Fig. (5). Extracellular (CSF) -endorphin level in the amygdala in PTSD and non-PTSD rats re-exposed to cue. Rats underwent a stressful procedure (exposure to a predator scent) over eight weeks experiment as described [157]. On the eighth week rats were defined as maladapted (PTSD-like) or non maladapted) non PTSD-like rats. A week after, microdialysis probes were co-implanted into their basolateral amygdala. During microdialysis sampling, rats were re-exposed to a cue (same bedding without a predator scent). Re-exposure to the cue, increased -endorphin concentration in the extracellular fluid of PTSD rats. This increment stayed significantly higher for two hours follow- ing the re-exposure (ANOVA for repeated measure revealed significance. *p<0.05 PTSD vs non PTSD). 1104 Current Drug Targets, 2009, Vol. 10, No. 11 Yadid et al.

CONCLUDING REMARKS AND PERSPECTIVES Currently, some evidence supports the possibility of - endorphin neurotransmission in controlling depression and Current pharmacological treatment for depression is PTSD. Therefore, understanding the role of -endorphin in based on the use of drugs that act mainly by enhancing brain the modulation of the anti-distress and post-operative mem- serotonin and noradrenaline neurotransmission. Although ory may assist in providing potential therapeutic strategies complete remission of symptoms is the goal of any depres- for the prevention of relapse to depressive state and PTSD. sion treatment, many patients fail to attain or maintain a Such treatments may be more efficient compared to currently long-term, symptom-free status. In view of this, there is an available treatments. intense search to identify novel targets for antidepressant therapy. 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Received: April 5, 2009 Revised: June 11, 2009 Accepted: June 23, 2009

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