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Peptides
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ossible involvement of neuropeptide Y Y1 receptors in antidepressant like effectf agmatine in rats
andkishor R. Kotagale, Nikhilesh P. Paliwal, Manish M. Aglawe, Milind J. Umekar, Brijesh G. Taksande ∗
ivision of Neuroscience, Department of Pharmacology, Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441 002, MS, India
a r t i c l e i n f o
rticle history:eceived 30 July 2012eceived in revised form 25 April 2013ccepted 27 April 2013vailable online xxx
eywords:gmatineeuropeptide YPY Y1 receptors
a b s t r a c t
Agmatine and neuropeptide Y (NPY) are widely distributed in central nervous system and criticallyinvolved in modulation of depressive behavior in experimental animals. However their mutual inter-action, if any, in regulation of depression remain largely unexplored. In the present study we exploredthe possible interaction between agmatine and neuropeptide Y in regulation of depression like behav-ior in forced swim test. We found that acute intracerebroventricular (i.c.v.) administration of agmatine(20–40 �g/rat), NPY (5 and 10 �g/rat) and NPY Y1 receptor agonist, [Leu31, Pro34]-NPY (0.4 and 0.8 ng/rat)dose dependently decreased immobility time in forced swim test indicating their antidepressant likeeffects. In combination studies, the antidepressant like effect of agmatine (10 �g/rat) was significantlypotentiated by NPY (1 and 5 �g/rat, icv) or [Leu31, Pro34]-NPY (0.2 and 0.4 ng/rat, icv) pretreatment.
epressionmmobility timeST
Conversely, pretreatment of animals with NPY Y1 receptor antagonist, BIBP3226 (0.1 ng/rat, i.c.v.) com-pletely blocked the antidepressant like effect of agmatine (20–40 �g/rat) and its synergistic effect withNPY (1 �g/rat, icv) or [Leu31, Pro34]-NPY (0.2 ng/rat, icv). The results of the present study showed that,agmatine exerts antidepressant like effects via NPYergic system possibly mediated by the NPY Y1 recep-tor subtypes and suggest that interaction between agmatine and neuropeptide Y may be relevant togenerate the therapeutic strategies for the treatment of depression.
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. Introduction
Agmatine [4-(amino butyl) guanidine] is a metabolite of l-rginine, synthesized by arginine decarboxylase and hydrolyzedo putrescine and urea by agmatinase. Agmatine is a biologi-ally active substance that activates both I1/I2 imidazoline and2-adrenergic receptors, blocks N-methyl-d-aspartic acid (NMDA)
eceptors and inhibits nitric oxide synthase (NOS) [1,12]. Agma-ine has been recognized as an important neurotransmitter in therain and gained much attention in several neurological disor-ers. Several lines of evidence suggest the prominent involvementf agmatine in central disorders such as schizophrenia, anxietynd depression [21,24,38–40,44]. Interestingly, plasma concentra-ions of agmatine were found to be altered in the acute stagef primary major depression and normalized after antidepres-ant treatment [25–27]. Moreover, recent study by Bernstein et al.2] have shown strong upregulation of the agmatine-degrading
Please cite this article in press as: Kotagale NR, et al. Possible involvement ofin rats. Peptides (2013), http://dx.doi.org/10.1016/j.peptides.2013.04.018
nzyme, agmatinase in patients with unipolar and bipolar depres-ion suggesting that reduction of the endogenous brain agmatineay play central role in the pathogenesis of the mood disorders.
These evidences strongly support the role of agmatine as a rel-evant endogenous antidepressant in the mammalian brain. Wehave recently demonstrated that agmatine significantly increasesNPY immunoreactivity in hypothalamic paraventricular and arcu-ate nucleus [37].
Neuropeptides including neuropeptide Y (NPY) are estab-lished as an attractive targets for neurological and stress relateddisorders [13–15,36,41,42]. NPY and NPY Y1 receptor ago-nists activates the hypothalamus-pituitary-adrenal (HPA) axisthat alters the secretion of various hypothalamic neuropeptides,increases brain level of monoamines and produces antidepressantactivity [6,13,18,19,23,30,34]. Furthermore, patients with majordepression and suicidal tendency showed a decreased level of NPY-immunoreactivity in caudate nucleus, cerebellum and cortex [41].Further, exogenous NPY and NPY Y1 agonists produced antidepres-sant like effect in animals models of depression [31,32,36]. In viewof this background, the role of NPY Y1 receptor has been proposedin the antidepressant action of NPY.
Apart from their parallel distribution in central nervous systemagmatine and NPY shows extensive resemblance with referenceto their physiological or pharmacological properties. Both these
neuropeptide Y Y1 receptors in antidepressant like effect of agmatine
neuromodulators released during stress [12–16] and are criti-cally implicated in the regulation of anxiety [7,14,36,38,42] anddepression [2–4,13,32,41,44]. However their mutual interaction,if any, in regulation of depression remain largely unexplored.
ince agmatine increases NPY immunoreactivity in hypothalamicaraventricular and arcuate nucleus, we hypothesized that antide-ressant like effect of agmatine might involve modulation of centralPYergic system. In this study we investigated the antidepressant
ike effect of agmatine in forced swim test in presence of NPY, NPY1 agonist, [Leu31, Pro34]-NPY and NPY Y1 antagonist, BIBP3226.
. Materials and methods
.1. Subjects
Adult Sprague-Dawley rats (220–250 g) were group housednder controlled environmental condition at 24 ± 1 ◦C under2:12 h light/dark cycle (lights on 07:00–19:00 h) but after intrace-ebroventricular (icv) cannulation they were housed individually.ood and water was available ad libitum. All experimental proce-ures were approved by Institutional Animal Ethical Committeend executed according to guidelines of the Committee for the Pur-ose of Control and Supervision of Experimental Animals (CPCSEA),inistry of Environment and Forests; Government of India; Newelhi.
.2. Drugs and administration
Agmatine sulfate, NPY, NPY Y1 receptor agonist [Leu31,ro34]-NPY and NPY Y1 receptor antagonist BIBP3226 (N2-iphenylacetyl)-N-[(4 -hydroxy-phenyl)-methyl]-d-argininemide) were purchased from Sigma–Aldrich Co., USA. All therugs were dissolved in artificial cerebrospinal fluid (aCSF) (aCSFomposition: 125 mM NaCl, 10 mM glucose, 1.25 mM NaH2PO4,.5 mM CaCl2, 1.5 mM MgSO4, 26 mM NaHCO3, adjust pH to 7.4ith 0.1 M NaOH) just before the experiments and infused by icv
The detailed procedure of the stereotaxic cannulation, drugdministration and post-surgical care has been described in ourrevious studies [38]. Rats were anesthetized with thiopentoneodium (60 mg/kg, ip) and a 22-gauge stainless steel guide cannulaC313G/Spc, plastic UK) was stereotaxically (David Kopf Instru-
ents, CA, USA) implanted into the right lateral ventricle. Theurgical coordinates −0.8 mm posterior, +1.2 mm lateral to mid-ine and −3.5 mm ventral to bregma were used for icv cannulation28]. The guide cannulae were then fixed to the skull with den-al cement (DPI-RR cold cure, acrylic powder, Dental Product ofndia, Mumbai) and secured in two stainless steel screws. A 28-auge stainless steel dummy cannula was used to occlude theuide cannula when not in use. Following surgery, the rats werelaced individually in cage and allowed to recover at least for 7ays before being tested in forced swim test. Rats were then ran-omly assigned to different groups and habituated to the testingnvironment by transferring to experimental room and twice dailyandling for 1 week. Drugs were injected (5 �l/rat) into the rightentricle over a one min period with a microliter syringe (Hamilton,eno, NV, USA) connected by PE-10 polyethylene tubing to a 28-auge internal cannula (C313I/Spc, plastic one, internal diameter.18 mm, outer diameter 0.20 mm) that extended 0.5 mm beyondhe guide cannula. The internal cannula was held in a position fornother 1 min after each injection to promote diffusion of drugsefore being slowly withdrawn to prevent backflow. After the com-
Please cite this article in press as: Kotagale NR, et al. Possible involvement ofin rats. Peptides (2013), http://dx.doi.org/10.1016/j.peptides.2013.04.018
letion of experimental protocol, dilute India ink was injected (icv)nd the animals were euthanized by intraperitoneal injection ofentobarbital sodium (80 mg/kg, ip). The brain of rat was dissectedut immediately to verify the distribution of ink in the ventricles.
PRESSs xxx (2013) xxx– xxx
The data from the animals with incorrect placement (20%) of can-nula were excluded from the observations. Data from the animalswith uniform ink distribution in the ventricles were considered forstatistical analysis.
2.4. Assessment of antidepressant activity
2.4.1. Forced swim testForced swim test (FST) was performed to access antidepres-
sant activity using procedure described by [20,29]. Separate groupof rats were individually forced to swim in cylindrical glass tank(46 cm tall × 20 cm in diameter) containing 30 cm of water and theduration of immobility was measured. Two swimming sessionswere carried out with an initial 15 min ‘pre-test’ followed by a 5 min‘test’ after 24 h. Animals were treated with different agents priorto the test session. Reduction in the duration of immobility wasconsidered as antidepressant like effect of the drug.
2.4.2. Dose specific effect of agmatine and NPY Y1 receptorligands on immobility time in FST
This experiment examined the dose dependent effect of agma-tine, NPY and NPY Y1 receptor agonist [Leu31, Pro34]-NPY andNPY Y1 receptor antagonist BIBP3226 on immobility time in FST.Different group of rats (n = 5–17) were administered with differ-ent doses of either agmatine (10, 20 and 40 �g/rat, icv), NPY (1,5 and 10 �g/rat, icv), [Leu31, Pro34]-NPY (0.2, 0.4 and 0.8 ng/rat,icv), BIBP3226 (0.1, 0.2 and 0.5 ng/rat, icv) or aCSF (5 �l/rat, icv)and 30 min thereafter immobility time was determined in the “testsession”.
The doses of agmatine, NPY, [Leu31, Pro34]-NPY and BIBP3226employed in the present study were selected on the basis of ourpreliminary experiments and available literature [10,11].
2.4.3. Influence of NPY Y1 receptor agonist on agmatine inducedantidepressant like effect
This experiment examined the antidepressant like effect ofagmatine in animals pretreated with NPY or NPY Y1 receptor ago-nist. For combination studies subeffective doses of drugs were used.Different groups of rats (n = 6–8) were pretreated with either NPY(1 and 5 �g/rat, icv), NPY Y1 agonist, [Leu31, Pro34]-NPY (0.2 and0.4 ng/rat, icv) or aCSF (5 �l/rat, icv). Fifteen min following thesetreatments, all animals received subeffective dose of either agma-tine (10 �g/rat, icv) or aCSF (5 �l/rat, icv) and the antidepressanteffect was measured for 5 min test session in FST.
2.4.4. Influence of NPY Y1 receptor antagonists on antidepressantlike effect of agmatine and its subeffective dose combination withNPY or NPY Y1 receptor agonist
Rats (n = 6–7) were injected with BIBP3226 (0.1 ng/rat, icv) oraCSF (5 �l/rat, icv) 15 min prior to administration of effective doseof agmatine (20 and 40 �g/rat, icv) or aCSF (5 �l/rat, icv). Fifteenmin thereafter forced swimming test was conducted as mentionedearlier.
Separate group of rats (n = 6–8) were pretreated with BIBP3226(0.1 ng/rat, icv) or aCSF (5 �l/rat, icv) 15 min before the administra-tion of per se non effective doses of agmatine (10 �g/rat, icv) andNPY (1 �g/rat, icv) or NPY Y1 agonist, [Leu31, Pro34]-NPY (0.2 ng/rat,icv). Immobility time was measured in forced swim test 15 minafter the last injection.
2.4.5. Locomotor activityAll animals were brought to the behavior study laboratory
neuropeptide Y Y1 receptors in antidepressant like effect of agmatine
24 h prior to start of the experiment. Locomotor activity wasmonitored in separate group of animals with an actophotometer(38 × 38 × 14 cm) (VJ instruments, Karanja, India) equipped withphotocells that automatically measured the movement of rat. Any
Fig. 1. Effect of agmatine, NPY, [Leu31 Pro34]-NPY and BIBP3226 in forced swimmingtest in rats. Rats were treated with agmatine (10–40 �g/rat, icv) or NPY (1–10 �g/rat,icv) or [Leu31 Pro34]-NPY (0.2–0.8 ng/rat, icv)) or BIBP3226 (0.1–0.5 ng/rat, icv)or aCSF (5 �l/rat, icv) and 15 min thereafter, were observed for 5 min in forceds*D
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Fig. 2. Effect of agmatine and NPY or [Leu31 Pro34]-NPY on immobility time inrat forced swimming test. NPY (1 or 5 �g/rat, icv) or [Leu31 Pro34]-NPY (0.2 or0.4 ng/rat, icv) or aCSF (5 �l/rat, icv) were injected 15 min before the administra-tion of agmatine (10 �g/rat, icv) or aCSF (5 �l/rat, icv) and 15 min after the lastinjections the rats were subjected to forced swimming test. Each bar is the meanimmobility time (s) ± SEM (n = 6–8). *P < 0.01, **P < 0.001 vs aCSF + aCSF treatment;$P < 0.05, $$P < 0.001 vs NPY + aCSF treatment (respective); #P < 0.05, ##P < 0.001 vs182
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wimming test. Each column represents mean ± SEM (n = 5–17). *P < 0.05, **P < 0.01,**P < 0.001 vs aCSF treated control animals (One way ANOVA followed by post hocunnett test).
ovement of the rat that interrupted photo beams was recordeds a motor count. Each rat was injected icv with aCSF, agmatine, orPYergic agents in their home cages and 15 min thereafter placed
n the actophotometer. Spontaneous locomotor activity of each ratas measured for 10 min. Animals were used only once and after
ach test the grid floor of actophotometer was carefully cleaned.he data are expressed as mean number of counts per 10 min.
.5. Data analysis
Data was presented as the mean ± SEM. The results of dose spe-ific study were analyzed by one-way ANOVA followed by postoc Dunnett test. For multiple comparisons, data were analyzedy one- or two-way ANOVA followed by post hoc Newman-euls/Bonferroni multiple comparison test respectively.
. Results
.1. Effects of agmatine, NPY, [Leu31, Pro34]-NPY and BIBP3226n the FST
As shown in Fig. 1, agmatine (20 and 40 �g/rat, icv)F(3,37) = 5.34, P < 0.01], NPY (5 and 10 �g/rat, icv) [F(3,36) = 14.34,
< 0.001], [Leu31, Pro34]-NPY (0.4 and 0.8 ng/rat, icv) [F(3,38) = 7.94, < 0.001] produced significant dose dependent reduction in theuration of immobility in rats subjected to FST. At higher dosesgmatine (40 �g/rat, icv) (P < 0.01), NPY (10 �g/rat, icv) or [Leu31,ro34]-NPY (0.8 ng/rat, icv) shortened immobility time by 33%P ≤ 0.01), 48% (P ≤ 0.001) and 32% (P < 0.001) respectively as com-ared to saline treated animals. Their respective lower dosesowever, did not affect duration of immobility significantly. Simi-
arly, animals injected with NPY Y1 receptor antagonist, BIBP32260.1–0.5 ng/rat) did not produce any significant change in the basalmmobility time of naive animals.
.2. NPY and [Leu31, Pro34]-NPY potentiated agmatine effect inST
Please cite this article in press as: Kotagale NR, et al. Possible involvement ofin rats. Peptides (2013), http://dx.doi.org/10.1016/j.peptides.2013.04.018
Fig. 2 depicts the effects of a combination of agmatine,PY or [Leu31, Pro34]-NPY on immobility time in FST. At
he given doses combination of the agmatine (10 �g/rat, icv)
[Leu31 Pro34]-NPY + aCSF treatment (respective); (Two way ANOVA followed by posthoc Newman-Keuls multiple comparison).
with NPY (1 and 5 �g/rat, icv) [FAgmatine Treatment (2,33) = 24.10,P < 0.001; FNPY Treatment (1,33) = 9.41, P < 0.01; FAgmatine × NPY Treatment(2,33) = 1.22, P = 0.31] or [Leu31, Pro34]-NPY (0.2 and 0.4 ng/rat, icv)resulted in a significant antidepressant like effect [FAgmatine Treatment(2,35) = 19.17, P < 0.001; FNPY Treatment (1,35) = 8.15, P < 0.01;FAgmatine × NPY Treatment (2,35) = 0.77, P = 0.47]. The doses of agma-tine, NPY or [Leu31, Pro34]-NPY did not influence the immobilitytime in FST.
3.3. NPY Y1 receptors antagonist, BIBP3226 blocked theantidepressant like effect of agmatine and its synergisticcombination with NPY receptor agonists
As depicted in Fig. 3, pretreatment of rats with NPY Y1receptors antagonist BIBP3226 (0.1 ng/rat) blocked the antidepres-sant like effect elicited by effective doses of agmatine (20 and40 �g/rat, icv) in FST) [FAgmatine Treatment (2,33) = 10.20, P < 0.001;FBIBP3226 Treatment (1,33) = 8.37, P < 0.01; FAgmatine × BIBP3226 Treatment(2,33) = 2.02, P = 0.15]. Administration of BIBP3226 to aCSF treatedanimals did not evoke any response in FST at the dose used here.
Similarly, as shown in Fig. 4, pretreatment of animalswith BIBP3226 (0.1 ng/rat, icv) significantly attenuated the anti-immobility effect induced by subeffective dose combination ofagmatine (10 �g/rat, icv) with NPY (1 �g/rat, icv) [F(3,28) = 5.51,P < 0.01] or [Leu31, Pro34]-NPY (0.2 ng/rat, icv) [F(3,27) = 6.89,P < 0.01]. Post hoc Newman-Keul mean comparison demonstratedthe significant attenuation of antidepressant effect exhibited by thecoadministration of agmatine and NPY (P < 0.01) or [Leu31, Pro34]-NPY (P < 0.05) combination.
3.4. 3.5. Effects of agmatine, NPY, [Leu31, Pro34]-NPY andBIBP3226 on locomotor activity
neuropeptide Y Y1 receptors in antidepressant like effect of agmatine
None of the above mentioned treatments alone or in combina-tion at different doses used here produced any effect on locomotoractivity as compared to control animals. The average locomotor
Fig. 3. Effect of NPY Y1 receptors antagonist, BIBP3226 with agmatine on immobil-ity time in forced swimming test in rats. BIBP 3226 (0.1 ng/rat, icv) or aCSF (5 �l/rat,icv) were injected 15 min before the administration of agmatine (20 or 40 �g/rat,icv) or aCSF (5 �l/rat, icv) and 15 min after the last injections the animals were sub-jected to forced swimming test. Each bar is the mean immobility time (s) ± SEM(tt
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Fig. 4. Effect of BIBP 3226 on the antidepressantlike effect of combine treatmentof agmatine and NPY or [Leu31 Pro34]-NPY in rat forced swimming test. Ratswere treated with BIBP 3226 (0.1 ng/rat, icv) or aCSF (5 �l/rat, icv) 15 min beforethe administration of agmatine (10 �g/rat, icv) and NPY (1 �g/rat, icv) or [Leu31
Pro34]-NPY (0.2 ng/rat, icv) and 15 min thereafter, animals were subjected to forcedswimming test. Each bar is the mean immobility time (s) ± SEM (n = 6–8). *P < 0.01vs aCSF + aCSF treatment, $P < 0.01 vs NPY + agmatine treatment, #P < 0.05 vs [Leu31
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n = 6–7). *P < 0.01 **P < 0.001 vs aCSF + aCSF treatment, $P < 0.01 vs aCSF + agmatinereatment (respective) (One way ANOVA followed by post hoc Newman-Keuls mul-iple comparison).
ounts of control animals were 156.6 ± 24.81 (ambulations) (dataot shown).
. Discussion
In consistent with several earlier finding [10,31,35,39,44] theesults of the present study demonstrated that agmatine, NPYnd NPY Y1 receptors agonist [Leu31, Pro34] NPY exhibited doseependent antidepressant-like effect in the animals subjected toorced swim test following their central administration. On thether hand, administration of NPY Y1 receptors antagonist, BIBP226 to naïve animals did not influence immobility time in FST. Ingreement with previous results acute administration of NPY Y1eceptors antagonist BIBP 3226 [8,33] had no effect on behaviorf animals subjected to open field or FST, its repeated administra-ion reported to enhance the hyperlocomotor activity in olfactoryulbectomized rats [10].
Subjects with mood disorders showed strong upregulationf agmatine-degrading, agmatinase in hippocampal interneuronsuggesting its functional relevance in the pathophysiology of theffective disorder [2]. Further, earlier studies from our laboratorynd results of other preclinical investigation have clearly shownhe antidepressant potential of agmatine administered exoge-ously [39,43,44]. Although accumulated evidences suggested the
nvolvement of its biological targets viz. imidazoline, �2-adrenergiceceptors, NMDA/Nitric oxide synthase pathways in antidepres-ant effect of agmatine [12], the exact mechanisms have not beenlarified yet. We have recently shown that agmatine increasesPY immunoreactivity in hypothalamic PVN and ARC [37]. NPY
s synthesized in ARC and transported to PVN to influence sev-ral other neuropeptides and monoamine critically involved in theathogenesis of depression [6,9]. Further, number of clinically usedntidepressant drugs not only trigger the release of NPY but alsonhance NPY Y1 type receptor mRNA [3,5,10,22]. In the presenttudy we found that, NPY or NPY Y1 agonist [Leu31, Pro34]-NPYt their subeffective doses significantly potentiated antiimmobil-
Please cite this article in press as: Kotagale NR, et al. Possible involvement ofin rats. Peptides (2013), http://dx.doi.org/10.1016/j.peptides.2013.04.018
ty effect agmatine in FST. In contrast, pretreatment of animalsith NPY Y1 receptors antagonist BIBP 3226 completely blocked
he agmatine induced antidepressant activity. NPY-like immunore-ctivity and NPY Y1 type receptor binding sites are reported to
Pro34]-NPY + agmatine treatment (One way ANOVA followed by post hoc Newman-Keuls multiple comparison).
be altered in certain brain regions in a genetic animal modelof depression [4]. The involvement NPY Y1 receptor is proposedin the antidepressant action of NPY as the behavioral effects ofNPY were abolished by a pre-treatment with NPY Y1 receptorsantagonists BIBP 3226 and BIBO3304 in the FST [31] control ani-mals. Acute, exogenous administration of NPY and the NPY Y1receptor agonist, [Leu31, Pro34]-NPY induces antidepressant-likeeffects in naive normal animals [10,31]. These results evidentlysupport our hypothesis that antidepressant like effect of agma-tine, atleast partly mediated via interaction with NPY Y1 receptors.We may recall that agmatine increases the NPY immunoreactivityin the hypothalamic nuclei like PVN and ARC [37], thus possi-bility also exist that agmatine might trigger the release of NPYwhich subsequently activate NPY Y Y1 receptor to induce antide-pressant like effect in FST. More precise studies are required toclarify this issue. The locomotor activity in the present study wascarried out to ensure that a decrease in immobility time in theforced swimming test was not due to increases in locomotor activ-ity. The antidepressant-like effect of agmatine, NPY or NPY Y1agonist [Leu31, Pro34]-NPY alone or in combination cannot beattributed to any locomotor component since activity in actopho-tometer remained unaffected. It is important to note that agmatineis one of the few neurotransmitters having affinity toward severalreceptors and produced diverse physiological functions. Agma-tine interact with �2-adrenoceptors, imidazoline receptors, NOand inhibits nitric oxide synthase [1,12,17,38]. Therefore, theirinvolvement in the observed effect of agmatine cannot be ruledout.
In conclusion, present study demonstrated that antidepressantlike effect of agmatine in FST was potentiated by NPY or NPYY1 agonist at their subeffective doses. Conversely, NPY Y1 antag-onist, BIBP3226 completely blocked the antidepressant effect ofagmatine and its synergistic effect with NPY or [Leu31, Pro34]-NPY.These results showed the possible involvement of NPY Y1 recep-
neuropeptide Y Y1 receptors in antidepressant like effect of agmatine
tors in antidepressant like effect of agmatine and suggest thatagmatine and NPYergic system interaction may be important toexplore the new therapeutic strategies for treatment of depressiveillness.
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