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Abstract Long-term use of opioid drugs such as morphine can induce addiction in the central nervous system through dysregulation of the reward system of the brain. Deep brain stimulation (DBS) is a non-pharmacological technique capable of attenuating behavioral responses associated with opioid drug consumption and possesses the capability to selectively activate and target localized brain regions with a high spatial resolution. However, long-term implantation of electrodes in brain tissue may limit the effectiveness of DBS due to changes in impedance, position, and shape of the tip of the stimulation electrode and the risk of infection of nerve tissue around the implanted electrode. The main objective of the current study is to evaluate the effect of temporal interference (TI) brain stimulation on addictive behaviors of morphine-induced conditioned place preference (CPP) in rats. TI stimulation is a non-invasive technique used transcranially to modulate neural activity within targeted brain regions. It involves applying two high-frequency currents with slightly different frequencies, resulting in interference and targeted stimulation of different brain areas with the desired spatial resolution. The results indicated that TI stimulation with the amplitude of $${\text{I}}_{1}{ = }{\text{I}}_{2}{ = 0.5}$$ I 1 = I 2 = 0.5 mA, carrier frequency of 2 kHz, frequency difference of 25 Hz, ON–OFF stimulation frequency of 0.25 Hz, and total duration of 10 min in three consecutive days resulted in a significant reduction of morphine preference in the morphine-stimulation group in comparison with the morphine group (p

Background: Escitalopram, a pharmacological compound, and crocin, the active compound of saffron, influence brain functions and serotonin levels. This study examined the efficacy of escitalopram with and without crocin in restoring the input-output (I/O) functions and long-term potentiation (LTP) within the hippocampal cornu ammonis 1 (CA1) region of stressed rats. Materials and Methods: Rats were divided into six groups: control (Co), sham (Sh), stress-recovery (St-Rec), stress-escitalopram (St-Esc), stress-crocin (St-Cr), and stress-escitalopram-crocin (St-Esc-Cr) groups. They underwent 14 days of restraint stress (6 h/day). After being subjected to stress, they received 14 days of escitalopram (20 mg/kg) and crocin (30 mg/kg), as well as co-administration of these two compounds during the next 14 days. The field excitatory postsynaptic potential (fEPSP) slope and amplitude were measured using I/O functions and LTP induction in the CA1 region. Corticosterone (CORT) levels were also evaluated. Results: The fEPSPs slope and amplitude in the I/O functions and LTP induction significantly decreased in stressed rats without therapeutic intervention. These variables in the I/O functions declined in rats with escitalopram administration alone. All electrophysiological parameters showed an increase in rats treated with crocin alone compared to stressed subjects without any treatment. Serum CORT levels decreased only with crocin treatment for stressed rats. Conclusion: Neural excitability and memory within the CA1 region were severely disrupted among stressed rats without any treatment. Furthermore, administering crocin alone improved neural excitability and memory post-chronic stress. Treatment with escitalopram alone also impaired neural excitability within the CA1 region. The use of escitalopram with and without crocin did not enhance memory under chronic stress.

Background: Chronic stress can lead to anxiety and depression. Escitalopram is a selective serotonin reuptake inhibitor (SSRI), and crocin is a natural compound derived from saffron. Both of them are used to treat these disorders in clinical and traditional medicine, respectively. This study compared the antidepressant and anxiolytic effects of escitalopram, crocin, and their combination in rats. Materials and Methods: Rats were divided into nine groups: control, sham, rest-depression, depression-rest, depression-crocin, depression-escitalopram10, depression-escitalopram20, depression-escitalopram10-crocin, and depression-escitalopram20-crocin. Forced swimming and open field tests (FST and OFT, respectively) were used to evaluate depression, anxiety, and locomotor activity. Results: In the FST, the immobility time on day 28 significantly decreased in all depressed groups that received escitalopram, crocin, and their combination compared to the rest-depression group. Whereas, conversely, the time spent at the center in the OFT was significantly higher in similar comparisons. The total distance traveled by the OFT was significantly lower in all depressed groups, except for the depression-escitalopram10 and depression-escitalopram20 groups. The total distance traveled was significantly higher in the depression-escitalopram20 compared to the rest-depression group. Conclusion: Crocin, both doses of escitalopram and their combination, reduced depression. A high dose of escitalopram, with and without crocin, was partially more effective than a low dose of escitalopram in reversing depression. There was anxiety-like behavior observed after inducing depression with and without a recovery period. Whereas, crocin alone and both doses of escitalopram, with and without crocin, decreased anxiety-like behaviors in subjects with depression. This effect may be attributed to a modulation of brain neurotransmitter ratios.

Stress and escitalopram (an anti-stress medication) can affect brain functions and related gene expression. This study investigated the protective effects of long-term escitalopram administration on memory, as well as on hippocampal BDNF and BCL-2 gene expressions in rats exposed to predictable and unpredictable chronic mild stress (PCMS and UCMS, respectively). Male rats were randomly assigned to different groups: control (Co), sham (Sh), predictable and unpredictable stress (PSt and USt, respectively; 2 h/day for 21 consecutive days), escitalopram (Esc; 10 mg/kg for 21 days), and predictable and unpredictable stress with escitalopram (PSt-Esc and USt-Esc, respectively). The passive avoidance test was used to assess behavioral variables. The expressions of the BDNF and BCL-2 genes were assessed using real-time quantitative PCR. Latency significantly decreased in the PSt and USt groups. Additionally, latency showed significant improvement in the PSt-Esc group compared to the PSt group. The expression of the BDNF gene significantly decreased only in the USt group. BDNF gene expression significantly increased in the PSt-Esc and USt-Esc groups compared to their respective stress-related groups, whereas the expression of the BCL-2 gene did not change significantly in both PSt-Esc and USt-Esc groups. PCMS and UCMS had devastating effects on memory. Escitalopram improved memory only under PCMS conditions. PCMS and UCMS exhibited fundamental differences in hippocampal BDNF and BCL-2 gene expressions. Furthermore, escitalopram increased hippocampal BDNF gene expression in the PCMS and UCMS subjects. Hence, neurogenesis occurred more significantly than anti-apoptosis under both PCMS and UCMS conditions with escitalopram.

Background and purpose: The central nucleus of the amygdala (CeA) is one of the nuclei involved in the reward system. The aim of the current study was to investigate the electrical stimulation (e-stim) effect of the CeA in combination with dopamine D1 receptor antagonist on morphine-induced conditioned place preference (CPP) in male rats. Experimental approach: A 5-day procedure of CPP was used in this study. Morphine was administered at an effective dose of 5 mg/kg, and SCH23390 as a selective D1 receptor antagonist was administrated into the CeA. In addition, the CeA was stimulated with an intensity of the current of 150 μA. Finally, the dependence on morphine was evaluated in all experimental groups. Findings /Results : Morphine significantly increased CPP. While the blockade of the D1 receptor of the CeA reduced the acquisition phase of morphine-induced CPP. Moreover, the combination of D1 receptor antagonist and e-stim suppressed morphine-induced CPP, even it induced an aversion. Conclusion and implication : The current study suggests that the administration of dopamine D1 receptor antagonist into the CeA in combination with e-stim could play a prominent role in morphine dependence.

Background and purpose: The lateral habenula (LHb), a key area in the regulation of the reward system, exerts a major influence on midbrain neurons. It has been shown that the gamma-aminobutyric acid (GABA)- ergic system plays the main role in morphine dependency. The role of GABA type B receptors (GABABRs) in the regulation of LHb neural activity in response to morphine, remains unknown. In this study, the effect of GABABRs blockade in response to morphine was assessed on the neuronal activity in the LHb. Experimental approach: The baseline firing rate was recorded for 15 min, then morphine (5 mg/kg; s.c) and phaclofen (0, 0.5, 1, and 2 μg/rat), a GABABRs’ antagonist, were microinjected into the LHb. Their effects on firing LHb neurons were investigated using an extracellular single-unit recording in male rats. Findings/Results: The results revealed that morphine decreased neuronal activity, and GABABRs blockade alone did not have any effect on the neuronal activity of the LHb. A low dose of the antagonist had no significant effect on neuronal firing rate, while blockade with doses of 1 and 2 μg/rat of the antagonist could significantly prevent the inhibitory effects of morphine on the LHb neuronal activity. Conclusion and implications: This result indicated that GABABRs have a potential modulator effect, in response to morphine in the LHb.

Objective(s): The central nucleus of the amygdala (CeA) is one of the most important areas for the morphine reward system. This study investigated the effect of electrical stimulation of CeA on morphine conditioned place preference (CPP) in male rats. Materials and Methods: After anesthetizing male Wistar rats, both electrode and cannula were implanted into CeA for stimulating (low intensity: 25 μA, and high intensity: 150 μA) and injecting (lidocaine and dopamine D2 receptor antagonist), respectively. Then, CPP induced by effective (5 mg/kg) and ineffective (0.5 mg/kg) doses of morphine was evaluated for five consecutive days (n = 6 / group).Results: The low electrical stimulation intensity of 25 μA suppressed both acquisition and expression phases, but the high intensity of 150 µA attenuated only the expression phase. On the other hand, intra-CeA administration of dopamine D2 receptor antagonist, eticlopride (2 µg/rat), with the effective dose of morphine, decreased CPP. In addition, infusion of lidocaine into the CeA inhibited morphine-induced CPP in both acquisition and expression phases with the effective dose of morphine.Conclusion: Electrical stimulation of the CeA may play an important role in attenuating morphine induced CPP via possible changes in neurotransmitters involved in the reward system such as dopamine (DA) and gamma-aminobutyric acid (GABA).

Introduction: The lack of social communication is associated with the primary risk of proper brain functions. It is reported that crocin helps relieve this problem. The present study examined the protective effect of two doses of crocin on Long-term potentiation (LTP) of hippocampal cornu ammonis 1 (CA1) area as a cellular mechanism in rats exposed to chronic social isolated stress. Methods: Rats were assigned to the control, sham, isolation stress, and two stress groups (receiving 30 and 60 mg/kg crocin). Chronic isolation stress (CIS) was induced 6 h/d, and crocin was administrated for 21 days. The field excitatory postsynaptic potential (fEPSP) slope and amplitude were measured by input/output functions and LTP induction in the CA1 area of the hippocampus. Also, the corticosterone and glucose levels were assayed in the hippocampus and frontal cortex. Results: The slope and amplitude of fEPSP severity were impaired in both input/output and LTP responses in the CIS group. Crocin at a dose of 30 and particularly 60 mg/kg improved input/output and LTP responses in the CIS group. Also, the corticosterone levels significantly increased in the frontal cortex and especially the hippocampus. In contrast, only a high dose of crocin decreased hippocampal corticosterone levels in the CIS condition. Finally, the glucose levels did not change in the hippocampus and frontal cortex in all experimental groups. Conclusion: The chronic isolation stress impaired neural excitability and Long-term plasticity in the CA1 area due to elevated corticosterone in the hippocampus and probably the frontal cortex. The low and high doses of crocin improved excitability and Long-term plasticity in the chronic isolation stress group by only decreasing corticosterone levels in the hippocampus, but not the frontal cortex.

Background and purpose: The nucleus accumbens (NAc) express both orexin-2 receptor (OX2R) and cannabinoid receptor type 1 (CB1R). Orexin and cannabinoid regulate the addictive properties of nicotine. In this study, the effect of the CB1R blockade on the electrical activity of NAc neurons in response to nicotine, and its probable interaction with the OX2R in this event, within this area, were examined via the single-unit recording. Experimental approach: The spontaneous firing rate of NAc was initially recorded for 15 min, and then 5 min before subcutaneous injection of nicotine (0.5 mg/kg)/saline, AM251 and TCS-OX2-29 were injected into the NAc. Neuronal responses were recorded for 70 min, after nicotine administration. Findings/Results: Nicotine excited the NAc neurons significantly and intra-NAc microinjection of AM251 (25 and 125 ng/rat), as a selective CB1R antagonist, prevented the nicotine-induced increases of NAc neuronal responses. Moreover, microinjection of AM251 (125 ng/rat), before saline injection, could not affect the percentage of change of the neuronal response. Finally, simultaneous intra-NAc administration of the effective or ineffective doses of AM251 and TCS-OX2-29 (a selective antagonist of OX2R) prevented the nicotine- induced increases of NAc neuronal responses, so that there was a significant difference between the group received ineffective doses of both antagonists and the AM251 ineffective dose. Conclusion and implications: The results suggest that the CB1R can modulate the NAc reaction to the nicotine, and it can be concluded that there is a potential interplay between the OX2R and CB1R in the NAc, in relation to nicotine.

Background: One of the problems of addiction treatment is the relapsing of withdrawal syndrome signs in the addicted person. Rewarding brain regions such as medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) are involved in addiction and onset of withdrawal syndrome. This study was performed to investigate the relationship between these areas in demonstration or relief of withdrawal signs, electrical stimulation and lesion of mPFC, as well as blocking the relative receptors in the VTA. Methods: In an experimental study, 42 male rats weighing 250-300 g were divided in 6 equal groups of control, morphine, and stimulation and lesion electrical receiver groups in mPFC region, and groups receiving the glutamate receptors antagonists by microinjection into the VTA. All of the groups, except the control group, received intraperitoneal morphine during 9 days as the protocol. Finally, on the 10th day, the symptoms of addiction in rats were evaluated. Findings: The electrical stimulation of mPFC significantly increased cycling and scratching (P < 0.01) and bodylifting (P < 0.05) in comparison to the morphine group. Whereas the lesion of this area, and also microinjection of glutamate antagonists into the VTA caused significant decrease of all the withdrawal symptoms in rats. Conclusion: Electrical stimulation of mPFC area increased the withdrawal symptoms in addicted rats, which was most likely due to increase of glutamatergic transmissions into the VTA and reinforcement of reward system; while destruction of this area and blocking of glutamate receptors, probably via decreasing of glutamatergic transmissions, caused decrease of morphine addiction.

Objective:Boswellia serrata oleo-gum resin (frankincense) exerted antioxidant and anti-inflammatory effects against several diseases, such as; asthma, rheumatoid arthritis and irritable bowel syndrome. In the current study, the influences of B. serrata resin extracton motor dysfunction and oxidative stress markers were investigated in the intrastriatal 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD). Materials and Methods:The animals were randomly assigned to sham, lesion (6-OHDA), and three lesion groups treated with ethyl alcoholic extract of B. serrata at doses of 125, 250 and 500 mg/kg for 3 weeks. The neurotoxin 6-OHDA (12.5 µg) was microinjected into the left striatum to induce PD in male rats. Motor behavior was assessed by rotational and elevated narrow beam tests. Oxidative stress markers were measured in striatal and midbrain homogenates. Results: There was a significant increase in contralateral rotations in 6-OHDA group versus sham group (p

قدمه: مطالعات نشان می‌دهند که دوپامین به ویژه از طریق گیرنده‌های D2 نقش مهمی در هومئوستاز انرژی دارد. مطالعه‌ی مشابهی نشان داد که گیرنده‌های D2 هیپوتالاموس از طریق کمپلکس پشتی واگ می‌توانند در تنظیم ترشح گرلین نقش داشته باشند. مطالعه‌ی حاضر با هدف بررسی نقش سیستم کولینرژیک واگ در تنظیم سطوح پلاسمایی لپتین و گلوکز توسط گیرنده‌های D2 هسته‌ی ونترومدیال هیپوتالاموس (Ventromedial hypothalamus یا VMH) انجام شد. روش‌ها: كانول‌گذاري در هسته‌ی VMH در موش‌هاي صحرايي نژاد Wistar (250-220 گرم) انجام شد. در روز آزمایش، آتروپین (آنتاگونیست کولینرژیک 5 میلی‌گرم/کیلوگرم به صورت زیر جلدی) یا سالین به حیوانات ناشتا (24-20 ساعت) تزریق شد. 30 دقیقه بعد، آگونیست (کینپیرول) و آنتاگونیست (سولپراید) گیرنده‌ی D2 به ترتیب در دزهای 5/0 و 005/0 میکروگرم و سالین (5/0 میکرولیتر) در VMH تزریق شدند. 0، 30 و 60 دقیقه بعد نمونه‌های خون جمع‌آوری و سطوح لپتین و گلوکز خون به ترتیب با استفاده از کیت Enzyme-linked immunosorbent assay (ELISA) و روش گلوکز اکسیداز اندازه‌گیری شد. یافته‌ها: سطح لپتین پلاسما به طور وابسته به زمان در گروه آتروپین-کینپیرول در مقایسه با سطح پایه و شاهد کاهش معنی‌داری یافت (001/0 > P). در حالی که افزایش گلوکز خون به طور وابسته به زمان در گروه آتروپین- کینپیرول (001/0 > P) پایدار بود. در گروه آتروپین- سولپراید تغییر معنی‌داری در سطح لپتین پلاسما در مقایسه با مقادیر پایه مشاهده نشد. نتیجه‌گیری: گیرنده‌های D2 در VMH اثر خود بر تنظیم سطوح لپتین و گلوکز را حداقل تا حدودی، از طریق مسیر کولینرژیک واگ انجام می‌دهند.

Background: In the present study, the effects of intra-basolateral amygdala (BLA) blockade of dopamine D1 receptor on morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats. Materials and Methods: A 5-day CPP paradigm was used. Morphine was injected subsequently at effective (5 mg/kg) and ineffective (0.5 mg/kg) doses. SCH 23390 (0.5– μg/rat), as a selective D1 receptor antagonist, was microinjected bilaterally into the BLA. Results: Effective dose of morphine induced a significant CPP, and increased the locomotor activity during the testing phase. The results showed that morphine-induced CPP was significantly suppressed by D1 receptors antagonist in BLA in the acquisition phase and caused an aversion even at high doses. The antagonist also significantly prevented CPP expression. Morphine increased the motor activity, but the D1 receptors blockade, significantly reduced it. Conclusions: The findings of this study suggest a possible role for BLA dopamine D1 receptors in reward responses in morphine dependency.

Background: Dopamine plays an important role in regulating gastric acid secretion in the central nervous system. Dopamine D2 receptors of hypothalamic ventromedial nucleus (VMH) are involved in modulation of food intake, suggesting a potential role of the VMH D2 receptor in modulating gastric acid secretion. Hence in this study, we investigated the effect of the VMH D2 receptor blockade on basal gastric acid secretion. Methods: A guide cannula was stereotaxically implanted in VMH of male Wistar rats weighing 220-250 g. The D2 receptors antagonist sulpiride (0.005, 0.050, 0.500, and 1.000 μg/0.5 μl) or saline (0.5 μl) were injected into VMH after a 5-day recovery period. Gastric acid secretion was measured using the pylorus-ligation method and titration with NaOH 0.01 N. Findings: Sulpiride at the doses of 0.050 (P < 0.010), 0.500 (P < 0.001), and 1.000 (P < 0.001) μg/0.5 μl significantly decreased basal gastric acid secretion in a dose- and time-dependent manner. Conclusion: Sulpiride at the dose of 0.500 μg/0.5 μl had maximum effect on the secretion activity of stomach. Blocking VMH D2 receptors decreases the secretion activity of stomach in rats.

Background: Alzheimer's disease is a disorder associated with neuronal degeneration in the areas involve in learning and memory. It has been proposed that erythropoietin probably has neuroprotective effects. Therefore, the aim of the present study was to evaluate the effect of erythropoietin on neuronal apoptosis in the granular layer of dentate gyrus of the hippocampus in an animal model of Alzheimer's disease. Methods: Animal model of Alzheimer's was established via bilateral intracerebroventricular (ICV) injection of streptozotocin (STZ). After 2 weeks and observation of cognitive disorder, rats received intraperitoneal (IP) injection of erythropoietin every other day with a dose of 5000 IU/kg for 2 weeks. Finally, the rats were anesthetized and their brains were dissected for immunohistochemical study. Terminal deoxynucleotidyl transferase biotin-dUTP Nick-End Labeling (TUNEL) method was used to study neuronal apoptosis. Findings: Intracerebroventricular injection of streptozotocin increased the number of apoptotic cells in the granular layer of dentate gyrus significantly (P < 0.05). Although erythropoietin had no effect on the control rats, it significantly reduced the number of apoptotic cells in the lesion group (P < 0.01) Conclusion: The results of this study indicate that erythropoietin may be effective in reducing the complications of neurodegenerative diseases by reducing neuronal apoptosis.

BACKGROUND: The prelimbic area (PL) of the prefrontal cortex is susceptible to abnormal developmental stimuli that raises the risk of addiction. Glutamate receptors play a key role in opiate reinforcement and reward functions in this area. Therefore, we examined the effect of the DL-2-amino-5-phosphonopentanoic acid (AP5), as N-methyl-D-aspartate (NMDA) receptor antagonist into the PL on the phases of conditioned place preference (CPP) induced by morphine. METHODS: Male Wistar rats were divided into 12 groups (3 surgical groups for each dose of morphine in any phase of CPP) and anaesthetized with chloral hydrate. Cannula was implanted into the PL and the AP5 was injected into this area and morphine-induced CPP was investigated. Data were processed with the commercially available SPSS 22 software using one-way ANOVA and Tukey's test. p

Background: One of the significant problems in multiple sclerosis (MS) is damage to the visual system, which is the result of demyelination. Studies have suggested a link between central nervous system demyelinating diseases and thyroid disorders, and probably the treatments that increase the level of thyroid hormones are beneficial in multiple sclerosis. Therefore, in this study, the effects of levothyroxine on lysolecithin-induced demyelination/remyelination in rat's optic chiasm were evaluated. Methods: Local demyelination was induced by injection of 2 µl lysolecithin 1% into the rat's optic chiasm. Experimental groups were control, sham, lesion (multiple sclerosis), and lesion-levothyroxine 20, 50 and 100 µg/kg (n = 9). Demyelination/remyelination was evaluated 7, 14 and 21 days after the initiation of treatment. Histomorphological changes were assessed using hematoxylin and eosin staining. Findings: Following the injection of lysolecithin into the optic chiasm, a large demyelination was occurred, which decreased over time, indicating remyelination in this area. Following the treatment with levothyroxine, there was a significant reduction in the amount of demyelination in the treated groups compared to the multiple sclerosis group. This decrease was particularly pronounced at the dose of 100 µg/kg. Conclusion: The results of this study show that injection of lysolecithin in the optic chiasm causes a reversible demyelination. Levothyroxine could produce protective effects against induced demyelination and accelerate remyelination. Therefore, thyroid hormones probably have healing effects in multiple sclerosis, although further studies are needed.

Stress is one of the effective factors in the development of depressive disorders that performs some parts of its effects by affecting hippocampus. Since doxepin has been shown to have neuroprotective effects, in this study, we focused on the effects of doxepin on the expression of involved genes in neuronal survival and plasticity in the rat hippocampus following chronic stress. Male Wistar rats were divided into four groups, the control, the stress, the stress-doxepin 1 mg/kg and the stress-doxepin 5 mg/kg, respectively. To induce stress, the rats were placed within adjustable restraint chambers for 6 h/day, for 21 days. Before daily induction of the stress, rats received an i.p. injection of doxepin. At the end of experiments, expression of Bax, Bad, Bcl-2, tumor necrosis factor alpha (TNF-α), mitogen‑activated protein kinase 14 (MAPK14) and serine-threonine protein kinase AKT1 genes were detected by reverse transcription polymerase chain reaction (RT-PCR) in the hippocampus. Results showed significant enhancements in expression of Bax, Bad and Bcl-2 genes in the stressed rats, whereas expression of TNF-α, MAPK14, and AKT1 genes didn′t show significant differences. Doxepin could decrease the expression of Bax and Bad genes in the stress group, but had no significant effects on the expression of other genes. The present findings indicated that doxepin can probably change the pattern of gene expression in the hippocampus to maintain neurons against destructive effects of stress.

مقدمه: اعتیاد، اختلال مغزی همراه با تغییرات نوروبیولوژیک است. کورتکس پره‌فرونتال در حافظه، یادگیری، پاداش و اعتیاد نقش دارد. این مطالعه، با هدف بررسی اثر تزریق 2-Amino-5-phosphopentanoic acid (AP5)، آنتاگونیست گیرنده‌ی گلوتامات، در ناحیه‌ی پره‌فرونتال بر تمایل به مورفین انجام شد. روش‌ها: در مجموع، از 27 گروه موش صحرایی نر نژاد ویستار (6 = n) استفاده شد. بدین منظور، از 7 گروه آزمایشی جهت تعیین دزهای مؤثر و غیر مؤثر مورفین و از 20 گروه آزمایشی جهت مطالعه‌ی اثر دزهای مختلف AP5 بر تمایل به دزهای متفاوت مورفین در مراحل اکتساب و بیان آزمون رفتاری ترجیح مکانی شرطی شده (CPP یا Conditioned place preference) استفاده گردید. در نهایت، شاخص CPP مورد ارزیابی قرار گرفت. یافته‌ها: شاخص CPP گروه‌هایی که دزهای 5/2 (050/0 > P)، 5 (001/0 > P)، 5/7 (010/0 > P) و 10 (001/0 > P) میلی‌گرم/کیلوگرم مورفین را دریافت کردند، به طور معنی‌داری نسبت به گروه شاهد (سالین) افزایش نشان داد؛ در حالی که شاخص CPP در دزهای 5/0 و 0/1 میلی‌گرم/کیلوگرم معنی‌دار نبود. تزریق دزهای مختلف AP5 همراه با دز مؤثر مورفین، کاهش معنی‌داری را در مراحل اکتساب و بیان CPP درگروه‌های آزمایش نسبت به گروه سالین و مورفین نشان داد، اما همراه با دز غیر مؤثر مورفین، کاهش معنی‌دار فقط در مرحله‌ی بیان CPP گروه آزمایش در مقایسه با گروه سالین و مورفین مشاهده شد (001/0 > P). نتیجه‌گیری: به نظر می‌رسد تزریق AP5 در کورتکس پره‌فرونتال، باعث افت CPP شود و در نتیجه، تمایل به مورفین را کاهش دهد. احتمال می‌رود این اثر به دلیل تضعیف یادگیری و اختلال حافظه‌ی ناشی از ناکارآمدی سیستم پاداش در پاسخ به مورفین باشد.

Background: The release of dopamine (DA) in the posterior ventral tegmental area (pVTA) plays an important role in cue-related learning, reward, and relapse. On the other hand, studies have shown that the use of N-methyl-D-aspartate receptor (NMDAR) antagonist (AP5) inhibits the expression of morphine (5 mg/kg, s. c) conditioned place preference (CPP). In this study, we have tried to show the interaction effect of the DA stimulatory agents through D1-like receptor (D1R) agonist (SKF38393) and D2-like receptor (D2R) antagonist (eticlopride; through disinhibition) with NMDAR antagonist into the pVTA on the expression of morphine CPP. Materials and Methods: The SKF38393 and eticlopride, individually and simultaneously (in ineffective doses), were injected into the pVTA with the AP5 in rats, and animals were then placed in a CPP apparatus. Results: Concomitant administration of D1R agonist (4 μg/rat) with NMDAR antagonist (1 μg/rat) induced the expression of morphine CPP, but the administration of D2R antagonist with NMDAR antagonist was unaffected on the expression of morphine CPP. Furthermore, concomitant administration of ineffective doses of D1R agonist and D2R antagonist with NMDAR antagonist had no effect on the expression of morphine CPP. Conclusions: The results showed using higher doses of D1R agonist with NMDAR antagonist could reverse the blocked expression of morphine CPP by NMDAR antagonists, while, the use of D2R antagonist with NMDAR antagonist could not. Therefore, presynaptic receptors such as D1R probably through releasing other stimulatory neurotransmitters can play a vital role in the expression of morphine CPP and cue-related learning.

Background: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the older population and characterized by progressive memory and cognitive impairment. Cyperus rotundus, a traditional medicinal herb, has analgesic, sedative, and anti-inflammatory effects and also used to increase memory in Islamic traditional medicine. This study was designed to consider the effects of C. rotundus extract on memory impairment and neurogenesis in the Beta-Amyloid rats' model. Materials and Methods: Forty-two male Wistar rats were randomly divided into six groups (n = 7) for the evaluation of baseline training performance in the Morris water maze test. Then, amyloid-beta (Aβ1-42) was injected in animal hippocampal CA1 bilaterally in four groups. The first probe trial was performed 21 days after Aβ injection. Then, 250, 500, and 750 mg/kg of C. rotundus extract were administered to three Aβ-injected groups for 1 month; after that, the second probe trial was performed, and rats were sacrificed after 28 days of the second probe trial. The neurogenesis was detected in the hippocampus, by immunohistochemical staining. Results: This study showed that spatial memory increased in the behavioral test in AD treated group with C. rotundus extract, compared with the AD group (P = 0.02). Immunohistochemical staining revealed that neuronal differentiation has been occurred in the hippocampus in the AD-treated group with C. rotundus extract compared with the AD group (P = 0.01). Conclusions: This study showed that C. rotundus extract, repaired spatial memory impairment in the Aβ rats, through increased neurogenesis in the hippocampus, which could be related to the flavonoid components in the extract.

Background: Degeneration of the nigrostriatal dopaminergic system is the pathologic hallmark of Parkinson's disease (PD), which leads to movement disorders. Compelling evidence implicates that oxidative stress plays an important role in degeneration of dopaminergic neurons in the disease. The aim of this study was to investigate the neuroprotective effect of crocin, a potent antioxidant in saffron, in an experimental model of Parkinson's disease in rat. Methods: 32 adult male Wistar rats were randomly divided into 4 groups of 8 including sham, parkinsonian and parkinsonian treated with crocin at doses of 30 and 60 mg/kg. 6-hydroxydopamine (6-OHDA) (16 µg in 0.2% ascorbate-saline) was infused into the left medial forebrain bundle. Crocin was injected intraperitoneally from 3 days before the surgery until 6 weeks. Rats were tested for rotational behavior by injection of apomorphine hydrochloride (2 mg/kg, intraperitoneally) at the weeks 2, 4 and 6. Malondialdehyde and nitrite levels were measured in the striatum at the end of the week 6. Findings: The apomorphine-induced contralateral body rotations were highly significant in parkinsonian group at the end of the weeks 2, 4 and 6 compared to the sham group (P < 0.001). Treatment of parkinsonian rats with crocin at the doses of 30 and 60 mg/kg did not change the rotations compared to the parkinsonian group. Malondialdehyde and nitrite levels in the striatum were significantly increased in parkinsonian group compared to the sham group (P < 0.050). Treatment of parkinsonian rats with crocin at a dose of 60 mg/kg significantly decreased the nitrite levels in the striatum compared to the parkinsonian rats (P < 0.05). However, treatment with crocin had no effect on malondialdehyde levels in the striatum. Conclusion: According to the present study, it seems that crocin at a dose of 60 mg/kg is effective on preventing the nitrosative stress in an experimental model of Parkinson's disease. However, crocin has no effect on improvement of rotational behavior and oxidative damage.

Background: Recent data have implicated stress as a risk factor in the development of neuropsychological disorders that impairs memory. Stress has different complex effects on memory. In other words, stress can increase or decrease the memory or has no effect on it. This study investigated different timing effects of stress on cognitive and spatial memory. Methods: In this study, 28 male Wistar rats were divided into four groups of 7, control, acute stress, middle stress, and chronic stress. Restraint stress was used to induce stress. In addition, memory function was evaluated via the novel object recognition (NOR) and object location (OLT) tests for estimating cognitive and spatial memory. At the end of the study, serum corticosterone levels were measured via enzyme-linked immunoassay (ELISA). Findings: In middle and chronic stress groups, the object exploration times during the NOR test session were significantly lower than control group (P < 0.001 and P < 0.05, respectively). There were no significant decreases in the time of object exploration during the test session of OLT task in all stressed groups compared to the control group. Corticosterone levels were significantly increased in middle and chronic stress groups compared to the control group (P < 0.01 and P < 0.05, respectively). Conclusion: Data correspond that chronic and especially middle stress impaired cognitive memory. Therefore, middle stress was the most deleterious stress model. On the other hand, acute, middle and chronic stress did not impair spatial memory in the OLT task. Therefore, different duration of stress was one of the most important factors in causing cognitive memory impairment.

Background: The nucleus accumbens (NAc) is a part of the rewarding cortico-mesolimbic dopamine (DA) pathway. This is a heterogeneous structure divided in two sub regions termed core and shell. DA function in the NAc is critical for goal-oriented behaviors, including those motivated by drug and brain stimulation reward. In the conditioned-place preference (CPP) paradigm, a test assessing animal′s ability to associate drug-induced effects with environmental cause to quantify drug reward for example morphine. Methods: In the present study, we investigated the influence of electrical stimulation with different current intensities on (25 and 100 µA) with and without an effective dose of morphine (0.5 and 5 mg/kg) on CPP. Results: Subcutaneous administration of morphine 5 mg/kg produced significant CPP in comparison with saline group. Our findings also showed that electrical stimulation of NAc (100 µA) significantly (P < 0.01) suppressed morphine-induced CPP that reveals impaired learning and memory formation in the process of conditioning. We found that morphine-induced CPP can be successfully suppressed by current intensity (100 µA). It was probably due to decreasing of dopamine contents and its metabolites in the NAc. Current intensity (100 µA) in combination with ineffective dose of morphine (0.5 mg/kg) increased morphine-induced CPP probability via the prove reward system. Conclusions: Since stimulation of dopaminergic neurons increases tendency to dependence to morphine, therefore in the present study, the stimulation of the NAc suppressed morphine-induced CPP that this shows impairment of learning and memory formation.

Background: The release of dopamine (DA) has certain roles in the induction of conditioned place preference (CPP) and motor learning in the ventral tegmental area (VTA). The aim of this study was to investigate the excitatory effects of DA through DA-D1 agonist (SKF38393) and elimination of the inhibitory effects of DA through DA-D2 antagonist (eticlopride) into the VTA and its synergistic effects with an ineffective dose of morphine in the induction of CPP. Materials and Methods: Morphine (2.5 mg/kg; s. c.) did not induce a significant CPP, without any effect on the locomotor activity during the testing phase. SKF38393 (0.125, 0.5, and 1 μg/side) and eticlopride (0.5, 1, and 2 μg/side) individually or simultaneously were microinjected bilaterally into the VTA. Results: The administration of SKF38393 (1 and 2 μg/rat) with ineffective morphine and also without morphine caused CPP on test day, while eticlopride (2 μg/rat) caused CPP with morphine only. Locomotor activity increased in groups receiving D1 agonist and D2 antagonist that presumed to be caused by the reinforcing effect. In addition, the concurrent administration of ineffective doses of D1 agonist and D2 antagonist into the VTA with ineffective morphine caused CPP but not with saline. Conclusions: This study showed that there was a need for morphine to activate the reward circuit through the D2 receptor in the VTA while the administration of the D1 agonist could independently activate the reward circuit. In addition, there was a probable synergistic effect using ineffective doses of D1 and D2 receptors, in the acquisition of morphine-induced CPP.

Background: Drug addiction is one of the social damages that researchers have tried to find suitable strategies for prevention and treatment of it. Meanwhile, short-term physical activity is acceptable parameter for treatment and prevention of addiction. On the other hand, prefrontal cortex, for a long time as mediating, is involved in many of the complex behavioral responses, especially those associated with addiction and drug abuse. In this paper, the effects of short-term physical activity (treadmill running) on withdrawal symptom with or without mPFC area have been evaluated. Methods: This experimental study was done on Wistar rats weighing 250 ± 300 g separated to four groups: control, shame, test 1 and test 2; one of the test groups had surgery and lesion on mPFC area. For studying the effects of short-term physical activity, we used treadmill with adjustable speed of 17 m/minute and a 15-degrees slope; after the injection of three doses of morphine, 10, 20, 40 mg in 9 days and running on the treadmill, in the tenth day, the symptoms of addiction were evaluated. Findings: The morphine injection and running on the treadmill without mPFC region destruction tended to decreasing morphine tendency. There was a significant difference between the rats, with or without mPFC area, received morphine but did not run on the treadmill in morphine tendency (P < 0.05). Conclusion: It seems that short-term physical activity (treadmill running) decreases the tendency of using morphine with mPFC area in comparison with other groups, especially with group operated in their mPFC area.

Background: Prefrontal cortex is one part of the regions contributed to addiction process and located at the frontal lobe of the brain. There is a central part of frontal lobe called medial prefrontal cortex (mPFC) plays an important role in the dopamine system network. The destruction or stimulation of cerebral nuclei such as ventral tegmental area (VTA) which is a part of the reward circuite can change the process of addiction. There is no evidence on clear role of mPFC in addiction; this research tried to determine the effects of destruction or stimulation of mPFC on producing addiction and reducing the signs of withdrawal syndrome. Methods: 60 male Wistar rats weighing 250-300 g were randomly selected and divided into four groups. The animals in tree groups (control, stimulated mPFC and destructed mPFC) received morphine for nine consecutive days as follow: 10 mg/kg for the first, 20 mg/kg for the second, and 40 mg/kg for third three-days. The Sham group received 0.2 cc normal saline instead of morphine during the same period. On the tenth day, the withdrawal syndrome signs were measured. Each rat received 1 cc naloxone and the signs were recorded for one hour and compared through Kruskal-Wallis H test. Findings: The electrical stimulation of mPFC increased behaviors such as jumping, shaking the body and standing significantly (P < 0.05), whereas the destruction of mPFC significantly reduced withdrawal signs, such as standing and jumping compared to the control group (P < 0.05); in one group, the shaking increased significantly (P < 0.05). Conclusion: This research showed that electrical destruction of mPFC could decrease tendency to morphine. The most probable mechanism prevented an increase in withdrawal signs should be a decrease in the reward level induced by dopamine decrease in addiction cycle; the destruction of mPFC decreased dopamine concentration with acceptable effects on addiction and reward. The reverse occurred with the stimulation of that region.

Background : Alzheimer′s disease was known as a progressive neurodegenerative disorder in the elderly and is characterized by dementia and severe neuronal loss in the some regions of brain such as nucleus basalis magnocellularis. It plays an important role in the brain functions such as learning and memory. Loss of cholinergic neurons of nucleus basalis magnocellularis by ibotenic acid can commonly be regarded as a suitable model of Alzheimer′s disease. Previous studies reported that exercise training may slow down the onset and progression of memory deficit in neurodegenerative disorders. This research investigates the effects of treadmill running on acquisition and retention time of passive avoidance deficits induced by ibotenic acid nucleus basalis magnocellularis lesion. Methods : Male Wistar rats were randomly selected and divided into five groups as follows: Control, sham, Alzheimer, exercise before Alzheimer, and exercise groups. Treadmill running had a 21 day period and Alzheimer was induced by 5 μg/μl bilateral injection of ibotenic acid in nucleus basalis magnocellularis. Results : Our results showed that ibotenic acid lesions significantly impaired passive avoidance acquisition ( P < 0.01) and retention ( P < 0.001) performance, while treadmill running exercise significantly ( P < 0.001) improved passive avoidance learning in NBM-lesion rats. Conclusion : Treadmill running has a potential role in the prevention of learning and memory impairments in NBM-lesion rats.

Background: There is only little information about the effects of GABA receptors agonist and antagonist on morphine self-administration. Present study was designed to assess role of GABAB receptors in the regulation of morphine-reinforced self-administration. Methods: This study was performed in four groups of rats: (1) Saline group, which received saline in the self-administration session. (2) Morphine group, which received morphine in saline solution in the self-administration session. (3) Baclofen + Morphine group, which received both baclofen 20 min before self- administration test and morphine in the self-administration session. (4) Phaclofen + Morphine group, which received both phaclofen 20 min before self- administration test and morphine in the self-administration session. The number of lever pressing and self-infusion were recorded. Results: Morphine significantly increased the number of active lever pressing dose dependently in self-administration session in comparative with saline group. Administration of baclofen, 20 min before morphine self-administration produced significant decrease in the initiation of morphine self-administration during all session. Conversely, pre-treatment of phaclofen increased the number of active lever pressing and self-infusion in this test. Conclusion: Our results indicated a short-term treatment by baclofen, reduced morphine-maintenance response in a dose-dependent manner, suggesting that GABAB receptor agonists could be useful for reversing the neuroadaptations related to opiates.

Background: Different stressors induce learning and memory impairment and physical activity influence learning and memory enhancement. In this research, we investigated the effect of synchronized running activity with stress on acquisition and retention time of passive avoidance test. Methods: Male Wistar rats were randomly divided into five groups as follows: Control (Co), Sham (Sh), Exercise (Ex), Stress (St), synchronized exercise with stress (St and Ex) groups. Chronic restraint stress was applied by 6 h/day for 21 days and treadmill running 1 h/day for 21 days. For evaluation of learning and memory, initial and step-through latency were determined at the end of study by using passive avoidance learning test. Results: Our results showed that: (1) Exercise under no stress provides beneficial effects on memory acquisition and retention time compared to Control group; especially retention time had significantly (P < 0.05) increased in exercised group. (2) Chronic stress with and without synchronized exercise significantly (P < 0.01, P < 0.05, respectively) impaired acquisition and retention time. (3) Body weight differences were significantly (P < 0.01, P < 0.001 and P < 0.001) lower than Control group in exercise, stress and synchronized exercise with stress groups, respectively. (4) Adverse effects of restraint stress (psychical stress) were probably greater than physical activity effects on learning, memory and weight loss. Conclusions: The data confirmed that synchronized exercise with stress had not significantly protective role in improvement of passive avoidance acquisition and retention time; hence it did not significantly improve learning and memory deficit in stressed rats; whereas exercise alone could improve memory deficit in rats.

Vascular cell adhesion molecule 1 (VCAM-1) plays an important role in tumour cell adhesion to endothelial cells. Some tumour cells also show aberrant expression of VCAM‐1. Toll-like receptor 4 (TLR4) agonists can increase VCAM-1 expression. Morphine, an opioid receptor agonist, is also a TLR4 agonist. In this study, we aimed to evaluate whether morphine increase VCAM-1 expression in a TLR4 dependent manner. A549 Lung cancer cells were treated with different doses of morphine and TLR4 antagonist for 24 and 48 h. TLR4 gene expression was evaluated by real-time PCR and VCAM-1 protein was measured by the enzyme-linked immunosorbent assay (ELISA). Morphine enhanced mRNA expression of TLR4 and protein level of VCAM-1. TLR4 antagonist returned VCAM-1expression to the normal level. Morphine effects VCAM-1expressions via TLR4 in lung cancer cell line. [ABSTRACT FROM AUTHOR]

Objective: Parkinson's disease (PD) is one of the most common neurodegenerative disorders which is characterized by tremor, rigidity, bradykinesia and postural disturbances. Studies indicate that grape juice and exercise may have beneficial effects on neurodegenerative disorders. Therefore, in the present study, we evaluated the effects of red grape juice (GJ) together with treadmill running on animal model of PD. Materials and Methods: 30 male Wistar rats were divided randomly into Sham, PD, PD treated with GJ (PD-GJ), PD treated with exercise (PD-Ex), and PD treated with GJ associated with exercise (PD-GJ-Ex) groups with six rats in each. In order to obtain the PD model, 6-OHDA was infused into left substantia nigra pars compacta. In order to prove that the lesions are created and to estimate their extent, apomorphine was administered (i.p.) and total number of induced rotations was recorded during 60 minutes. Exercise was applied by treadmill and GJ was added into drinking water for 30 days and rotations test was performed again. Results: Our results indicate that there was a significant difference in number of rotations between PD and Sham groups (p

Background: Alzheimer’s disease is a prevalent disease resulting in learning and memory impairments. Recently, erythropoietin (EPO) has been demonstrated to improve cognitive functions and to have neuroprotective effects. This study aimed to evaluate the effects of erythropoietin on learning and memory in rats after intracerebroventricular (ICV) injection of streptozotocin (STZ), a well defined model for Alzheimer’s disease. Methods: To produce Alzheimer’s disease model in rats, STZ was infused in lateral ventricles of the brain. Two weeks later, the rats were tested by passive avoidance learning test to confirm the induction of learning and memory impairments. They then received EPO (5000 IU/kg) once every two days for two weeks. Finally, behavioral tests were conducted again. Findings: A reduction in time delay for the first entrance of rats to dark chamber as a result of ICV-STZ was found; i.e. there was a significant deference between the sham and the ICV-STZ groups. Although EPO did not have any significant effects on time delay for the first entrance to dark chamber in the sham group, it prevented impairments resulting from ICV-STZ. In fact, the index significantly increased in the STZ-EPO group compared to the STZ group. However, there was not a significant difference between the STZ-EPO and sham groups. Conclusion: The present results suggest use of EPO to probably cause significant improvements of learning and memory defects in Alzheimer’s patients.

Background: Given the positive effects of exercise on the central nervous system, the aim of the present study was to evaluate the effects of treadmill running on learning and memory in rats with induced Alzheimer’s disease and intracerebroventricular injection of streptozotocin (STZ). Methods: Studied rats were divided in 4 groups: the sham-rest, the sham-exercise, the alzheimer-rest and the alzheimer-exercise. To produce rat Alzheimer’s model, STZ was infused in lateral ventricles of the brain. The exercise program was treadmill running with 20 m/min velocity and 0O inclination for 50 min/day, for 4 weeks. For evaluation of learning and memory in rats, passive avoidance learning test was used. Findings: Totally 37 rats in 4 groups were examined. The latency time for the first entrance to dark chamber one day and one week after shock was significantly shorter in Alzheimer–rest group comparing to Alzheimer–exercise and sham–rest groups. Conclusion: These results suggest that exercise probably is effective in prevention and alleviation of cognitive disorders in Alzheimer’s disease.

• مقدمه: بیماری آلزایمر یک اختلال عصبی پیش‌رونده و برگشت ناپذیر می‌باشد. این بیماری علت مهم دمانس پیری است که با تخریب نورونی و زوال شناختی، به ویژه در سنین پیری مشخص می‌شود. با تزریق استرپتوزوتوسین به داخل بطن‌های جانبی مغز رت، مدل مناسبی از آلزایمر نوع اسپورادیک ایجاد می‌شود. ژل رویال ماده لزجی است که توسط زنبورهای عسل کارگر جوان از جنس Apis mellifera تولید می‌گردد. در مطالعات پیشین نشان داده شده است که ژل رویال دارای خواص نوروژنز بوده، موجب القای تمایز نورونی نیز می‌شود. مطالعه‌ی حاضر قصد داشت تا اثر این ماده را بر یادگیری و حافظه در رت پس از تزریق استرپتوزوتوسین به داخل بطن‌های جانبی مغزی (icv) بررسی نماید. • روش‌ها: 48 عدد موش صحرایی نر با وزن 350-300 گرم، به چهار گروه شم، شم- ژل رویال، استرپتوزوتوسین و استرپتوزوتوسین- ژل رویال تقسیم شدند. گروه استرپتوزوتوسین و استرپتوزوتوسین- ژل رویال تحت عمل جراحی، تزریق دوطرفه‌ای از استرپتوزوتوسین (mg/kg 5/1) دریافت نمودند و دو گروه دیگر به همین ترتیب و با همین دوز نرمال سالین دریافت کردند. گروه شم- ژل رویال و استرپتوزوتوسین- ژل رویال به مدت 10 روز غذای حاوی ژل رویال (3 درصد وزنی) دریافت نمودند ولی گروه شم و استرپتوزوتوسین با غذای معمولی فاقد ژل رویال تغذیه شدند. حافظه و یادگیری در این حیوانات، از طریق آزمون یادگیری اجتنابی غیر فعال بررسی شد. • یافته‌ها: نتایج حاصل از آزمون یادگیری اجتنابی غیر فعال نشان داد که شاخص‌های حافظه و یادگیری در گروه استرپتوزوتوسین در مقایسه با گروه شم به طور قابل ملاحظه‌ای تخریب شده است؛ اما تفاوت معنی‌داری بین گروه‌های شم و استرپتوزوتوسین- ژل رویال وجود نداشت. با این که ژل رویال شاخص‌های یادگیری و حافظه را در گروه شم- ژل رویال بهبود بخشید ولی این تغییرات در مقایسه با گروه شم معنی‌دار نبود. • نتیجه‌گیری: این تحقیق نشان داد که تزریق استرپتوزوتوسین به داخل بطن‌های جانبی مغز موجب اثرات مخربی بر یادگیری و حافظه در رت می‌شود. با این وجود مصرف غذای حاوی ژل رویال از اثرات تخریبی استرپتوزوتوسین جلوگیری کرد. نتایج مشاهده شده در این تحقیق پیشنهاد می‌کند که ممکن است ژل رویال دارای اثرات مطلوبی بر جلوگیری و تخفیف بیماری آلزایمر باشد.

Background: Along with increased age, learning and memory being two of the survival necessities decrease and may even deteriorate. This has motivated researches in the field of geriatric medicine to find new medicines effective on learning and memory amplification. Studies have shown that through advanced age, increased oxidative stressors lead to damaged brain processes including cognitive functions. Since types of red grape juice contain antioxidants, this study aimed to examine the effect of this material on passive avoidance memory in 1-year old rats. Methods: Twenty rats, each weighing about 270-330 g, were divided into two test and control groups. Both groups with no limitation had access to water vessel. In the control group, the water container contained pure water and in the test group it contained 80% pure water along with 20% grape juice. To prevent modification of ingredients, vessels contents were regularly refreshed. The passive avoidance memory and learning test was done in the learning device following intending treatments for all groups and in similar conditions. In this test, increased time delay for the first time of entry to the dark chamber and sum of the remaining time in the lighted chamber as well as decreased remaining time in the dark chamber indicate improved passive avoidance memory. To data analysis, the Mann-Whitney test was employed. Findings: Compared with the control group, learning and passive avoidance memory indices had significantly increased in the test group. Conclusion: Our results show that drinking grape juice causes increased learning and passive avoidance indices in rats; probably the reason was existence of antioxidant substances in the grape juice. Key words: Red grape juice, Rat, Learning, Passive avoidance memory.