Publications by authors named "Mohammad-Reza Zarrindast"

398 Publications

The bidirectional effect of prelimbic 5-hydroxytryptamine type-4 (5-HT4) receptors on ACPA-mediated aversive memory impairment in adult male Sprague-Dawley rats.

Iran J Basic Med Sci 2021 Jun;24(6):726-733

Institute for Cognitive Science Studies, Tehran, Iran.

Objectives: This study aimed at investigating the effect of serotonergic 5-HT4 receptor agonist/antagonist on memory consolidation deficit induced by ACPA (a potent, selective CB cannabinoid receptor agonist) in the pre-limbic (PL) cortex.

Materials And Methods: We used the step-through passive avoidance test to evaluate memory consolidation of male Sprague-Dawley (SD) rats. Bilateral post-training microinjections of the drugs were done in a volume of 0.6 μl/rat into the PL area (0.3 μl per side).

Results: The results showed a significant interaction between RS67333 hydrochloride (5-HT4 receptor agonist) or RS23597-190 hydrochloride (5-HT4 receptor antagonist) and ACPA on consolidation of aversive memory. RS67333 hydrochloride (0.5 μg/rat) enhanced consolidation of memory and its co-administration at the ineffective dose of 0.005 μg/rat with ineffective (0.001 μg/rat) or effective (0.1 μg/rat) doses of ACPA improved and prevented impairment of memory caused by ACPA, respectively. In other words, RS67333 had a bidirectional effect on ACPA-caused amnesia. While RS23597-190 hydrochloride had no effect on memory at the doses used (0.005, 0.01, 0.1, or 0.5 μg/rat); but its concomitant use with an effective dose of ACPA (0.1 μg/rat) potentiated amnesia. None of the drugs had an effect on locomotor activity.

Conclusion: This study revealed that activation or deactivation of the 5-HT4 receptors in the PL may mediate the IA memory impairment induced by ACPA indicating a modulatory role for the 5-HT4 serotonergic receptors.
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http://dx.doi.org/10.22038/ijbms.2021.49501.11317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487599PMC
June 2021

The effect of URB597, exercise or their combination on the performance of 6-OHDA mouse model of Parkinson disease in the elevated plus maze, tail suspension test and step-down task.

Metab Brain Dis 2021 Oct 2. Epub 2021 Oct 2.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Parkinson disease (PD) is a progressive neurodegenerative disorder that is often accompanied by motor and psychiatric symptoms. Various approaches have been proposed for the treatment of PD. Here, we investigated the effect of a low dose of fatty acid amide hydrolase inhibitor URB597 (as an enhancer of endocannabinoid anandamide levels), exercise or their combination on some behavior alterations in PD mice lesioned by 6-hydroxydopamine (6-OHDA). The impact of swimming exercise (5×/week for 4 weeks) and URB597 (0.1 mg/kg, 2×/week for 4 weeks) on the anxiety-related behavior (elevated plus maze; EPM), depression-related behavior (tail suspension test; TST), and passive avoidance memory (step-down task) was examined in the sham and male NMRI mouse of PD model. The results show that URB597 prevented memory deficits and elicited antidepressant- and anxiolytic-like effects but did not affect hypolocomotion in the PD mice. However, URB597 did not have a significant effect on the performance of the sham mice in the performed tests. Moreover, swimming training abolished depressive- and anxiogenic-like behaviors and increased locomotion without affecting memory deficits in the PD mice. Meanwhile, swimming decreased immobility time and increased locomotion in the sham mice. Furthermore, URB597 in association with swimming training prevented all deficits induced in the PD mice, while this combination impaired memory and produced the positive effects on depression- and anxiety-related behaviors and locomotion of the sham mice. It is concluded that although URB597 or exercise alone had positive effects on most behavioral tests, their combination improved all parameters in the PD mice.
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http://dx.doi.org/10.1007/s11011-021-00851-zDOI Listing
October 2021

Synergistic effect between imipramine and citicoline upon induction of analgesic and antidepressant effects in mice.

Neurosci Lett 2021 08 30;760:136095. Epub 2021 Jun 30.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Imipramine is a tricyclic antidepressant (TCA) drug that is sometimes used to treat neuropathic pain. Citicoline is a dietary supplement that has been used as a neuroprotective agent for neurological disorders. Probable interaction between imipramine and citicoline on pain and depression behaviors was examined in mice using a tail-flick test, open field test (OFT), forced swimming test (FST), and tail suspension test (TST). The results indicated that the intraperitoneal (i.p.) administration of citicoline (50 mg/kg) induced analgesic and antidepressant-like behaviors in mice. Similarly, i.p. injection of imipramine (5 mg/kg) induced dose-dependent anti-nociceptive and anti-depressive effects. Co-administration of different doses of imipramine (1.25, 2.5, and 5 mg/kg) along with an ineffective dose of citicoline (6.25 mg/kg) increased tail-flick latency and decreased immobility time in the FST, suggesting an analgesic and antidepressant-like behaviors. Interestingly, there is a synergistic effect between imipramine and citicoline upon the induction of analgesic and antidepressant effects. All doses of the drugs had no significant effect on the locomotor activity. Based on these results, it can be concluded that the administration of citicoline (as an adjuvant drug) in combination with imipramine increased the efficacy of TCA drugs for modulation of pain and depression behaviors.
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http://dx.doi.org/10.1016/j.neulet.2021.136095DOI Listing
August 2021

Cannabinoids and sleep-wake cycle: The potential role of serotonin.

Behav Brain Res 2021 08 30;412:113440. Epub 2021 Jun 30.

Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Cannabis sativa (Marijuana) has a long history as a medicinal plant and Δ9-tetrahydrocannabinol (Δ9-THC) is the most active component in this plant. Cannabinoids are interesting compounds with various modulatory effects on physiological processes and cognitive functions. The use of cannabinoids is a double-edged sword, because they induce both adverse and therapeutic properties. One of the most important roles of cannabinoids is modulating sleep-wake cycle. Sleep, its cycle, and its mechanism are highly unknown. Also, the effects of cannabinoids on sleep-wake cycle are so inconsistent. Thus, understanding the role of cannabinoids in modulating sleep-wake cycle is a critical scientific goal. Cannabinoids interact with many neurotransmitter systems. In this review article, we chose serotonin due to its important role in regulating sleep-wake cycle. We found that the interaction between cannabinoids and serotonergic signaling especially in the dorsal raphe is extensive, unknown, and controversial.
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http://dx.doi.org/10.1016/j.bbr.2021.113440DOI Listing
August 2021

Anodal tDCS applied to the left frontal cortex abrogates scopolamine‑induced fear memory deficit via the dopaminergic system.

Acta Neurobiol Exp (Wars) 2021 ;81(2):171-180

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Evidence suggests that transcranial direct current stimulation (tDCS) modulates conditioned fear memories and has effects on cognitive flexibility via the dopaminergic system. This study examines whether modulation of scopolamine‑induced fear memory deficit by anodal tDCS could be mediated by the dopaminergic system. The male NMRI mice received scopolamine, 30 min before fear conditioning, and showed impaired contextual memory retention. Mice subjected to left frontal anodal stimulation for 20 or 30 min, before fear conditioning, impaired fear memory retrieval. Anodal application for 20 min significantly decreased scopolamine response on fear retention, while the one applied for 30 min did not alter. Moreover, anodal stimulation for 30 min abolished scopolamine‑induced fear memory deficit. Dopaminergic antagonists SCH23390 and sulpiride, alone or in combination, prevented the abolishment effect of anodal stimulation on scopolamine‑induced fear memory deficit, whereas they did not alter the impairing effect of scopolamine at the dose of 2 mg/kg. Our data suggest that anodal stimulation for 30 min abrogates the impairing effect of scopolamine on fear memory retention. This influence could be prevented by dopaminergic antagonists, indicating the involvement of the dopaminergic system in the effect of anodal stimulation on scopolamine‑induced fear memory deficit.
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January 2021

Cholestasis and behavioral disorders.

Gastroenterol Hepatol Bed Bench 2021 ;14(2):95-107

Department of Neuroscience, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran.

Acute and chronic failure in liver function may give rise to cognitive and non-cognitive impairments in the brain, namely hepatic encephalopathy (HE). Liver diseases may cause cholestasis, which is defined as the impaired secretion of bile. It is characterized by the accumulation of substances in plasma that are normally excreted in bile such as bile acids. Cholestasis can lead to hepatic encephalopathy. Several investigations have indicated that HE induces several symptoms, such as the impairment of learning and memory, anxiolytic-like behaviors, alterations in sleep pattern, and tremors. It has been reported that after HE, all classical neurotransmitter systems such as opioidergic, dopaminergic, cholinergic, GABAergic, adrenergic, serotonergic, and glutamatergic systems can be altered. This review focuses on cholestasis, hepatic encephalopathy, and behavioral disorders.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101523PMC
January 2021

Effects of Morphine and Maternal Care on Behaviors and Protein Expression of Male Offspring.

Neuroscience 2021 07 26;466:58-76. Epub 2021 Apr 26.

Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Amir-Almomenin Hospital, Islamic Azad University, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

Genes and environment interact during development to alter gene expression and behavior. Parental morphine exposure before conception has devastating effects on the offspring. In the present study, we evaluated the role of maternal care in the intergenerational effect of maternal morphine exposure. Female rats received morphine or saline for ten days and were drugfree for another ten days. Thereafter, they were allowed to mate with drug-naïve male rats. When pups were born, they were cross-fostered to assess the contribution of maternal care versus morphine effects on the offspring. Adult male offspring were examined for anxiety-like behavior, spatial memory, and obsessive-compulsive-like behavior. To determine the mechanisms underlying the observed behavioral changes, protein levels of acetylated histone H3, BDNF, Trk-B, NMDA subunits, p-CREB, and 5-HTR were measured in the brain. Our results indicate that maternal caregiving is impaired in morphine-abstinent mothers. Interestingly, maternal care behaviors were also affected in drug-naïve mothers that raised offspring of morphine-exposed mothers. In addition, the offspring of morphine abstinent and non-drug dependent mothers, when raised by morphine abstinent mothers, exhibited more anxiety, obsessive-compulsive behaviors and impaired spatial memory. These altered behaviors were associated with alterations in the levels of the above-mentioned proteins. These data illustrate the intergenerational effects of maternal morphine exposure on offspring behaviors. Moreover, exposure to morphine before gestation not only affects maternal care and offspring behavior, but also has negative consequences on behaviors and protein expression in adoptive mothers of affected offspring.
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http://dx.doi.org/10.1016/j.neuroscience.2021.04.011DOI Listing
July 2021

Punicalagin effect on total sleep deprivation memory deficit in male Wistar rats.

J Integr Neurosci 2021 Mar;20(1):87-93

Department of Anatomical Sciences & Cognitive Neuroscience, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, 19395-1495 Tehran, Iran.

Sleep deprivation has deteriorating effects on cognitive functions and activation of brain inflammation mechanisms has been reported by some studies following total sleep deprivation. Some studies have reported the health benefits of punicalagin, a main abstract from L., including those for the treatment of Alzheimer's disease. The antioxidant characteristic of punicalagin and the fact that sleep deprivation accelerates mediators of inflammation led us to further explore the possible neuroprotective role of punicalagin in total sleep deprivation memory impairment in a rat model. In this study, male Wistar rats were implanted with a canula in the lateral ventricle to receive intracerebroventricular injections (drug or vehicle). The animals were trained for the passive avoidance test and then received intracerebroventricular injections of different doses of punicalagin (0.001, 0.01, or 0.1 µg/rat). Then, they were placed in the sleep deprivation apparatus for 24 hours and tested afterwards for memory retrieval and locomotion. Our results indicated that 24 hours of total sleep deprivation impaired memory processes. PG microinjection before TSD did not prevent the deteriorating effect of total sleep deprivation on memory, and only showed a tendency of restoring the memory impairment. Comparison of the locomotor activity between the animals in different groups showed a significant increase in the total sleep deprivation sham groups that received two of the highest doses of punicalagin. Considering the reported beneficial actions of PG by other studies, further investigation is needed into the possible effects of PG in memory alterations.
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http://dx.doi.org/10.31083/j.jin.2021.01.378DOI Listing
March 2021

Association of microbiota-derived propionic acid and Alzheimer's disease; bioinformatics analysis.

J Diabetes Metab Disord 2020 Dec 23;19(2):783-804. Epub 2020 Jun 23.

Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran.

Purpose: Microbiota-derived metabolites could alter the brain tissue toward the neurodegeneration disease. This study aims to select the genes associated with Propionic acid (PPA) and compromise Alzheimer's disease (AD) to find the possible roles of PPA in AD pathogenesis.

Methods: Microbiota-derived metabolites could alter the brain tissue toward the neurodegeneration disease. This study aims to select the genes associated with Propionic acid (PPA) and compromise Alzheimer's disease (AD) to find the possible roles of PPA in AD pathogenesis.

Results: Amongst all genes associated with PPA and AD, 284 genes to be shared by searching databases and were subjected to further analysis. AD-PPA genes mainly involved in cancer, bacterial and virus infection, and neurological and non-neurological diseases. Gene Ontology and pathway analysis covered the most AD hallmark, such as amyloid formation, apoptosis, proliferation, inflammation, and immune system. Network analysis revealed hub and bottleneck genes. MCODE analysis also indicated the seed genes represented in the significant subnetworks. and were the hub, bottleneck, and seed genes.

Conclusions: PPA interacted genes implicated in AD act through pathways initiate neuronal cell death. In sum up, AD-PPA shared genes exhibited evidence that supports the idea PPA secreted from bacteria could alter brain physiology toward the emerging AD signs. This idea needs to confirm by more future investigation in animal models.
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http://dx.doi.org/10.1007/s40200-020-00564-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843825PMC
December 2020

Comparison and interaction of morphine and CB1 agonist conditioned place preference in the rat model of early life stress.

Int J Dev Neurosci 2021 May 18;81(3):238-248. Epub 2021 Feb 18.

Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran.

Early life stress (ELS) disrupts brain development and subsequently affects physical and psychological health. ELS has been associated with an increased risk of relapse and inadequate treatment response in addicted patients. The current study was designed to find the effect of ELS on the rewarding effect of morphine and cannabinoid and their interaction. Pregnant female Wistar rats were used in this study. On postnatal day 2 (PND2), pups were separated from their mothers for 3 hr daily. This procedure was repeated every day at the same time until PND 14. The control group was kept in the standard nesting way with their mothers. The adult male offspring of maternal separated (MS) and standard nested (SN) rats were used. Using conditioned place preference task (CPP), the rewarding effect of morphine (0.75, 1.25, 2.5, and 5 mg/kg) was evaluated in both MS and SN groups. Besides, the rewarding effect of cannabinoids was investigated using the administration of CB1 receptor agonist (ACPA, 0.25, 0.5, 1 µg/rat) and inverse agonist (AM-251, 30, 60, and 90 ng/rat) in the nucleus accumbens (NAc). To evaluate the interaction between NAc cannabinoidergic system and morphine, the noneffective dose of ACPA and AM-251 were administered with a noneffective dose of morphine (0.75 mg/kg) on both MS and SN animals. Obtained results indicated that MS groups had a leftward shift in the rewarding effect of morphine and conditioned with low doses of morphine. However, they had a rightward shift in the rewarding effect of cannabinoids. In addition, coadministration of noneffective doses of morphine and ACPA potentiate conditioning in both MS and SN groups. Previous evidence shows that ELS induced changes in the brain, especially in the reward circuits. Here, we demonstrated that MS animals are more sensitive to the rewarding effect of morphine compared with SN animals. In addition, ELS disrupts the cannabinoid system and affect the rewarding effect of cannabinoids.
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http://dx.doi.org/10.1002/jdn.10094DOI Listing
May 2021

The effect of alpha-2 adrenergic receptors on memory retention deficit induced by rapid eye movement sleep deprivation.

Iran J Basic Med Sci 2020 Dec;23(12):1571-1575

Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran.

Objectives: Evidence shows that sleep deprivation (SD) disrupts the formation of hippocampus-related memories. Moreover, α2 adrenergic receptors that are wildly expressed in the CA1 hippocampal region have a significant role in modulating both sleep and memory formation. In the present research, we wanted to investigate the effect of stimulation and blockage of CA1 α2 adrenergic receptors by clonidine (an agonist of α2 adrenergic receptor) and yohimbine (an antagonist of α2 adrenergic receptor), respectively, on memory retention impairment induced by REM SD (RSD) in rats.

Materials And Methods: Multiple platform apparatus were used to induce RSD, and the passive avoidance task was used to assess memory consolidation. Clonidine and yohimbine were injected intra-CA1.

Results: The results showed that RSD (for 24 and 36, but not 12 hr) decreased memory retention, with no effect on locomotion. Post-training intra-CA1 infusion of a subthreshold dose of yohimbine (0.001 μg/rat) did not alter, while clonidine (0.1 μg/rat) restored memory retention impairment induced by RSD (24 and 36 hr). Also, none of the interventions did not influence locomotor activity.

Conclusion: Our data strongly showed that CA1 α2 adrenergic receptors have a critical role in RSD-induced memory retention impairment.
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http://dx.doi.org/10.22038/ijbms.2020.44891.10468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811809PMC
December 2020

Adding extended-release methylphenidate to psychological intervention for treatment of methamphetamine dependence: A double-blind randomized controlled trial.

Med J Islam Repub Iran 2020 14;34:137. Epub 2020 Oct 14.

Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine (SATiM), Tehran University of Medical Sciences, Tehran, Iran.

Iran has been faced with an emerging epidemic of methamphetamine (MA) use during recent years. No effective pharmacotherapy has been identified for MA treatment; and psychological interventions are the only available effective treatment. The aim of this study is to investigate the efficacy and safety of extended-release methylphenidate (ER-MTP) for the treatment of methamphetamine dependence. Sixty-two people with methamphetamine dependence, according to DSM-IV-TR, were randomly assigned to either fixed-dose extended-release methylphenidate (ER-MTP) (60 mg per day) or placebo for 12 weeks. All participants received twice-weekly cognitive behavioral treatment for stimulant dependence. Recent drug use and craving level were measured using weekly rapid urine test and craving visual analogue scale, respectively. The severity of addiction was measured using the Addiction Severity Index at baseline and study completion. Assessment of MA withdrawal was conducted using Amphetamine Withdrawal Questionnaire and Amphetamine Selective Severity Assessment at baseline, day 3, week 1, week 4 and week 12. Depression and high-risk behaviors assessed with the Beck Depression Inventory and the high-risk behavior questionnaire at baseline, weeks 4 and 12 of the study. SPSS software version 22 was used for data analysis and p<0.05 was considered significant. Percent of weekly MA negative urine tests was not significantly different between groups during the course of the study (p=0.766). Two groups showed similar retention rates. Changes in MA craving, withdrawal, addiction severity, depression and high-risk behaviors were not significantly different between groups. No serious adverse event was observed. Our finding did not show the superiority of fixed-schedule ER-MTP over placebo when added to an intensive biweekly outpatient psychosocial treatment. Further studies using individually tailored flexible-dose regimes might provide new insights regarding the safety and efficacy of psychostimulant maintenance treatment for MA dependence.
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http://dx.doi.org/10.34171/mjiri.34.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787037PMC
October 2020

Harmaline potentiates morphine-induced antinociception via affecting the ventral hippocampal GABA-A receptors in mice.

Eur J Pharmacol 2021 Feb 17;893:173806. Epub 2020 Dec 17.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

Morphine is one of the most effective medications for treatment of pain, but its side effects limit its use. Therefore, identification of new strategies that can enhance morphine-induced antinociception and/or reduce its side effects will help to develop therapeutic approaches for pain relief. Considering antinociceptive efficacy of harmaline and also highlighted the important role of GABA-A receptors in the pain perception, this research aimed to determine whether the ventral hippocampal (vHip) GABA-A receptors are involved in the possible harmaline-induced enhancement of morphine antinociception. To achieve this, vHip regions of adult male mice were bilaterally cannulated and pain sensitivity was measured in a tail-flick apparatus. Intraperitoneally administration of morphine (0, 2, 4 and 6 mg/kg) or harmaline (0, 1.25, 5 and 10 mg/kg) increased the percentage of maximal possible effect (%MPE) and induced antinociception. Interestingly, co-administration of sub-effective doses of harmaline (5 mg/kg) and morphine (2 mg/kg) induced antinociception. Intra-vHip microinjection of muscimol (0, 200 and 300 ng/mice), a GABA-A receptor agonist, enhanced the anti-nociceptive effects of harmaline (2.5 mg/kg)+morphine (2 mg/kg) combination. Microinjection of the same doses of muscimol into the vHip by itself did not alter tail-flick latency. Intra-vHip microinjection of bicuculline (100 ng/mouse), a GABA-A receptor antagonist, did not cause a significant change in MPE%. Bicuculline (60 and 100 ng/mouse, intra-vHip) was administered with the harmaline (5 mg/kg)+morphine (2 mg/kg), and inhibited the potentiating effect of harmaline on morphine response. These findings favor the notion that GABAergic mechanisms in the vHip facilitate harmaline-induced potentiation of morphine response in the tail-flick test in part through GABA-A receptors. These findings shall provide insights and strategies into the development of pain suppressing drugs.
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http://dx.doi.org/10.1016/j.ejphar.2020.173806DOI Listing
February 2021

Synergistic antidepressant- and anxiolytic-like effects of harmaline along with cinanserin in acute restraint stress-treated mice.

Psychopharmacology (Berl) 2021 Jan 14;238(1):259-269. Epub 2020 Nov 14.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O.Box 13145-784, Tehran, Iran.

Rationale: Acute restraint stress (ARS) is an experimental paradigm used for the induction of rodent models of stress-produced neuropsychiatric disorders, such as depression and anxiety. β-carbolines and serotonin (5-HT) systems are involved in the modulation of depression and anxiety behaviors.

Objective: This study was designed to examine the effects of intracerebroventricular (i.c.v.) injection of cinanserin (5-HT2 receptor antagonist) on harmaline-induced responses on depression- and anxiety-like behaviors in the ARS mice.

Methods: For i.c.v. infusion, guide cannula was surgically implanted in the left lateral ventricle of mice. The ARS model was conducted via movement restraint at a period of 4 h. Depression- and anxiety-related behaviors were evaluated by forced swim test (FST) and elevated plus maze (EPM), respectively.

Results: The results displayed that the ARS mice showed depressive- and anxiety-like responses. I.p. administration of different doses of harmaline (0.31, 0.625 and 1.25 mg/kg) or i.c.v. microinjection of cinanserin (1, 2.5, and 5 μg/mouse) blocked depression- and anxiogenic-like behaviors in the ARS mice. Furthermore, co-administration of harmaline (1.25 mg/kg; i.p.) and cinanserin (5 μg/mouse; i.c.v.) prevented the depression- and anxiogenic-like effects in the ARS mice. We found a synergistic antidepressant- and anxiolytic-like effects of harmaline and cinanserin in the ARS mice.

Conclusions: These results propose an interaction between harmaline and cinanserin to prevent depressive- and anxiogenic-like behaviors in the ARS mice.
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http://dx.doi.org/10.1007/s00213-020-05679-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666640PMC
January 2021

How do stupendous cannabinoids modulate memory processing via affecting neurotransmitter systems?

Neurosci Biobehav Rev 2021 01 7;120:173-221. Epub 2020 Nov 7.

Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

In the present study, we wanted to review the role of cannabinoids in learning and memory in animal models, with respect to their interaction effects with six principal neurotransmitters involved in learning and memory including dopamine, glutamate, GABA (γ-aminobutyric acid), serotonin, acetylcholine, and noradrenaline. Cannabinoids induce a wide-range of unpredictable effects on cognitive functions, while their mechanisms are not fully understood. Cannabinoids in different brain regions and in interaction with different neurotransmitters, show diverse responses. Previous findings have shown that cannabinoids agonists and antagonists induce various unpredictable effects such as similar effect, paradoxical effect, or dualistic effect. It should not be forgotten that brain neurotransmitter systems can also play unpredictable roles in mediating cognitive functions. Thus, we aimed to review and discuss the effect of cannabinoids in interaction with neurotransmitters on learning and memory. In addition, we mentioned to the type of interactions between cannabinoids and neurotransmitter systems. We suggested that investigating the type of interactions is a critical neuropharmacological issue that should be considered in future studies.
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http://dx.doi.org/10.1016/j.neubiorev.2020.10.018DOI Listing
January 2021

URB597 abrogates anxiogenic and depressive behaviors in the methamphetamine-withdrawal mice: Role of the cannabinoid receptor type 1, cannabinoid receptor type 2, and transient receptor potential vanilloid 1 channels.

J Psychopharmacol 2021 Jul 6;35(7):875-884. Epub 2020 Nov 6.

Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran.

Background: Methamphetamine is an addictive stimulant that possesses toxicity in the brain when taken repeatedly or at higher doses. Methamphetamine neurotoxicity is associated with numerous forms of mental impairment, including depression and anxiety. Evidence has also demonstrated that the endocannabinoid system is involved in the regulation of anxiety and depression.

Aims: This study was designed to determine the involvement of the endocannabinoid system in anxiety- and depression-related behaviors in methamphetamine-withdrawal male NMRI mice.

Methods: The elevated plus maze and forced swim test were used to assess the level of anxiety and depression.

Results: We found that methamphetamine (30 mg/kg, intraperitoneal) evoked depressive- and anxiogenic-like effects at 3 days post-administration. Injection of URB597 (5-10 ng/mouse, intracerebroventricular), 10 min before the test, prevented the emotional deficits induced by methamphetamine withdrawal. Moreover, the cannabinoid receptor type 1 antagonist AM251 (1 μg/mouse) or cannabinoid receptor type 2 antagonist AM630 (5 and 10 μg/mouse) suppressed the antidepressant activity in the methamphetamine-withdrawal mice treated with URB597. The transient receptor potential vanilloid 1 antagonist capsazepine (25 μg/mouse) prevented while capsazepine (100 μg/mouse) potentiated the antidepressant efficacy in the methamphetamine-withdrawal mice treated with URB597. The higher dose of AM630 and two higher doses of capsazepine had antidepressant efficacy, by themselves. Furthermore, capsazepine (50 μg/mouse) increased locomotion in the methamphetamine-withdrawal mice treated with URB597.

Conclusions: The results suggest that URB597 has a potential for preventing methamphetamine withdrawal-evoked anxiety and depression. Cannabinoid type 1 receptors, cannabinoid type 2 receptors and transient receptor potential vanilloid 1 differently affect depression-related behaviors in methamphetamine-withdrawal mice treated with URB597.
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http://dx.doi.org/10.1177/0269881120965934DOI Listing
July 2021

Verapamil Inhibits Mitochondria-Induced Reactive Oxygen Species and Dependent Apoptosis Pathways in Cerebral Transient Global Ischemia/Reperfusion.

Oxid Med Cell Longev 2020 17;2020:5872645. Epub 2020 Oct 17.

Anatomical Sciences Department, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

The prefrontal cortex is the largest lobe of the brain and is consequently involved in stroke. There is no comprehensive practical pharmacological strategy for ameliorating prefrontal cortex injury induced by cerebral ischemia. Therefore, we studied the neuroprotective properties of verapamil (Ver) on mitochondrial dysfunction and morphological features of apoptosis in transient global ischemia/reperfusion (I/R). Ninety-six Wistar rats were allocated into four groups: control, I/R, I/R+Ver (10 mg/kg twice 1 hour prior to ischemia and 1 hour after reperfusion phase), and I/R+NaCl (vehicle). Animals were sacrificed, and mitochondrial dysfunction parameters (i.e., mitochondrial swelling, mitochondrial membrane potential, ATP concentration, ROS production, and cytochrome c release), antioxidant defense (i.e., superoxide dismutase, malondialdehyde, glutathione peroxidase, catalase, and caspase-3 activation), and morphological features of apoptosis were determined. The results showed that mitochondrial damage, impairment of antioxidant defense system, and apoptosis were significantly more prevalent in the I/R group in comparison with the other groups. Ver decreased mitochondrial damage by reducing oxidative stress, augmented the activity of antioxidant enzymes in the brain, and decreased apoptosis in the I/R neurons. The current study confirmed the role of oxidative stress and mitochondrial dysfunction in I/R progression and indicated the possible antioxidative mechanism of the neuroprotective activities of Ver.
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http://dx.doi.org/10.1155/2020/5872645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591985PMC
May 2021

State-dependent memory and its modulation by different brain areas and neurotransmitters.

EXCLI J 2020 3;19:1081-1099. Epub 2020 Aug 3.

Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

The state-dependent memory defines as a state that the retrieval of recently obtained information may be potential if the subject exists in a similar physiological situation as for the period of the encoding stage. Studies revealed that exogenous and endogenous compounds could induce state-dependent memory. The state-dependent memory made it probable to differentiate the effects of drugs per se on learning from the effects due to alterations in drug state during the task. Studies proposed the role of regions beyond the limbic formation and illustrated that state-dependent memory produced by various neurotransmitter systems and pharmacological compounds. Our review of the literature revealed that: (a) re-administration of drugs on the same state induce state-dependent memory; (b) many neurotransmitters induce endogenous state-dependent memory; (c) there are cross state-dependent learning and memory between some drugs; (d) some sites of the brain including the CA1 areas of the hippocampus, central nucleus of the amygdala (CeA), septum, ventral tegmental area (VTA), and nucleus accumbens (NAC) are involved in state-dependent memory. See also Figure 1(Fig. 1).
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http://dx.doi.org/10.17179/excli2020-2612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527511PMC
August 2020

The effect of alpha lipoic acid on passive avoidance and social interaction memory, pain perception, and locomotor activity in REM sleep-deprived rats.

Pharmacol Rep 2021 Feb 30;73(1):102-110. Epub 2020 Sep 30.

Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran.

Background: Evidence shows the vital role of sleep in the modulation of cognitive functions. Sleep deprivation (SD) can disrupt learning and memory processes. SD also affects pain perception and locomotor activity. Furthermore, alpha lipoic acid (ALA) may induce antioxidant and neuroprotective effects. ALA affects memory processes, pain subthreshold, and locomotor activity. The goal of the present study was to investigate the effect of REM (rapid-eye movement) SD and ALA on social and passive avoidance memory, locomotor activity, and pain perception.

Methods: Multiple-platform apparatus was used to induce REM SD for 24 h. Three-chamber paradigm test, the shuttle box, locomotion apparatus, and hot plate were used to assess social interaction memory, passive avoidance memory, locomotor activity, and pain perception, respectively. ALA was injected intraperitoneally at the doses of 35 and 70 mg/kg.

Results: 24 h REM SD impaired both types of memory. In addition, ALA (35 mg/kg) reversed REM SD-induced memory impairments. However, ALA (70 mg/kg) impaired social memory with no effect on REM SD-induced memory impairments. ALA (70 mg/kg) also decreased pain subthreshold in REM SD rats.

Conclusion: REM SD impairs social interaction and passive avoidance memory. Furthermore, ALA may exhibit a dose-dependent manner in some cognitive tasks. ALA can induce a therapeutic effect at one dose, and an impairment effect at another dose (lower or higher), while the cognitive task and the conditions are equal.
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http://dx.doi.org/10.1007/s43440-020-00161-8DOI Listing
February 2021

The effect of 5-HT serotonin receptors in the CA3 hippocampal region on D-AP5-induced anxiolytic-like effects: Isobolographic analyses.

Behav Brain Res 2021 01 28;397:112933. Epub 2020 Sep 28.

Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Neuroendocrinology, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Increasing evidence shows the close relationship between hippocampal glutamatergic and serotonergic systems through the modulation of behavioral responses. This study aimed to investigate the possible involvement of 5-HT receptors in the CA3 hippocampal region in anxiolytic-like effects induced by D-AP5 (a competitive antagonist of the glutamate NMDA [N-Methyl-D-aspartate] receptor). Male Wistar rats were placed in the elevated plus maze (EPM) apparatus that is used to assess anxiety-related behaviors, and the percentages of open arm time (%OAT) and open arm entries (%OAE) which are associated with anxiety-related behaviors were measured. The close arm entries (CAE) which is correlated with locomotor activity was also evaluated. The results showed that, intra-CA3 injection of D-AP5 (0.4 μg/rat), RS67333 (1.2 μg/rat; a 5-HT receptor agonist), and RS23597-190 (1.2 μg/rat; a 5-HT receptor antagonist) increased %OAT and %OAE, indicating the anxiolytic-like effect of these drugs. Also, only RS23597-190 (1.2 μg/rat) decreased CAE. Intra-CA3 injection of sub-threshold dose of RS67333 (0.012 μg/rat) or RS23597-190 (0.012 μg/rat), 5 min before the injection of D-AP5 (0.2 μg/rat) increased %OAT, indicating potentiating the anxiolytic-like effect of D-AP5. The isobolographic analyses also showed the additive or synergistic anxiolytic-like effect of intra-CA3 co-administration of D-AP5 with RS67333 or RS23597-190, respectively. In conclusion, CA3 5-HT receptors are involved in D-AP5-induced anxiolytic-like behaviors in rats.
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http://dx.doi.org/10.1016/j.bbr.2020.112933DOI Listing
January 2021

The role of cannabinoid 1 receptor in the nucleus accumbens on tramadol induced conditioning and reinstatement.

Life Sci 2020 Nov 13;260:118430. Epub 2020 Sep 13.

Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran.. Electronic address:

Aims: Previous investigations demonstrated that tramadol, as a painkiller, similar to morphine induces tolerance and dependence. Furthermore, the cannabinoid receptor 1 (CB1R) located in the nucleus accumbens (NAc) plays a critical role in morphine-induced conditioning. Therefore, the main objective of this study was to evaluate the role of NAc CB1R in tramadol induced conditioning and reinstatement.

Main Methods: In the present experiment, the effect of NAc CB1 receptors on tramadol induced conditioning was tested by microinjecting of arachidonylcyclopropylamide (ACPA, CB1R agonist) and AM 251 (CB1R inverse agonist) in the NAc during tramadol-induced conditioning in the adult male Wistar rats. In addition, the role of NAc CB1R in the reinstatement was also evaluated by injecting ACPA and AM 251 after a 10-days extinction period.

Key Findings: The obtained data revealed that the administration of tramadol (1,2, and 4 mg/kg, ip) dose-dependently produced conditioned place preference (CPP). Moreover, intra-NAc administration of ACPA (0.25, 0.5, and 1 μg/rat) dose-dependently induced conditioning, while the administration of AM-251 (30, 60, and 120 ng/rat) induced a significant aversion. In addition, the administration of a non-effective dose of AM251 during tramadol conditioning inhibited conditioning induced by tramadol. On the other hand, the administration of ACPA after extinction induced a significant reinstatement. Notably, the locomotor activity did not change among groups.

Significance: Previous studies have shown that tramadol-induced CPP occurs through μ-opioid receptors. The data obtained in the current study indicated that CB1R located in the NAc is involved in mediating conditioning induced by tramadol. Besides, CB1R also plays a vital role in the reinstatement of tramadol-conditioned animals. It might be due to the effect of opioids on enhancing the level of CB1R.
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http://dx.doi.org/10.1016/j.lfs.2020.118430DOI Listing
November 2020

The interaction effect of sleep deprivation and cannabinoid type 1 receptor in the CA1 hippocampal region on passive avoidance memory, depressive-like behavior and locomotor activity in rats.

Behav Brain Res 2021 01 10;396:112901. Epub 2020 Sep 10.

Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Neuroendocrinology, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Increasing evidence shows the interaction effect of cannabinoids and sleep on cognitive functions. In the present study, we aimed to investigate the interaction effect of cannabinoids type 1 receptor (CB1r) in the CA1 hippocampal region and sleep deprivation (SD) on passive avoidance memory and depressive-like behavior in male Wistar rats. We used water box apparatus to induce total SD (TSD) for 24 h. The shuttle-box was applied to assess passive avoidance memory and locomotion apparatus was applied to assess locomotor activity. Forced swim test (FST) was used to evaluate rat's behavior. ACPA (CB1r agonist) at the doses of 0.01, 0.001 and 0.0001 μg/rat, and AM251 (CB1r antagonist) at the doses of 100, 10 and 1 ng/rat were injected intra-CA1, five minutes after training via stereotaxic surgery. Results showed SD impaired memory. ACPA at the doses of 0.01 and 0.001 μg/rat impaired memory and at all doses did not alter the effect of SD on memory. AM251 by itself did not alter memory, while at lowest dose (1 ng/rat) restored SD-induced memory deficit. Both drugs induced depressive-like behavior in a dose-dependent manner. Furthermore, both drugs decreased swimming at some doses (ACPA at 0.0001 μg/rat, AM251 at 0.001 and 0.01 ng/rat). Also, ACPA at the highest dose increased climbing of SD rats. In conclusion, we suggest CB1r may interact with the effect of SD on memory. Additionally, cannabinoids may show a dose-dependent manner in modulating mood and behavior. Interestingly, CB1r agonists and antagonists may exhibit a similar effect in some behavioral assessments.
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http://dx.doi.org/10.1016/j.bbr.2020.112901DOI Listing
January 2021

A possible neuroprotective property of ethanol and/or NeuroAiD on the modulation of cognitive function.

Neurotoxicol Teratol 2020 Nov - Dec;82:106927. Epub 2020 Aug 27.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Cognitive impairments and poor performance on tasks needing behavioral flexibility are observable in chronic alcohol exposure. NeuroAid decreases cognitive deficits and improves functional outcomes by restoring neuronal circuits. The aim of the current study was to assess the hypothesis that ethanol exposure would induce neurobehavioral defects which may be reversed by the neuroprotective property of NeuroAid. Adult male Wistar rats were treated with saline, ethanol (0.2 g/kg), NeuroAid (0.8 g/kg) and ethanol (0.2 g/kg) + NeuroAid (0.8 g/kg). Then, behavioral tests were performed using the Y-maze apparatus, hot-plate and tail-flick apparatuses, locomotion apparatus as well as the loss of righting reflex (LORR) and hanging protocols (performance in a wire hanging test). Our results indicated that intraperitoneal (i.p.) administration of ethanol alone and administration of ethanol along with NeuroAid for one week reversed ethanol-induced spatial memory deficits in rats (P < 0.01). Interestingly, treatment with ethanol (0.2 g/kg) for one week induced nociception (P < 0.01). Moreover, one week administration of ethanol (0.2 g/kg) along with NeuroAid (0.8 g/kg) increased latency to LORR (P < 0.001) while four weeks administration of ethanol (0.2 g/kg) along with NeuroAid (0.8 g/kg) decreased sleep time (P < 0.01). In addition, a single administration of all drugs did not alter locomotor activity (P > 0.05) and hanging (P > 0.05). Improvement of behavioral tasks after one-week i.p. administration of ethanol and/or NeuroAid in comparison with a single administration of ethanol and/or NeuroAid may be due to the neuroprotective property of ethanol and/or NeuroAiD.
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http://dx.doi.org/10.1016/j.ntt.2020.106927DOI Listing
September 2021

Toxic effect of calcium/calmodulin kinase II on anxiety behavior, neuronal firing and plasticity in the male offspring of morphine-abstinent rats.

Behav Brain Res 2020 10 22;395:112877. Epub 2020 Aug 22.

Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Pharmacology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

Studies have shown that epigenetic changes such as alteration in histone acetylation and DNA methylation in various brain regions play an essential role in anxiety behavior. According to the critical role of calcium/calmodulin protein kinaseII (CaMKII) in these processes, the present study examined the effect of CaMKII inhibitor (KN93) on neuronal activity and level of c-fos in the amygdala and nucleus accumbens (NAC) in the offspring of morphine-exposed parents. Adult male and female Wistar rats received morphine orally (for 21 days). After the washout period (10 days), rats were mated with either drug-naïve or morphine-exposed rats. KN93 was microinjected into the brain of male offspring. The anxiety-like behavior, the neuronal firing rate in the NAC and the amygdala and level of c-fos were assessed by related techniques. Data showed the offspring with one and/or two morphine-abstinent parent(s) had more anxiety-like behavior than the control group. However, the administration of KN-93 decreased anxiety in the offspring of morphine-exposed rats compared with saline-treated groups. The expression level of the c-fos was not significantly altered by the inhibition of CaMKII in the amygdala, but the c-fos level was reduced in the NAC. The neuronal firing rate of these groups was associated with an increase in the amygdala in comparison to the saline groups but was decreased in the NAC. Results showed that CaMKII had a role in anxiety-like behavior in the offspring of morphine-exposed parents, and changes in neuronal firing rate and c-fos level in the NAC might be involved in this process.
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http://dx.doi.org/10.1016/j.bbr.2020.112877DOI Listing
October 2020

Tropisetron But Not Granisetron Ameliorates Spatial Memory Impairment Induced by Chronic Cerebral Hypoperfusion.

Neurochem Res 2020 Nov 14;45(11):2631-2640. Epub 2020 Aug 14.

Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran.

Tropisetron and Granisetorn are 5-HT3 antagonists with antiemetic effects. Tropisetron also has a partial agonistic effect on alpha-7 nicotinic acetylcholine receptors (α7 nAChRs). On the other hand, chronic cerebral hypoperfusion (CCH) attenuates cerebral blood flow and impairs cognitive functions. The goal of this study was to investigate the effect of Tropisetron and Granisetron on CCH-induced spatial memory impairment in rats. Forty-eight male Wistar rats were used in this study. 2-VO surgery was done to induce CCH and Radial Eight Arm Maz apparatus was used to evaluate spatial memory (working and reference memory). Tropisetron was injected intraperitoneally at the doses of 1 and 5 mg/kg, and Granisetron was injected intraperitoneally at the dose of 3 mg/kg. Dorsal hippocampal (CA1) neurons count, Interleukin 6 (IL-6) serum level, and serotonin-reuptake transporter (SERT) gene expression were also evaluated. The results showed, CCH impaired working and reference memory, increased IL-6 serum level, and decreased CA1 neurons and SERT expression. Tropisetron at the dose of 5 mg/kg restored all the effects of CCH. However, Granisetron did not restore CCH-induced memory impairment. Furthermore, Granisetron had no effect on IL-6. While, it increased SERT expression and CA1 neurons. In conclusion, Tropisetron but not Granisetron, ameliorated spatial memory impairment induced by CCH. We suggested conducting more detailed studies investigating the role of serotonergic system (5-HT3 receptors and serotonin transporters) and also α7 nAChRs in the effects of Tropisetron.
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http://dx.doi.org/10.1007/s11064-020-03110-2DOI Listing
November 2020

Curcumin prevents cognitive deficits in the bile duct ligated rats.

Psychopharmacology (Berl) 2020 Dec 6;237(12):3529-3537. Epub 2020 Aug 6.

Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.

Rationale: Bile duct ligation (BDL) in rodents can cause impaired liver function and cognition deficits. Curcumin has shown a preventive and therapeutic role in memory impairment.

Objectives: Therefore, this study aimed to explore the effect of curcumin on the performance of male adult Wistar rats that underwent BDL, a model of hepatic encephalopathy (HE) in the Morris water maze (MWM).

Methods: Four weeks after surgery, sham (manipulation of common bile duct without ligation) and BDL rats underwent the MWM test.

Results: The representative data showed that BDL rats exhibited impairments in spatial learning and reference memory in the MWM compared with the sham rats. Treatment of BDL rats with curcumin (40 mg/kg, i.p., for 4 weeks) prevented these impairments, while it did not affect spatial learning and memory in the sham rats, by itself. Curcumin increased expression levels of the pro-survival B cell lymphoma extra-large (Bcl-xL) gene and two genes involved in mitochondrial function, peroxisome proliferative-activated receptor-γ co-activator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM), in the hippocampus of BDL rats compared with the vehicle-treated sham or BDL rats, while it decreased the pro-apoptotic Bcl-2-associated X protein (Bax) gene expression level. BDL up-regulated Bax and down-regulated TFAM, by itself. Furthermore, curcumin reduced the mRNA level of Bax, while it increased Bcl-2 and TFAM mRNA levels.

Conclusions: These findings demonstrate the beneficial effect of curcumin on cognitive function in BDL rats of the HE model. The curcumin effect may be related to mitochondrial function improvement in the HE.
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http://dx.doi.org/10.1007/s00213-020-05633-6DOI Listing
December 2020

Alteration of orexin-A and PKCα in the postmortem brain of pure-opioid and multi-drug abusers.

Neuropeptides 2020 Oct 29;83:102074. Epub 2020 Jul 29.

Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Amir-Almomenin Hospital, Islamic Azad University, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address:

Finding changes induced by the drug of abuse is one of the most important approaches to design new drugs for the treatment of substance use disorders (SUD). Postmortem study is the most reliable method for detecting alteration in the brain of SUD patients. Recently, the role of orexinergic system in SUD is in consideration. In the current study, we evaluated the level of orexin-A in the CSF and protein kinase Cα (PKCα) in the brain of pure-opioid (POA) and multi-drug abusers (MDA). A total of 56 POA, 45 MDA, and 13 matched control brains were collected from the legal medicine center, Tehran, Iran. The CSF was gathered from the third ventricle immediately after opening the skull and kept at -80 °C. The medial prefrontal cortex (mPFC), lateral prefrontal cortex (lPFC), orbitofrontal cortex (OFC), nucleus accumbens (NAc), and amygdala were dissected from fresh brain, frozen with liquid nitrogen and kept at -80 °C. The level of orexin-A evaluated in the CSF. Using western blotting, the level of PKCα assessed in the brain. Obtained data revealed that the level of orexin-A increased in POA and MDA compared with the control group (p < 0.05). In addition, the level of PKCα increased in the prefrontal cortex and amygdala of the abusers compared with the control group, although we did not detect changes in the level of PKCα in the NAc. Along with animal studies, the current results showed that the level of orexin increased in the CSF of drug abusers, which might be related to increases in the activation of lateral hypothalamic orexinergic neurons faced with the drug of abuse. Enhancement in the level of PKCα in the drug reward circuits might be adaptational changes induced by orexin and drugs of abuse.
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http://dx.doi.org/10.1016/j.npep.2020.102074DOI Listing
October 2020

Evaluation of the relationship between the gene expression level of orexin-1 receptor in the rat blood and prefrontal cortex, novelty-seeking, and proneness to methamphetamine dependence: A candidate biomarker.

Peptides 2020 09 12;131:170368. Epub 2020 Jul 12.

Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Cognitive Neuroscience, Institute for Cognitive Science Studies, Tehran, Iran. Electronic address:

Background: previous studies have suggested that methamphetamine (METH) abuse may affect orexin regulation. However, the data regarding the relationship between the current level of orexin and the vulnerability to METH abuse are minimal. Here, we have investigated the correlation between the gene expression level of the orexin-1 receptor (OX1R) in the rat prefrontal cortex (PFC) and blood lymphocytes and susceptibility to METH dependence and its impact on novelty-seeking behavior.

Methods: male Wistar rats were first examined for novelty-seeking behavior by the novel object recognition test, and the expression level of OX1R in their blood lymphocytes was evaluated by real-time PCR. Then, the susceptibility to METH abuse was investigated by voluntary METH oral consumption test. According to the amounts of METH consumption, the animals were divided into two groups of METH preferring and non-preferring. Half of the rats in each group were sacrificed, and the level of OX1R in their blood lymphocytes and PFC tissue was measured. The other half were sacrificed for the same reason after two weeks of drug abstinence.

Results: The indexes of novelty-seeking behavior were significantly higher in the METH- preferring group compared to the non-preferring animals. Furthermore, the expression level of OX1R in the blood lymphocytes and PFC in the preferring group was considerably higher than the non-preferring group.

Conclusion: Up-regulation of the mRNA expression level of OX1R in the lymphocytes and PFC may predict vulnerability to the METH consumption and novelty-seeking, which may serve as a potential biomarker for METH abuse.
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http://dx.doi.org/10.1016/j.peptides.2020.170368DOI Listing
September 2020

Combined treatment of scopolamine and group III mGluR antagonist, CPPG, exerts antidepressant activity without affecting anxiety-related behaviors.

Physiol Behav 2020 10 27;224:113034. Epub 2020 Jun 27.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Department of Neuroendocrinology, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Clinical trials have revealed that the muscarinic receptor antagonist scopolamine produces a fast and potent antidepressant response. However, the anticholinergic adverse effects and the risk of psychosis at higher doses limit the widespread clinical use of scopolamine. Combination therapy of scopolamine and other antidepressants in treating depression has been suggested. Our experimentswere designed to examine the effects of the combining ineffective doses of scopolamine and a group III metabotropic glutamate receptor (mGluR) antagonist, CPPG, on depression- and anxiety-related behaviors in male NMRI mice. The forced swim test (FST) and the elevated plus maze (EPM) were selected to evaluate depression- and anxiety-related behaviors, respectively. Intraperitoneal (i.p.) administration of scopolamine (0.01-0.5 mg/kg) exerted profound antidepressive and anxiogenic effects. Intracerebroventricular (i.c.v.) administration of CPPG (12.5-50 nmol/mouse) elicited significant antidepressive and anxiolytic effects. Moreover, the ineffective dose of CPPG (12.5 nmol/mouse) plus ineffective doses of scopolamine (0.01 or 0.05 mg/kg) showed antidepressant-like effect while these combinations had no effect anxiety-related behaviors. It should be noted that none of the compounds altered locomotor activity. Results identify the combined administration of scopolamine and CPPG as a possible hopeful target in the future treatment of the depressive disorder.
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http://dx.doi.org/10.1016/j.physbeh.2020.113034DOI Listing
October 2020

The protective effect of alpha lipoic acid (ALA) on social interaction memory, but not passive avoidance in sleep-deprived rats.

Naunyn Schmiedebergs Arch Pharmacol 2020 11 24;393(11):2081-2091. Epub 2020 Jun 24.

Department of Bioscience and Biotechnology, Malek Ashtar University of Technology, P.O. Box: 13145-784, Tehran, Iran.

Sleep is involved in maintaining energy, regulating heat, and recovering tissues. Furthermore, proper cognitive functions need sufficient sleep. Many studies have revealed the impairment effect of sleep deprivation (SD) on cognitive functions including learning and memory. Alpha lipoic acid (ALA) is a potent free radical scavenger, biological antioxidant, and neuroprotective agent. Furthermore, ALA improves learning and memory performance, decreases oxidative stress, and enhances antioxidant biomarkers. In this study, we aimed to investigate the effect of ALA on social interaction and passive avoidance memories in sleep-deprived rats. Total sleep deprivation (TSD) apparatus was used to induce SD (for 24 h). Three-chamber paradigm test and shuttle box apparatus were used to evaluate social interaction and passive avoidance memory, respectively. Rats' locomotor apparatus was used to assess locomotion. ALA was administered intraperitoneally at doses of 17 and 35 mg/kg for 3 consecutive days. The results showed SD impaired both types of memories. ALA at the dose of 35 mg/kg restored social interaction memory in sleep-deprived rats; while, at the dose of 17 mg/kg attenuated impairment effect of SD. Moreover, ALA at the dose of 35 mg/kg impaired passive avoidance memory in sham-SD rats and at both doses did not rescue passive avoidance memory in sleep-deprived rats. In conclusion, ALA showed impairment effect on passive avoidance memory, while improved social interaction memory in sleep-deprived rats.
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http://dx.doi.org/10.1007/s00210-020-01916-zDOI Listing
November 2020
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