Protective Effects of Long-Term Escitalopram Administration on Memory and Hippocampal BDNF and BCL-2 Gene Expressions in Rats Exposed to Predictable and Unpredictable Chronic Mild Stress.

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.

The electrical stimulation of the central nucleus of the amygdala in combination with dopamine receptor antagonist reduces the acquisition phase of morphine-induced conditioned place preference in male rat.

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.

The role of NMDA glutamate receptors in the lateral habenula on morphine-induced conditioned place preference in rats.

The lateral habenula (LHb) has received special attention due to its role in modulating motivated behavior, stress response, and rewarding and aversive stimuli through monoamine transmission. In the present study, the involvement of the N-methyl-d-aspartate (NMDA) receptors of the LHb in the expression and acquisition phases of morphine-induced conditioned place preference (CPP) was studied in male rats. Bilateral injections of agonist/antagonist (MK-801) of NMDA receptor were performed during the conditioning sessions of the acquisition phase. In other separate groups, drugs were also injected into the LHb before the test session during the expression phase of CPP. A 5-day CPP bias paradigm was used to study the effect of injections of NMDA and MK-801 into the LHb on morphine reward-related behavior. Different doses of NMDA plus morphine reduced the CPP score during the acquisition phase, whereas MK-801 significantly increased conditioning scores during the acquisition phase of CPP. The injection of agonists and antagonists of NMDA receptors in LHb had no significant effect on CPP scores and locomotion during the expression phase of CPP, whereas the motor activity in the acquisition phase was affected by the drugs. The reduction effect of NMDA on the CPP scores during the acquisition phase was blocked by pretreatment with MK-801. Our findings also suggest that NMDA receptors in the LHb may be involved in the acquisition phase of morphine-induced CPP.

Effects of GABAB receptor blockade on lateral habenula glutamatergic neuron activity following morphine injection in the rat: an electrophysiological study.

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.

Morphine upregulates Toll-like receptor 4 expression and promotes melanomas in mice.

BACKGROUND: Morphine and other opioids are used to manage cancer-related pain; however, the role of these drugs in cancer progression remains controversial. Emerging evidence indicates that morphine can activate Toll-like receptor 4 (TLR4) and its signaling pathways, by the way the activation and expression of TLR4 can promote melanoma. In this study, we investigated the effects of morphine on the expression of TLR4 and promotion of melanoma in mice. METHODS: Mice melanoma cells (B16F10) were cultured with morphine (0.1, 1 and 10 µM) for 24 h. In the other experiment, cells were treated with morphine with or without TLR4 agonist (LPS) or antagonist (TAK-242). In in-vivo model, B16F10 cells were subcutaneously injected to C57BL/6 mice, and morphine was administrated in three different treatment protocols after developing palpable tumors (acute treatment, chronic daily injections, escalating doses of morphine). In another set of experiments, B16F10 cells were pretreated with LPS (5 µg/ml) 24 h before injection into mice. Control group received normal saline. We measured cell proliferation, the expression level of Tlr4, Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (Nf-κb1) genes, TLR4 protein expression, and tumor volume. RESULTS: Chronic, acute, and escalating doses of morphine increased tumor. Morphine increased the expression of Tlr4 and Nf-κb1 regardless of the treatment protocol used. CONCLUSION: Morphine increases the progression of melanoma cancer and may be related to the increased expression of TLR4. Our results suggest that morphine should be used with caution in patients with melanoma.HighlightsMorphine increases the expression of TLR4 in melanoma.Morphine increases melanoma progression.These effects are mostly observed with chronic and escalating morphine administration.

Involvement of AMPA receptors of lateral habenula in the expression and acquisition phases of morphine-induced place preference.

The lateral habenula (LHb), known as the brain structure of the epithalamic, plays the main role in depression and drug addiction. The glutamatergic system influences morphine reward. The effect of activation/inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) in the LHb on different phases of morphine-induced conditioned place preference (CPP) remains unknown. In this research, the effect of bilateral intra-LHb microinjection of AMPARs agonist and antagonist on the acquisition and expression phases of CPP in male rats has been investigated. Different doses of NBQX, the antagonist of AMPARs, in combination with the effective dose of morphine, increased the CPP score during the acquisition phase. While AMPA, the agonist of AMPARs, significantly reduced the conditioning scores in the acquisition phase. Pretreatment with NBQX (0.5 and 1 µg/rat) reversed the inhibitory effect of AMPA (1 µg/rat) on the acquisition phase of morphine-induced CPP. The antagonist (1 µg/rat) increased the effect of a high dose of agonist (2 µg/rat) on CPP. On the other hand, NBQX significantly increased CPP scores during the expression phase. AMPA did not significantly affect CPP scores in the expression phase, but significantly reduced locomotor activity in the test phase. These results confirmed the importance of AMPARs in the LHb in morphine reward. Our data also suggest that injection of an AMPARs antagonist into the LHb may alter the AMPA-induced morphine response in a dose-dependent manner.

Effects of treadmill exercise and chronic stress on anxiety-like behavior, neuronal activity, and oxidative stress in basolateral amygdala in morphine-treated rats.

The basolateral amygdala (BLA), which is sensitive to stress, is necessary for reward-seeking behavior and addiction. Regular exercise can produce various positive effects by affecting the BLA. Therefore, we aimed to investigate the effects of chronic stress and treadmill running (TR) on anxiety-like behavior, neuronal activity, lipid peroxidation (measured by malondialdehyde (MDA) levels, a marker for oxidative stress), and total thiol in BLA, in morphine-treated rats. Male Wistar rats were restricted in restraint stress and/or ran on the treadmill and treated with morphine (5 mg/kg) for 21 days. Anxiety-like behavior was evaluated using an elevated plus maze (EPM) and open field tests (OFTs), on day 22. On day 23, neuronal activity in BLA was assessed via single-unit recording. Finally, MDA and total thiol were assessed in BLA. Our results showed that chronic administration of morphine (5 mg/kg) did not affect anxiety-like behavior. However, the morphine-treated rats, subjected to chronic stress and exercise, showed fewer anxiety-like behaviors. Morphine increased BLA's MDA levels but it was prevented by TR. Glutamatergic and GABAergic basal neuronal activities were low in morphine-treated rats but after acute morphine application, there was a significant decrease in GABAergic neuronal activities in the morphine-exercise-stress (Mor-Exe-St) group. The results of this study showed that in morphine-treated rats, stress and exercise or their combination could have either co-directional or opposite effects to the chronic effects of morphine. These results indicate the existence of common pathways similar to endogenous opioids.

The Protective Effects of Crocin on Input-Output Functions and Long-term Potentiation of Hippocampal CA1 Area in Rats Exposed to Chronic Social Isolated Stress.

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. Highlights: Neuronal excitability and long-term plasticity of CA1 were impaired by chronic isolation stress.The memory was protected by low and particularly high doses of crocin in the chronic isolation stress condition.Crocin decreased the corticosterone levels in hippocampus, but not frontal cortex. Plain Language Summary: The lack of social communication (isolation stress) is associated with the primary risk of brain functions. On the other hand, crocin as one of effective components of saffron is helpful for improvement of memory. Therefore, the protective effect of two doses of crocin on cellular mechanism of memory in rats exposed to chronic social isolated stress was investigated in present study. Chronic isolation stress (CIS) was induced 6h/day, and crocin was administrated for a period of 21 days at two doses of 30 and 60 mg/kg. The electrophysiological and cellular mechanism of memory in the CA1 area of the hippocampus were investigated. Also, the corticosterone and glucose levels were assayed in the hippocampus and frontal cortex. It was concluded that 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. Also, the corticosterone levels significantly increased in the frontal cortex and especially the hippocampus. Also, the glucose levels did not change in the hippocampus and frontal cortex in all experimental groups.

Involvement of GABAA receptors of lateral habenula in the acquisition and expression phases of morphine-induced place preference in male rats.

The lateral habenula (LHb) is a critical brain structure involved in the aversive response to drug abuse. It has been determined that the gamma-aminobutyric acid (GABA)-ergic system plays the main role in morphine dependency. The role of GABA type A receptors (GABAARs) in LHb on morphine-induced conditioned place preference (CPP) remains unknown. In this study, the effect of bilateral intra-LHb microinjection of GABAAR agonist and antagonist on the acquisition and expression phases of CPP, utilizing a 5-day CPP paradigm in male rats, was evaluated. Subcutaneous administration of different doses of morphine caused a dose-dependent CPP. Intra-LHb microinjection of the GABAAR agonist, muscimol, in combination with morphine (5 mg/kg; subcutaneously) enhanced CPP scores in the acquisition phase of morphine CPP, whereas the GABAAR antagonist, bicuculline, significantly reduced the conditioning scores in the acquisition phase. Furthermore, pretreatment with a high dose of bicuculline reversed the additive effect of muscimol during the acquisition phase, yet the low dose of antagonist had no significant effect on agonist-induced CPP scores. On the other hand, muscimol (3 µg/rat) significantly increased CPP scores in the expression phase but bicuculline did not induce a significant effect on CPP scores. Bicuculline and muscimol microinjections did not affect locomotor activity in the testing sessions. Our results confirm that GABAARs in LHb play an active role in morphine reward. In addition, microinjections of bicuculline/muscimol may alter the morphine response through the GABAergic system.

Effect of electrical stimulation of central nucleus of the amygdala on morphine conditioned place preference in male rats.

Objectives: 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).

Preventive effects of fixed and progressive forced exercises on memory and brain electrical activity in morphine-addicted rats.

Exercise and addiction influence brain functions. The preventive effects of fixed and progressive forced exercises on both brain functions and body weight were investigated in morphine-addicted rats. Thirty-five rats were allocated to control, morphine, fixed exercise-morphine, and progressive exercise-morphine groups. Forced exercise was applied 1h/day for 21 days with morphine sulfate administered at doses of 10, 20, 30, 40, and 50 mg/kg for 5 consecutive days. The 50 mg/kg dose was repeated over the five subsequent days. Brain performance was evaluated using the passive avoidance test and EEG recordings. The passive avoidance test revealed no significant changes in brain functions (namely, latency, total dark stay time, and number of times entering the dark compartment). Compared to the control, the morphine group exhibited significantly lower alpha and beta waves but significantly higher delta and theta ones. Compared to the morphine group, the progressive and fixed exercise-morphine groups exhibited significant changes in their passive avoidance performance and only in the alpha wave of their EEG recordings. Progressive exercise improved learning, memory, and memory consolidation but reduced locomotor activity whereas fixed exercise affected EEG recordings in the addicted subjects. Clearly, different (fixed or progressive) exercise models produced different changes in brain functions.

Molecular Mechanisms of Exercise in Brain Disorders: a Focus on the Function of Brain-Derived Neurotrophic Factor-a Narrative Review.

The natural aging process as well as many age-related diseases is associated with impaired metabolic adaptation and declined ability to cope with stress. As major causes of disability and morbidity during the aging process, brain disorders, including psychiatric and neurodegenerative disorders, are likely to increase across the globe in the future decades. This narrative review investigates the link among exercise and brain disorders, aging, and inflammatory biomarkers, along with the function of brain-derived neurotrophic factor. For this study, related manuscript from all databases, Google scholar, Scopus, PubMed, and ISI were assessed. Also, in the search process, the keywords of exercise, neurodegeneration, neurotrophin, mitochondrial dysfunction, and aging were used. Mitochondrial abnormality increases neuronal abnormality and brain disease during the aging process. Stress and inflammatory factors caused by lifestyle and aging also increase brain disorders. Evidences suggest that exercise, as a noninvasive treatment strategy, has antioxidant effects and can reduce neuronal lesions. Brain-derived neurotrophic factor expression following the exercise can reduce brain symptoms; however, careful consideration should be given to a number of factors affecting the results.

Supplementation of Carvacrol Attenuates Hippocampal Tumor Necrosis Factor-Alpha Level, Oxidative Stress, and Learning and Memory Dysfunction in Lipopolysaccharide-Exposed Rats.

Background: Carvacrol is a natural phenolic monoterpene with anti-inflammatory and antioxidant bioactivities. Neuroinflammatory and oxidative stress responses play a crucial role in the pathogenesis of Alzheimer's disease. The present study examined the effect of carvacrol on brain tumor necrosis factor-alpha (TNF-α) level and oxidative stress as well as spatial learning and memory performances in lipopolysaccharide (LPS)-exposed rats. Materials and Methods: The rats were treated with either carvacrol (25 and 50 mg/kg) or Tween 80 for 2 weeks. Thereafter, LPS (1 mg/kg) or saline was intraperitoneally administered on days 15-19, 2 h before Morris water maze task, and treatments with carvacrol or Tween 80 were performed 30 min prior to behavioral testing. The level of TNF-α, lipid peroxidation, and total thiol concentration were measured in the hippocampus and cerebral cortex at the end of the experiment. Results: It was found that LPS-exposed rats exhibited spatial learning and memory dysfunction, which was accompanied by increased TNF-α level and lipid peroxidation, and decreased total thiol concentration in the hippocampus and/or cortex. Moreover, treatment with carvacrol at a dose of 25 mg/kg attenuated learning and memory impairments, decreased TNF-α and lipid peroxidation level in the hippocampus and cortex, and increased total thiol concentration in the cortex. Conclusion: Carvacrol exerts neuroprotective effects against LPS-induced spatial memory deficits through attenuating hippocampal TNF-α level and oxidative stress in rats.

Involvement of Basolateral Amygdala Dopamine D1 Receptors in the Acquisition and Expression of Morphine-Induced Place Preference in Rats.

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.

Effects of electrical stimulation and temporary inactivation of basolateral amygdala on morphine-induced conditioned place preference in rats.

In the present study, to evaluate the role of the basolateral amygdala (BLA) in morphine addiction, the BLA was stimulated electrically, or inactivated temporarily using lidocaine. The electrical stimulation (ES) was delivered to BLA with low or high intensities (LI or HI: 25 or 150 µA, respectively), and five minutes before morphine administration with effective or ineffective doses, lidocaine was microinjected into the BLA. Using a 5-day conditioned place preference (CPP) paradigm, the dependence on morphine was evaluated. The results showed that LI-ES of BLA induced CPP in both the acquisition and expression phases, in the control and the ineffective dose of morphine groups. HI-ES had no effect on CPP acquisition but induced aversion in the expression, with both effective and ineffective doses of morphine. Inactivation of BLA using lidocaine, inhibited morphine-induced CPP in both acquisition and expression phases. The results of the present study indicate the prominent role of BLA in morphine addiction and dependence. Considering the contradictory results of different intensities of ES, it can be inferred that there are different neural circuits in this area of the brain, in relation to the reward responses.

Effect of forced treadmill exercise on stimulation of BDNF expression, depression symptoms, tactile memory and working memory in LPS-treated rats.

Neuroinflammation has been implicated in cognitive dysfunction and the occurrence of depression in neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is believed to be involved with the benefits of exercise training in boosting memory and learning processes and antidepressant therapies. This study aimed to investigate the effect of forced treadmill exercise on hippocampal BDNF expression levels, depression symptoms, tactile memory and working memory in lipopolysaccharide (LPS)-treated rats. For this purpose, 40 male Wistar rats received 0.25 mg/kg of LPS or saline intraperitoneally for 9 consecutive days before exercise. They again received a single injection of 0.5 mg/kg of LPS or saline on days 20 and 41 after exercise. Exercise groups had to run on a motorized treadmill 5 days a week for 8 weeks. Following the last exercise training session, forced swim test (FST), Y maze and novel object recognition (NOR) task were performed. Finally, the hippocampus of rats was removed and used for determination of BDNF expression levels by real-time polymerase chain reaction (real-time PCR). The data showed that LPS decreased BDNF expression levels, Y maze score, and recognition index in NOR and increased immobility time in FST (p < 0.05). In contrast, forced treadmill exercise increased BDNF expression levels and improved the percentage of spontaneous alternation, recognition index, and immobility time in LPS-treated rats (p < 0.05). There was a significant correlation between BDNF expression levels with immobility time and recognition index (p < 0.05) but not with the percentage of spontaneous alternation (p > 0.05). The findings suggest that forced treadmill exercise may protect the brain of LPS-treated rats by improving the symptoms of depression and cognitive function through its effect on BDNF expression levels.

Comparing the Therapeutic Effects of Crocin, Escitalopram and Co-Administration of Escitalopram and Crocin on Learning and Memory in Rats with Stress-Induced Depression.

BACKGROUND: Depression affects various brain functions. According to previous studies, escitalopram influences brain functions in depression and crocin reduces memory impairments. Therefore, this study aimed to compare the therapeutic effects of using crocin and escitalopram (separately and in combination) on learning and memory in rats with stress-induced depression. METHODS: Fifty-six rats were allocated into seven groups of control, sham, continuous depression, recovery period, daily injections of escitalopram, crocin and escitalopram-crocin during 14 days after inducing depression by stress. Passive avoidance (PA) test was used to assess brain functions. RESULTS: Latency has significant differences in depression group. Also, it significantly increased in depression-crocin, depression-escitalopram and depression-escitalopram-crocin groups compared to the depression group. The dark stay (DS) time was significantly higher in the depression and depression-recovery groups. However, the DS time significantly decreased in the depression-crocin, depression-escitalopram and depression-escitalopram-crocin groups. Furthermore, the number of entrances to the dark room was significantly lower in depression-crocin and depression-escitalopram-crocin groups compared to the depression one. CONCLUSION: Different depression treatments (i.e. crocin, escitalopram and crocin-escitalopram) reduced depression-induced memory deficits. Crocin and escitalopram-crocin, respectively, improved brain functions and locomotor activity more than escitalopram. Comparatively, in subjects with depression, crocin, which is an effective saffron constituent, partially affected the memory deficits better than escitalopram (as a chemical component).

Mutual assistance of nucleus accumbens cannabinoid receptor-1 and orexin receptor-2 in response to nicotine: a single-unit study.

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.

Lateral habenula electrical stimulation with different intensities in combination with GABAB receptor antagonist reduces acquisition and expression phases of morphine-induced CPP.

The lateral habenula (LHb) plays a principal role in response to aversive stimuli and negative emotional states. In this study, we have evaluated the effects of unilateral electrical stimulation (e-stim) of the LHb on morphine-conditioned place preference (CPP), before or after bilateral injections of Gamma-aminobutyric acid-B receptor (GABABR) antagonist, phaclofen, in male rats. Morphine (5 mg/kg; s.c.) induced a significant CPP, using a 5-day CPP paradigm. Intra-LHb microinjection of phaclofen or the LHb e-stim decreased only the acquisition of CPP. The 150 µA stimulation plus phaclofen significantly suppressed the expression phase but induced aversion in the acquisition of CPP, and an e-stim of 25 µA in combination with the antagonist, significantly prevented only the acquisition phase. The findings of this study confirm the possible role of GABABRs in the LHb on the acquisition and the expression of CPP. These results show that e-stim of LHb alone or plus phaclofen may change the GABA transmission, involving into CPP. Therefore, the GABAergic system, especially through GABABRs, may play a prominent role in the behavioral responses to morphine-induced CPP by LHb stimulation.

Effects of Cyperus rotundus Extract on Spatial Memory Impairment and Neuronal Differentiation in Rat Model of Alzheimer's Disease.

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 (Aß1-42) was injected in animal hippocampal CA1 bilaterally in four groups. The first probe trial was performed 21 days after Aß injection. Then, 250, 500, and 750 mg/kg of C. rotundus extract were administered to three Aß-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 Aß rats, through increased neurogenesis in the hippocampus, which could be related to the flavonoid components in the extract.