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 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.

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 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.

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.

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).

Prefrontal dopaminergic system and its role in working memory and cognition in spinal cord-injured rats.

NEW FINDINGS: What is the central question of this study? How does spinal cord injury affect prefrontal cortex function and the expression of dopamine receptors? What is the main finding and its importance? Spinal cord injury impaired cognitive function, which was associated with reduced dopamine receptor expression in the prefrontal cortex. ABSTRACT: The effect of spinal cord injury (SCI) has been studied widely in paraplegia and motor areas of the brain, but its mechanisms in memory and cognitive impairment remain controversial. Here, we focused on the impact of SCI on prefrontal performance via dopamine levels and receptors. We divided 18 male rats into three groups, i.e. control, laminectomy and SCI groups. Laminectomy and SCI were induced at T10 of the spinal cord. One week later, after locomotor recovery, the novel object recognition and T-maze (spontaneous alternation) tests were applied. After behavioural assessments, the rats were killed and their brain tissues harvested. According to the behavioural findings, cognitive function was impaired in the SCI group (P < 0.05). Also, SCI significantly increased the dopamine level and decreased the expression of dopamine receptors in the prefrontal cortex 2 weeks after injury (P < 0.05). Given the role of dopamine in cognition, SCI could impair novel object recognition and spatial working memory via dopaminergic systems.

Therapeutic effects of Cyperus rotundus rhizome extract on memory impairment, neurogenesis and mitochondria in beta-amyloid rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disturbance leading to memory deficit, cognitive decline, and behavioral disturbance. Deposition of Amyloid beta plaques, neurofibrillary tangle and mitochondrial impairment are common neuropathological signs in AD. In this study, the effect of standardized Cyperus rotundus(C. rotundus) extract in three different doses of 250, 500, and 750 mg/kg on memory, neurogenesis and mitochondrial mass in the beta amyloid rat model was assessed. For this purpose, 42 male Wistar rats were randomly divided into six groups (n = 7) to evaluate baseline training performance in Morris water maze test. Amyloid beta (Aß) was injected in animal hippocampal CA1 bilaterally in four groups. After 21 days, a decrease was observed in spending time in target quadrant in the first probe trial in Aß injected groups. Following that, 250, 500, and 750 mg/kg of C. rotundus extracts were administered to three out of four groups for a period of one month. BrdU (Bromodeoxyuridine) was intraperitoneally injected in all groups on the last 7 days of treatment. Then, 28 days after the last BrdU injection, the second probe trial was run, and rats were sacrificed. The neurogenesis and mitochondrial distribution were detected in hippocampus, by immunohistochemical staining. At last, it was observed that C. rotundus, almost recovered memory impairment, in addition to increasing in mitochondrial mass in CA1 and neurogenesis in dentate gyruse in the beta-amyloid rat model of Alzheimer's disease.

Pretreatment with crocin along with treadmill exercise ameliorates motor and memory deficits in hemiparkinsonian rats by anti-inflammatory and antioxidant mechanisms.

The motor symptoms of Parkinson's disease (PD) are preceded by non-motorized symptoms including memory deficits. Treatment with dopamine replacement medications, such as L-DOPA only control motor symptoms and does not meet the clinical challenges of the disease, such as dyskinesia, non-motor symptoms, and neuroprotection. The purpose of the current study was to examine the neuroprotective potential of crocin and physical exercise in an animal model of PD. Male Wistar rats ran on a horizontal treadmill and/or pretreated with crocin at a dose of 100 mg/kg. Then, 16 µg of the neurotoxin 6-hydroxydopamine (6-OHDA) was microinjected into left medial forebrain bundle. Crocin treatment and/or exercise continued for 6 more weeks. Spatial and aversive memories, rotational behaviour, inflammatory and oxidative stress parameters were assessed at the end of week 6 post surgery. The results showed that pretreatment with crocin alone and in combination with exercise decreased the total number of rotaions as compared with 6-OHDA-lesioned group. Furthermore, treatment of parkinsonian rats with crocin along with exercise training improved aversive and spatial memories. Biochemical analysis showed that crocin and exercise (alone and in combination) reduced tumor necrosis factor- (TNF) α levels in the striatum. Moreover, treatment with crocin at a dose of 100 mg/kg decreased the lipid peroxidation levels in the hippocampus, while exercise training increased the total thiol concentration. In conclusion, our findings indicated that pretreatment with crocin along with treadmill exercise ameliorated motor and memory deficits induced by 6-OHDA, which is considered to be due to their antioxidant and anti-inflammatory activities. The results suggest that combined therapy with crocin and exercise may be protective for motor and memory deficits in PD patients.

Electrical stimulation mPFC affects morphine addiction by changing glutamate concentration in the ventral tegmental area.

Morphine addiction is known as a serious social problem. Medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) are two important sites of the brain that contribute to this type of addiction, and a complicated relation exists in between. In addition, neurotransmitters like glutamate and γ--Amino Butyric Acid (GABA) play an important role in the formation of these relations. Thus, the present study was undertaken to investigate these relations by evaluating the level of associated changes in the indicated neurotransmitters in the VTA, using HPLC method. This was performed after electrical stimulation and inducing lesion of mPFC and through microinjections of N-Methyl-D-Aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, respectively AP5 and CNQX, into the VTA of addicted rats. Our results showed that intra-peritoneal (i.p.) administration of morphine in 9 days in the morphine group, and also electrical stimulation (100 µA) of mPFC, receiving (i.p.) morphine, caused an increase in the glutamate release in the VTA, compared to the control group, but the increase of glutamate levels in the VTA in the morphine-stimulation group was not significant, compared to the morphine group. Moreover, GABA release into this area was decreasing in morphine and morphine- stimulation groups, compared to the control group. Our findings also showed that electrical lesion (0.4 mA) of mPFC, and also microinjection of glutamate antagonists into the VTA, receiving (i.p.) morphine in rats, caused a decrease of glutamate in the VTA. Therefore, it could be concluded that the relation between mPFC and VTA is highly effective in the formation of reward system.

Blockade of prelimbic glutamate receptor reduces the reinforcing effect of morphine.

The prelimbic cortex (PrL) as a part of the medial prefrontal cortex (mPFC) plays a crucial role in drug addiction. Previous studies have shown that glutamatergic transmission through the NMDA and AMPA receptors plays an important role in morphine rewarding properties. In this study, we evaluated the effect of glutamate receptors blockade within the PrL on morphine self-administration. Male Wistar rats were randomly selected and divided into 7 groups. Trained rats were placed in self-administration apparatus, where they pressed an active lever for receiving morphine (5 mg/mL) in test groups and saline in saline group during 11 consecutive days for 2 h per session. The effects of intra-prelimbic AMPA receptor antagonist (CNQX; 0.5 and 2.5 µg/0.5 µL) and the NMDA antagonist (AP5; 0.1 and 1 µg/0.5 µL) on self-administration were tested. Our results demonstrated that intra-prelimbic injection of different doses of CNQX and AP5, and co-administration of these 2 drugs before self-administration significantly decreased active lever pressing compared with morphine group (p < 0.001). Also, the number of self-infusion significantly decreased in test groups compared with morphine group (p < 0.001). These findings suggest that a reduction in PrL glutamatergic output can modulate morphine reinforcement.

Effects of electrical lesion of basolateral amygdala nucleus on rat anxiety-like behaviour under acute, sub-chronic, and chronic stresses.

Stress contributes, as a risk factor, to such psychological disorders as anxiety. The effects of electrical lesions in the basolateral amygdala nucleus (BLA) were investigated on the locomotor activity and anxiety-like behaviour in different stress durations. For this purpose, rats were randomly allocated to control, sham, and experimental groups, the latter including groups with and without BLA nucleus subjected to acute, sub-chronic, and chronic stress conditions for 1, 7, and 21 days, respectively, applied 6 h/d. The induced anxiety behaviour was evaluated using the open field test (OFT) while other variables were measured. Findings revealed that sub-chronic stress led to significantly reduced (P<.05) anxiety behaviours as measured by entries into and the time spent in the centre area while it also led to significant impairments in exploratory and locomotor activities, indicating intensified anxiety-like behaviour. BLA lesion affected rat behaviour differently such that it significantly (P<.05) decreased fear under sub-chronic and chronic stress conditions as evidenced by the subjects' greater tendency to enter the centre area in the open field test and their increased number of rearing events (P<.01). However, BLA lesion led to no significant decrease in the locomotor activity of subjects exposed to sub-chronic or chronic stress conditions as compared with those in similar groups but without BLA lesion. Finally, BLA lesion was found not only to decrease significantly (P<.01) adrenal gland and body weights, particularly under sub-chronic stress, but also to play a critical role in modulating adrenal functions by decreasing adrenal gland weight, and thereby reducing depression-like symptoms.

The Effects of Crocin on 6-OHDA-Induced Oxidative/Nitrosative Damage and Motor Behaviour in Hemiparkinsonian Rats.

BACKGROUND: Crocin is considered to prevent oxidative stress-related diseases, such as ischemia and Alzheimer's. The aim of the present investigation was to evaluate the effects of crocin on motor behaviour and 6-OHDA-induced oxidative/nitrosative damage to the striatum in an experimental model of Parkinson's disease. METHODS: Left medial forebrain bundle was lesioned by microinjection of 6-OHDA (16µg in 0.2% ascorbate-saline). Crocin (30 and 60 mg/kg) was injected intraperitoneally three days before surgery until six weeks. Rotational behaviour and biochemical analysis were used to evaluate the effect of crocin in a unilateral 6-OHDA-induced model of Parkinson's disease. RESULTS: The contralateral rotations induced by apomorphine in 6-OHDA lesioned group were highly significant (P < 0.001) as compared to the sham group. Moreover, chronic administration of crocin at doses of 30 and 60 mg/kg over six weeks did not change the rotations. The TBARS and nitrite levels in the striatum were also significantly (P < 0.05) increased in lesioned group. Treatment with crocin at a dose of 60 mg/kg significantly decreased the nitrite levels (P < 0.05) in the striatum. CONCLUSION: Crocin at a dose of 60 mg/kg could be effective in preventing the nitrosative damage in the striatum. Further investigations using higher doses of crocin is suggested to get the full neuroprotective effects of crocin in Parkinson's disease.

The Effect of Preventive, Therapeutic and Protective Exercises on Hippocampal Memory Mediators in Stressed Rats.

BACKGROUND: Exercise plays a significant role in learning and memory. The present study focuses on the hippocampal corticosterone (CORT), interleukin-1 beta (IL-1ß), glucose, and brain-derived neurotrophic factor (BDNF) levels in preventive, therapeutic, and protective exercises in stressful conditions. METHODS: Forty male rats were randomly divided into four groups: the control group and the preventive, therapeutic, and protective exercise groups. The treadmill running was applied at a speed of 20-21m/min and a chronic stress of 6 hours/day for 21 days. Subsequently, the variables were measured in the hippocampus. RESULTS: The findings revealed that the hippocampal CORT levels in the preventive exercise group had a significant enhancement compared to the control group. In the protective and particularly the therapeutic exercise groups, the hippocampal CORT levels declined. Furthermore, the hippocampal BDNF levels in the preventive and the therapeutic exercise groups indicated significantly decreased and increased, respectively, in comparison with the control group. In the preventive exercise group, however, the hippocampal glucose level turned out to be substantially higher than that in the control group. CONCLUSION: It appears that the therapeutic exercise group had the best exercise protocols for improving the hippocampal memory mediators in the stress conditions. By contrast, the preventive exercise group could not improve these mediators that had been altered by stress. It is suggested that exercise time, compared to stress, can be considered as a crucial factor in the responsiveness of memory mediators.

Effect of forced exercise and exercise withdrawal on memory, serum and hippocampal corticosterone levels in rats.

Evidence suggests that there are positive effects of exercise on learning and memory. Moreover, some studies have demonstrated that forced exercise plays the role of a stressor. This study was aimed at investigating the effects of different timing of exercise and exercise withdrawal on memory, and serum and hippocampal corticosterone (CORT) levels. Wistar rats were randomly divided into five groups: control, sham, exercise-rest (exercise withdrawal), rest-exercise (exercised group), and exercise-exercise (continuous exercise). Rats were forced to run on a treadmill for 1 h/day at a speed 20-21-m/min. Memory function was evaluated by the passive avoidance test in different intervals (1, 7 and 21 days) after foot shock. Findings showed that after the exercise withdrawal, short-term and mid-term memories, had significant enhancement compared to the control group, while the long-term memory did not present this result. In addition, the serum and hippocampal CORT levels were at the basal levels after the rest period in the exercise-rest group. In the rest-exercise group, exercise improved mid- and long-term memories, whereas continuous exercise improved all types short-, mid- and long-term memories, particularly the mid-term memory. Twenty-one and forty-two days of exercise significantly decreased the serum and hippocampal CORT levels. It seems that exercise for at least 21 days with no rest could affect biochemical factors in the brain. Also, regular continuous exercise plays an important role in memory function. Hence, the duration and withdraw of exercise are important factors for the neurobiological aspects of the memory responses.

Novel effects of Rosa damascena extract on memory and neurogenesis in a rat model of Alzheimer's disease.

The number of older people who are suffering from memory impairment is increasing among populations throughout the world. Alzheimer's disease (AD) affects about 5% of people over 65 years old. The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage in the early stages of AD. Emerging evidence suggests that loss of neurons and synapses are correlated with dementia in this devastating disease. Therefore, neurogenesis and synaptogenesis in adulthood could serve as a preventive as well as a therapeutic target for AD. This study investigated the effect of Rosa damascena extract on neurogenesis and synaptogenesis in an animal model of AD. Molecular, cellular, and behavioral experiments revealed that this treatment could induce neurogenesis and synaptic plasticity and improve memory in AD. Our study suggests that R. damascena is a promising treatment for mild memory impairments and AD.

Effects of cholestasis on learning and locomotor activity in bile duct ligated rats.

BACKGROUND: Cognitive functions are impaired in patients with liver disease. Bile duct ligation causes cholestasis that impairs liver function. This study investigated the impact of cholestasis progression on the acquisition and retention times in the passive avoidance test and on the locomotor activity of rats. METHODS: Cholestasis was induced in male Wistar rats by ligating the main bile duct. Locomotor activity, learning and memory were assessed by the passive avoidance learning test at day 7, day 14, and day 21 post-bile duct ligation. The serum levels of bilirubin, alanine aminotransferase, and alkaline phosphatase were measured. RESULTS: The results showed that acquisition time and locomotor activity were not affected at day 7 and day 14, but they were significantly (P < 0.05) impaired at day 21 post-bile duct ligation compared with the results for the control group. Additionally, memory was significantly impaired on day 7 (P < 0.01), day 14, and day 21 (P < 0.001) compared with the control groups. The levels of total bilirubin, direct bilirubin, indirect bilirubin, alanine aminotransferase, and alkaline phosphatase were significantly higher at day 7, day 14, and day 21 post-bile duct ligation compared with the levels in the sham group. CONCLUSION: Based on these findings, both liver and memory function were affected in the early stage of cholestasis (7 days after bile duct ligation), while learning and locomotor activity were impaired at 21 days after bile duct ligation following the progression of cholestasis.

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.

Erythropoietin improves spatial learning and memory in streptozotocin model of dementia.

Alzheimer's disease is associated to impairments of learning and memory. Because studies demonstrated that erythropoietin has positive effects on central nervous system, the aim of this study was to evaluate the effect of erythropoietin on spatial learning and memory in a well defined model for Alzheimer's disease. Rat model of Alzheimer's was created by injecting streptozotocin in lateral ventricles of the brain. Two weeks later, the rats were assessed through passive avoidance learning test to confirm the induction of Alzheimer's. After that, they received erythropoietin (5000IU/kg) every other day, for two weeks and then spatial learning and memory were assessed by a 5-day protocol of Morris water maze test in them. The results showed that streptozotocin severely damaged learning and memory in rats. Erythropoietin had no significant effect in the control rats; however, it significantly improved learning and memory in rats with Alzheimer's disease, as the task performance of the rats treated with erythropoietin was like the control group. The results suggest that erythropoietin can be considered as an effective treatment for neurodegenerative damages.

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.