The role of hippocampal 5-HT1D and 5-HT1F receptors on learning and memory in rats.

Serotonin is a neurotransmitter, which is involved in memory via its receptors. The 5-HT1D and 5-HT1F receptors mainly exist in the hippocampus, which plays an important role in memory processing. However, few studies have assessed the effect of these serotonin receptors on memory. We evaluated the effect of a 5-HT1D receptor agonist, PNU142633, 5-HT1D receptor antagonist, BRL15572 hydrochloride, and 5-HT1F receptor agonist, LY344864, on the recognition and avoidance memory in the hippocampus area. Fifty adult male Wistar rats weighing 200-250 g were divided into the control, sham-operated, PNU, BRL, and LY groups (n=10 per group). Bilateral guide cannulas were implanted into the dentate gyrus area of the hippocampus. The drugs were administered at the dose of 1 µg/µl before the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The results showed that in the NOR test, the administration of PNU and LY had no significant effect on recognition index; however, the recognition index was increased by BRL. In the PAL test, the administration of PNU had no significant effect on recognition index, but the administration of BRL and LY increased the time spent in the dark compartment of the apparatus and decreased the step-through latency into the dark compartment apparatus. It can be concluded that the inhibition of the hippocampal 5-HT1D receptor improved cognition memory but impaired avoidance memory. Activation of the hippocampal 5-HT1F receptor had no effect on cognitive memory but impaired avoidance memory.

The effects of polyvinyl alcohol-coated selenium nanoparticles on memory impairment in rats.

Some mineral elements exert beneficial neuroprotection, especially in the form of nanoparticles. The aim of the present study was to evaluate the effects of selenium nanoparticles (SeNPs) and polyvinyl alcohol (PVA)-coated SeNPs (PVA-SeNPs) on Alzheimer's disease (AD) in a rat model of AD. Twenty-eight rats were randomly divided into four groups of seven rats: control, Alz, Alz + Se, and Alz + Se-PV groups. PVA-SeNPs and SeNPs were chemically synthesized and orally administrated (0.4 mg/kg) to the AD rats for one month. AD was induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ). The memory function was assessed by the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The expression of hippocampal brain-derived neurotrophic factor (BDNF) and stress oxidative markers (MDA and TAC), and the number of amyloid-beta (Aß) plaques were assessed using ELISA kits, biochemical methods, and Congo red staining, respectively. The results of the behavioral tests showed that the discrimination index in the NOR test increased in the Alz + PVA-SeNPs group compared to the Alz group. Memory performance in the PAL task improved in the PVA-SeNPs and SeNPs groups compared to the Alz group. The level of the BDNF in both of the Alz treatment groups (PVA-SeNPs and SeNPs) showed a significant increase compared to the Alz group. MDA levels and Aß plaques decreased in both NPs-treated Alz groups, while TAC levels decreased in all Alz groups. PVA-SeNPs were more effective than SeNPs in the improvement of the cognition deficit. The results suggest that PVA-SeNPs improve the cognition and memory deficit induced by an ICV injection of STZ through a decrease in the number of Aß plaques and malondialdehyde levels and an increase in the BDNF levels.

Combined Effect of Co-administration of Stromal Cell-Derived Factor-1 and Granulocyte-Colony Stimulating Factor on Rat Model of Alzheimer's Disease.

Introduction: Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by amyloid plaque deposits, neuronal cell loss, and memory impairment. Granulocyte-colony stimulating factor (G-CSF) is a growth factor associated with AD improvement. Stromal cell-derived factor-1 (SDF-1) mediates therapeutic effects of G-CSF. This study investigated the effect of combination treatment of G-CSF and SDF-1 on amyloid plaque deposits, apoptosis, and behavior of AD rats. Methods: Intracerebroventricular amyloid-beta [Aß(1-42)] peptide was used to induce AD in Aß rats. There were six groups including naive control, sham-operated, Aß, Aß + G-CSF, Aß + SDF-1, and Aß + G-CSF + SDF-1. SDF-1 intra-cerebroventricular (ICV), G-CSF Subcutaneous (SC), or a combination of them were administered to Aß rats weekly for 2 months. The cognition and memory were assessed using the novel object recognition, passive avoidance, and Morris water maze tests. Next, rat brains were removed and the amyloid plaque and apoptosis were detected in the brain and hippocampus using immunohistochemistry and TUNEL assay, respectively. Results: The amyloid-beta and apoptotic cell levels dropped in groups receiving SDF-1 and G-CSF combination compared to the Aß group. Also, number of microglial cells increased significantly in the combination group compared to other treatment groups. Moreover, learning and memory were significantly improved in the combination group compared to the Aß groups (P < 0.05). Conclusion: SDF-1 and G-CSF combination therapy can offer a promising strategy for AD.

Chronic stimulation of the serotonergic 5-HT4 receptor modulates amyloid-beta-related impairments in synaptic plasticity and memory deficits in male rats.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory decline and impaired hippocampal synaptic plasticity. The serotonin 5-HT4 receptor is involved in learning and memory processes. This study explored the effects of chronic stimulation of 5-HT4R on cognition, memory, long-term potentiation (LTP), paired-pulse ratio (PPR), and neuronal apoptosis in a rat model of amyloid-beta (Aß)-induced AD. Thirty-five male Wistar rats were randomly divided into three groups as follows: the sham, Aß, and Aß + BIMU8 groups. Aß (6 µg/µl) was administrated by intracerebroventricular (icv) injection. The animals were treated with BIMU8 (1 µg/µL, ICV) as a 5-HT4R agonist for 30 days. Memory and behavioral changes were assessed by the passive avoidance learning, novel object recognition, open field, and elevated plus maze tests. Hippocampal synaptic plasticity was evaluated in the dentate gyrus (DG) in response to the stimulation applied to the perforant pathway. Furthermore, neuronal apoptosis was measured in the hippocampus. Data were analyzed by SPSS version 19 using one-way ANOVA, followed by Tukey's post hoc test. Aß induced memory deficits and neuronal loss and inhibited LTP induction. Aß also increased the normalized PPR. BIMU8 enhanced the slope of the field excitatory postsynaptic potential in LTP and improved cognition behavior. Paired-pulse inhibition or facilitation was not affected by LTP induction in Aß animals receiving the BIMU8. It can be concluded that the stimulation of the 5-HT4 receptor modulated the Aß-induced cognition and memory deficits, probably via a decrease in the hippocampal apoptotic neurons and an improvement in the hippocampal synaptic functions without involving its inhibitory interneurons.

Protective effect of chronic administration of pelargonidin on neuronal apoptosis and memory process in amyloid-beta-treated rats.

OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with impaired cognitive skills and learning and memory dysfunctions.  It has been suggested that pelargonidin (PG), as an antioxidant agent, has a neuroprotective effect. PG could prevent damaging effects of amyloid-beta (Aß) deposition. The aim of this study was to determine the chronic effect of PG on hippocampal neurons and memory processes in a rat model of AD. MATERIALS AND METHODS: Twenty-eight male adult rats were divided into sham, AD, AD+PG (5 µg, intracerebroventricular), and PG (5 µg, intracerebroventricular) groups. Intracerebroventricular (ICV) injection of Aß peptides (6 µg) was done using stereotaxic surgery. ICV administration of PG or saline was performed daily for 28 consecutive days. Behavioral analysis was performed using the novel object recognition (NOR) and passive avoidance tests. Neuronal apoptosis was detected using TUNEL assay in the hippocampus. RESULTS: The ICV injection of Aß reduced step-through latency and discrimination index in behavioral tests (p<0.001). Aß increased the number of apoptotic neurons (p<0.001). PG treatment decreased the time spent in the dark compartment and neuronal apoptosis in the AD+PG rats (p<0.001). PG increased the discrimination index in the NOR test (p<0.001). Although PG did not change behavioral variables, it decreased cell death in the PG group. CONCLUSION: PG attenuated neuronal apoptosis and improved cognition and memory deficiency in AD rats. The protective effect of PG against Aß may be due to its anti-apoptotic property. It is suggested that PG can be useful to treat AD.

Therapeutic effects of melatonin-treated bone marrow mesenchymal stem cells (BMSC) in a rat model of Alzheimer's disease.

The therapy based on mesenchymal stem cells(MSCs) has received growing attraction for Alzheimer's disease(AD). However, a great challenge in this regard is the low survival rate of MSCs following transplantation. This study seeks to improve the therapy based on Bone Marrow MSCs (BM-MSCs) through melatonin (MT) pre-treatment, which is 'a known antioxidant' in an animal model of AD. In this paper, we separated BMSCs from the rat tibia and femur bones and then pretreated cells were with 5µM of MT for 24 h.The sample consisted of 40 male Wistar rats randomly assigned to the control, sham,MT-pretreated BMSCs and amyloid-beta (Aß) peptide BMSCs groups.Two months after the cell transplantation,a number of tests including novel object recognition, Morris water maze, passive avoidance test, and open field test were undertaken. 69 days after the cell therapy,the rats were sacrificed.We removed brain tissues histopathological analysis and carried out immunohistochemistry for Beta tubulin, GFAP and iba1 proteins.The results suggested that both MT-BMSCs and BMSCs moved to brain tissues following the intravenous transplantation.However,MT-BMSCs had a significant effect on boosting learning, cognition and memory in comparison with BMSCs (P < 0.05). Furthermore, there was a significant rise in GFAP and Beta tubulin and substantial fall in microglial cells in the BMSCs in comparison with MT-BMSCs.Stem cell therapy has been proposed as an effective strategy for neurodegenerative diseases,but its therapeutic features are restricted.It has been shown that the pretreatment of MSCs with melatonin partly would boost cells efficiency and thereby alleviate AD complications such as memory and cognition.

Protective Effects of 5-HT1A Receptor Inhibition and 5-HT2A Receptor Stimulation Against Streptozotocin-Induced Apoptosis in the Hippocampus.

INTRODUCTION: Intracerebroventricular administration of streptozotocin (icv-STZ) induced apoptosis changes in neurons similar to Alzheimer's disease. The serotonergic system via its receptor involved in survival of neurons. The present study examined the ability of selective 5-HT1A receptor antagonist (NAD-299) and 5-HT2A receptor agonist (TCB-2) to attenuate the apoptosis caused by the icv-STZ in the rat. METHODS: The icv-STZ (3 mg/kg, 10 µL, twice) induced neuronal loss in the hippocampus of adult male rats. Animals were divided into naive control, sham-operated, STZ+saline (1 µL, icv), STZ+NAD-299 (5 µg/µL, icv), STZ+TCB-2 (5 µg/µL, icv), and STZ+NAD-299+TCB-2 (5 µg/µL of any agent, icv) groups. Following the 35 days' treatment period, neuronal apoptosis was detected using the Tunnel. Cells with morphological features of apoptotic cell were contended by microscopy. RESULTS: TCB-2 and NAD-299 administration decreased number of apoptotic neurons in the treatment group compared with the STZ group. Combined treatment of STZ rat with NAD+TCB more decreased number of apoptotic cells in compare to TCB-2 or NAD-299 treated STZ groups. CONCLUSION: Treatment with 5-HT1A receptor antagonist or 5-HT2A receptor agonist diminished apoptosis. The beneficial effect of 5HT1A receptor inhibition was potentiated with activation of 5-HT2A receptor in prevention of apoptosis in hippocampus.

Melatonin-pretreated adipose-derived mesenchymal stem cells efficeintly improved learning, memory, and cognition in an animal model of Alzheimer's disease.

Currently, mesenchymal stem cells (MSCs) based therapy has extensive attraction for Alzheimer's disease (AD). However, low survival rate of MSCs after transplantation is a huge challenging. The current study aimed to improve adipose-derived MSCs (AD-MSCs)-based therapy by their pre-treatment with melatonin (MT) 'a well-known antioxidant' in an animal model of AD. In this study, after isolating rat AD-MSCs from the epididymal white adipose tissues, the cells were pretreated with 5µM of MT for 24 hours. Forty male Wistar rats were randomly allocated to control, sham, amyloid-beta (Aß) peptide, AD-MSCs and MT-pretreated ADMSCs groups. The novel object recognition, passive avoidance test, Morris water maze and open field test were performed two months following the cell transplantation. The rats were sacrificed 69 days following cell therapy. The brain tissues were removed for histopathological analysis and also immunohistochemistry was performed for two Aß1-42 and Iba1 proteins. It has been revealed that both AD-MSCs and MT-AD-MSCs migrated to brain tissues after intravenous transplantation. However, MT-ADMSCs significantly improved learning, memory and cognition compared with AD-MSCs (P<0.05). Furthermore, clearance of Aß deposition and reduction of microglial cells were significantly increased in the MT-ADMSCs compared with AD-MSCs. Although stem cell therapy has been introduced as a promising strategy in neurodegenerative diseases, however, its therapeutic properties are limited. It is suggested that pretreatment of MSCs with melatonin partly would increase the cells efficiency and consequently could decrease AD complication including memory and cognition.

Serotonin type 6 receptor antagonist attenuates the impairment of long-term potentiation and memory induced by Abeta.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory impairment and synaptic loss. Long-term potentiation (LTP), a type of synaptic plasticity, is impaired during AD. Serotonin type 6 receptor (5-HT6R) inactivation is proposed as a therapeutic target for AD. This study examined the effects of chronic administration of the 5-HT6R antagonist, SB-258585, on cognitive, memory, and hippocampal plasticity in a rat model of AD. Abeta neurotoxicity was induced in rats using Aß (1.35 pmol intracerebroventricular [ICV] injection). The following groups were formed: control sustained surgery and saline-treated, Aß+saline (1 µL ICV for 30 days), and Aß+SB-258585 (0.024 mg/kg, ICV for 30 days). The learning and memory were tested using the novel object recognition and passive avoidance tests. Next, anesthetized rats were placed in a stereotaxic apparatus. The population spike (PS) amplitude and the slope of the excitatory postsynaptic potentials (fEPSPs) of the LTP were measured following high-frequency stimulation in the dentate gyrus. The Aß injection reduced step-through latency in the passive avoidance test and decreased the discrimination index in the novel object test. Aß diminished both the amplitude of hippocampal neuron population spikes and the slope of excitatory postsynaptic potentials, compared to the control group. The administration of SB-258585 in rats receiving Aß attenuated the Aß-induced deficits in cognition, memory, and LTP in comparison with the Aß group. It can be concluded that chronic treatment with SB-258585 antagonist can prevent Aß-related deficiencies in learning and memory performance by improving neuronal plasticity. SB-258585 can prevent the progression of AD.

Comparison of The Melatonin Preconditioning Efficacy between Bone Marrow and Adipose-Derived Mesenchymal Stem Cells.

OBJECTIVE: Mesenchymal stem cells (MSC) from various sources have the potentials to positively affect regenerative medicine. Furthermore, pre-conditioning strategies with different agents could improve the efficacy of cell therapy. This study compares the effects of an anti-inflammatory and antioxidant agent, melatonin, on protection of bone marrow-derived MSCs (BMSCs) and adipose tissue-derived MSCs (ADSCs). MATERIALS AND METHODS: In this experimental study, rat BMSCs and ADSCs were isolated and expanded. Pre-conditioning was performed with 5 µM melatonin for 24 hours. Cell proliferation and viability were detected by MTT assay. Expression of BAX, BCL2, melatonin receptors and osteocalcin genes were evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). Also, apoptosis was detected with tunnel assay. Osteogenic differentiation was analyzed using alizarin red staining. RESULTS: No significant increase was found in cell viability between BMSCs and ADSCs after melatonin preconditioning. Following melatonin preconditioning, BAX expression was significantly down-regulated in both ADSCs and BMSCs (P<0.05), with the difference being more significant in ADSCs compared to BMSCs. BCL2 expression was increased significantly in both cell types after preconditioning. Metalothionine 1 and Metalothionine 2 were both upregulated significantly in the two cell types (P<0.05). Melatonin increased osteogenesis capability through increasing osteocalcin expression. However, expression of osteocalcin in BMSCs before and after preconditioning was higher than that in ADSCs. On the other hand, melatonin expression in ADSCs was in higher levels than in BMSCs. Melatonin also improved alizarin red concentration significantly in both BMSCs and ADSCs (P<0.05). Alizarin red staining severity increased significantly in ADSCs after preconditioning compared to BMSCs (P<0.05). CONCLUSION: Here we have shown that the effects of preconditioning on melatonin expression in ADSCs are higher than those in BMSCs. These findings could be used in adoption of a proper preconditioning protocol based on the sources of MSCs in specific clinical applications, especially in bone regeneration.

Pretraining hippocampal stimulation of melatonin type 2 receptors can improve memory acquisition in rats.

BACKGROUND: Learning and memory are among the most important cognitive functions of the brain. Melatonin receptor type 2 (MT2R) is located in the hippocampus and participates in learning and memory processes. In the present study, we examined the role of hippocampal MT2R activation in the acquisition, consolidation, and retrieval of learning and memory in novel object recognition (NOR) and passive avoidance (PA) tasks. METHODS: IIK7 (0.03, 0.3, and 3 µg/µl/side), as a selective MT2R agonist, or vehicle was injected bilaterally into the dentate gyrus (DG) region of the hippocampus in rats five minutes before training, immediately after training, and five minutes before the retrieval-behavioral tasks, respectively. The discrimination index (DI) was measured in the NOR task, while step-through latency in acquisition (STLa), number of trials to acquisition (NOT), step-through latency in the retention trial (STLr), and time spent in the dark compartment (TDC) were determined in the PA task. RESULTS: The pretraining intrahippocampal injection of IIK7 at all doses significantly improved acquisition in the PA task. On the other hand, the posttraining intrahippocampal administration of IIK7 had no significant effects on consolidation. The preretrieval intrahippocampal injection of IIK7 at different doses attenuated the retrieval of memory. However, the NOR data showed that the intrahippocampal injection of IIK7 at different doses had no significant effects on the acquisition, consolidation, or retrieval in this task. DISCUSSION: Based on the findings, stimulation of MT2R could improve acquisition, whereas it had no effects on consolidation. It could impair retrieval in the PA task, while it had no effects on object recognition in rats.

Influence of hippocampal GABAB receptor inhibition on memory in rats with acute ß-amyloid toxicity.

The neurotransmitter γ-aminobutyric acid (GABA) is involved in the process of memory. It has been reported that the inhibition of GABAB receptors has beneficial effects on cognition. The aim of this study was to investigate the role of CGP35348 (a GABAB receptor antagonist) on dentate gyrus GABAB receptor inhibition and its effects on learning and memory impairments that had been induced in adult male rats by microinjection of ß-amyloid (Aß). Seventy Wistar male rats were randomly divided into seven groups: control, sham (receiving the Aß vehicle only), Aß, Aß + CGP35348 (1, 10, and 100 µg/µL), and CGP35348 alone (10 µg/µL). Memory impairment was induced by unilateral interventricular microinjection of Aß (6 µg/6 µL). Rats were cannulated bilaterally in the dentate gyrus, and then, they were treated for 20 consecutive days. Learning and memory were assessed using the novel object recognition and passive avoidance learning tests. The discrimination index and the step-through latency were significantly increased in the Aß + CGP35348 group in comparison to the Aß only group (P < 0.05 and P < 0.01, respectively). Data showed that the discrimination index was decreased in the Aß + CGP35348 group in comparison with the control group (P < 0.05) and sham group (P < 0.01). Moreover, the step-through latency was significantly decreased in the Aß + CGP35348 group in comparison to the control and sham groups (P < 0.01). Data from this study indicated that intra-hippocampal microinjection of the GABAB receptor antagonist counteracts the learning, memory, and cognitive impairments induced by Aß. It can be concluded that the GABAB receptor antagonist is a possible therapeutic agent against the progression of acute Aß toxicity-induced memory impairment.

5-Hydroxytryptamine receptor 6 antagonist, SB258585 exerts neuroprotection in a rat model of Streptozotocin-induced Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline. It has been suggested that 5-hydroxytryptamine receptor 6 (5-HT6R) might be involved in AD pathology. The aim of this study was to evaluate the effect of a 5-HT6R antagonist on cognition, learning, memory, and hippocampal apoptosis in an experimental rat model of AD. AD was induced by intracerebroventricular (icv) administration of streptozotocin (STZ; 3 mg/kg, 10 µL, twice). Adult, male rats were divided into the following groups: control, sham, AD (saline treatment, 1 µL icv for 30 days), and AD + SB258585 (5-HT6R antagonist, 1 µg/µL icv for 30 days). Following the treatment period, novel object recognition (NOR) and passive avoidance learning (PAL) tests were conducted to measure cognition, as well as learning and memory, respectively. TUNEL staining was used to evaluate apoptosis in the hippocampus. This study demonstrates that icv STZ injections induce apoptosis in hippocampal cells, decrease the NOR discrimination index, increase the number of trials needed to reach acquisition and the time spent in the dark compartment during PAL, as compared with sham and control groups. Subsequent administration of SB258585 in the STZ treated rats increased the NOR discrimination index, decreased the number of trials till acquisition and the time spent in the dark compartment during PAL, while decreasing neuronal apoptosis, as compared to the untreated AD group. Thus, we conclude that long-term administration of the 5-HT6R antagonist SB258585, ameliorates AD-associated cognitive and behavioral impairments through the suppression of apoptosis in the hippocampus.

The effect of chronic stimulation of serotonin receptor type 7 on recognition, passive avoidance memory, hippocampal long-term potentiation, and neuronal apoptosis in the amyloid ß protein treated rat.

RATIONALE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment, neuronal death, and synaptic loss in the hippocampus. Long-term potentiation (LTP), a type of synaptic plasticity, occurs during learning and memory. Serotonin receptor type 7 (5-HTR7) activation is suggested as a possible therapeutic target for AD. OBJECTIVE: The aim of the present study was to examine the effects of chronic treatment with the 5-HTR7 agonist, AS19, on cognitive function, memory, hippocampal plasticity, amyloid beta (Aß) plaque accumulation, and apoptosis in an adult rat model of AD. METHODS: AD was induced in rats using Aß (single 1 µg/µL intracerebroventricular (icv) injection during surgery). The following experimental groups were included: control, sham-operated, Aß + saline (1 µL icv for 30 days), and Aß + AS19 (1 µg/µL icv for 30 days) groups. The animals were tested for cognition and memory performance using the novel object recognition and passive avoidance tests, respectively. Next, anesthetized rats were placed in a stereotaxic apparatus for electrode implantation, and field potentials were recorded in the hippocampal dentate gyrus. Lastly, brains were removed and Aß plaques and neuronal apoptosis were evaluated using Congo red staining and TUNEL assay, respectively. RESULTS: Administration of AS19 in the Aß rats increased the discrimination index of the novel object recognition test. Furthermore, AS19 treatment decreased time spent in the dark compartment during the passive avoidance test. AS19 also enhanced both the population spike (PS) amplitude and the field excitatory postsynaptic potential (fEPSP) slope evoked potentials of the LTP components. Aß plaques and neuronal apoptosis were decreased in the AS19-treated Aß rats. CONCLUSIONS: These results indicate that chronic treatment with a 5-HTR7 agonist can prevent Aß-related impairments in cognition and memory performance by alleviating Aß plaque accumulation and neuronal apoptosis, hence improving neuronal plasticity. AS19 may be useful as a therapeutic agent for AD.

The effects of the 5-HT7 receptor on hippocampal long-term potentiation and apoptosis in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder involving synaptic loss and impairments in learning and memory. Long-term potentiation (LTP) of synaptic function is a model of learning- and memory-related neural plasticity, of which serotonin (5-HT) is a key modulator in the hippocampus. As the 5-HT7 receptor subtype is implicated in hippocampal neuronal function, dendritic rearrangement, and neurogenesis, the aim of this study was to assess the effect of 5-HT7 receptor activation on hippocampal synaptic plasticity and apoptosis in a rat model of AD. AD was induced via intracerebroventricular (icv) administration of streptozotocin (STZ). Forty adult male Wistar rats were divided into naive control, sham-operated, AD+saline (1µL icv for 30days), and AD+AS19 (a selective 5-HT7 receptor agonist, 1µg/µL, icv for 30days) groups. Following the treatment period, rats were anesthetized and placed in a stereotaxic apparatus. LTP was induced by high-frequency stimulation of the perforant pathway. The population spike (PS) and field excitatory postsynaptic potentials (fEPSP) in the dentate gyrus of the hippocampus were measured. Then, neuronal apoptosis was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The PS and fEPSP of the AD+saline group were significantly decreased compared to the control and sham-operated groups. Moreover, the PS and fEPSP of the AD+AS19 group were significantly increased compared to the AD+saline group. We found that STZ-induced AD impaired LTP in the dentate granule cells. One month of AS19 treatment restored hippocampal LTP and reduced neuronal apoptosis in the AD+AS19 group. These findings suggest that 5-HT7 receptor activation by AS19 improves synaptic dysfunction in a rat model of AD via reduction of apoptosis in the hippocampus and it could potentially prevent the progression of AD.

Study the Effect of Endocannabinoid System on Rat Behavior in Elevated Plus-Maze.

INTRODUCTION: Previous studies have shown that cannabinoidergic system is involved in anxiety. However, there are controversial reports in the experimental studies. The aim of this study is to evaluate the effect of pharmacological stimulation or blocking of CB1 receptors and inhibition of endocannabinoid degradation in anxiety like behavior in elevated plus-maze (EPM) test in rat. The EPM is one of the most widely used animal models of anxiety. METHODS: Male Wistar rats were randomly allocated to ten groups. Different groups of animals intraperitoneally received Win-55212 (0.3, 1 and 5 mg/kg) as CB1 receptor agonist, AM-251 (0.3, 1 and 5 mg/kg) as CB1 receptor antagonist, URB-597 (0.03, 0.1 and 0.3 mg/kg) as endocannabinoid breakdown inhibitor or saline (as control group) 30 min before submitting into EPM test. RESULTS: The results showed that compared to the control group, Win-55212 (1 and 5 mg/kg) and URB-597 (0.1 and 0.3 mg/kg) significantly increased both of the time and percentage of entries into open arms. AM-251 (1 and 5 mg/kg) significantly decreased the time and percentage of entries into open arms in the EPM test. These substances have no effects on the total distance covered by animals and number of closed arm entries. DISCUSSION: It is concluded that activation of cannabinoid receptor exert anxiolytic effect while blocking of cannabinoid receptor resulted in anxiety behavior. The locomotor activity was not significantly changed by cannabinoid system. It is suggested that potentiation of cannabinoid system may be therapeutic strategy for the anxiety behavior.

Investigating the effect of hydro-alcoholic extract of Salix aegyptiaca on anxiety in male rat.

BACKGROUND: Anxiety disorders are frequently common neuropsychiatric disorders. Herbal medicines are widespread and used universal as a treatment compound for anxiety. The present study investigated the effects of hydro-alcoholic extract of Salix aegyptiaca blossom on rat behavior in the elevated plus-maze (EPM) and compared results with the effects of diazepam, as a positive control drug. MATERIALS AND METHODS: Seventy adult male Wistar rats were divided into seven groups (N = 10). Animals received S. aegyptiaca extract (25, 50, 100 mg/kg) or Diazepam (0.3, 0.6, or 1.2 mg/kg) intraperitoneally and the control group was given the vehicle (10 ml/kg) 30 min before submitting into plus-maze test. The number of entries into the open and closed arms, the percentage of entries into the open arms of the EPM, and the time spent in the open arms were recorded. RESULTS: The results revealed significant increases in percentage of entries into the open arms (P < 0.01) and in the time spent in the open arms (P < 0.01) after administration of diazepam (0.3, 0.6) and S. aegyptiaca (50, 100 mg/kg) in compare with control group. S. aegyptiaca extract has no effects on the total distance covered by animals and number of closed arms entries, whereas diazepam decreased these parameters. The locomotor activity was not significantly changed by S. aegyptiaca. CONCLUSION: Single-session administration of optimum doses of total extract of S. aegyptiaca has anxiolytic effects in rat similar to the low dose of diazepam. More research is needed for better understanding of anxiolytic properties and neurobiological mechanisms of action and probable interactions of S. aegyptiaca extract with neurotransmitters.

Effects of phosphodieastrase type 5 inhibitions on morphine withdrawal symptoms in mice / Efectos comportamentales por inhibición de la fosfodiesterasa tipo 5 sobre los síntomas de abstinencia de morfina en ratones

BACKGROUND: Chronic morphine exposure creates dependence and, upon cessation, withdrawal symptoms. Studies indicate the phosphodiesterase type 5 (PDE5) inhibitor sildenafil may provide centrally mediated benefits against withdrawal, and therefore, this study evaluated morphine withdrawal signs in dependent mice with and without sildenafil treatment. METHOD: Dependence was induced by repeated treatments with morphine over 5 consecutive days. The morphine-dependent mice received sildenafil (1, 5, 10, or 20 mg/kg, i.p.) 15 min prior to the precipitation of morphine withdrawal. On the last day, naloxone was injected 2 hours after the last morphine injection, and withdrawal signs were evaluated for 30 min after naloxone injection. RESULTS: The administration of sildenafil reduced all of the morphine withdrawal symptoms. CONCLUSIONS: The administration of sildenafil diminished morphine withdrawal signs in morphine-dependent mice. We hypothesize that the mechanism involves enhanced cyclic guanosine monophosphate (cGMP) activity, but further studies are recommended for a better understanding

ANTECEDENTES: se sabe que la exposición crónica a la morfina conduce a la dependencia. El cese en el consumo de morfina conlleva al desarrollo del síndrome de abstinencia. Numerosos estudios indican los efectos beneficiosos del sildenafil en el sistema nervioso central. Es por ello que el presente estudio evaluó el efecto del sildenafil sobre el síndrome de abstinencia a la morfina. MÉTODO: los ratones dependientes de morfina recibieron dosis diferentes de sildenafil (1, 5, 10 o 20 mg/kg i.p.) 15 minutos antes de producir el síndrome de abstinencia a la morfina. En el último día, la naloxona se inyectó dos horas después de la última inyección de morfina. Los signos de abstinencia fueron evaluados durante 30 minutos después de la inyección de naloxona. RESULTADOS: la administración de sildenafil redujo todos los síntomas de abstinencia relacionados con la morfina. CONCLUSIONES: se puede concluir que la administración de sildenafil disminuyó los signos de abstinencia a la morfina. Estos resultados muestran cómo los incrementos en el nivel del GMP cíclico mediante la vía PDE5 reduce los síntomas de abstinencia a la morfina

Effects of phosphodieastrase type 5 inhibitions on morphine withdrawal symptoms in mice.

BACKGROUND: Chronic morphine exposure creates dependence and, upon cessation, withdrawal symptoms. Studies indicate the phosphodiesterase type 5 (PDE5) inhibitor sildenafil may provide centrally mediated benefits against withdrawal, and therefore, this study evaluated morphine withdrawal signs in dependent mice with and without sildenafil treatment. METHOD: Dependence was induced by repeated treatments with morphine over 5 consecutive days. The morphine-dependent mice received sildenafil (1, 5, 10, or 20 mg/kg, i.p.) 15 min prior to the precipitation of morphine withdrawal. On the last day, naloxone was injected 2 hours after the last morphine injection, and withdrawal signs were evaluated for 30 min after naloxone injection. RESULTS: The administration of sildenafil reduced all of the morphine withdrawal symptoms. CONCLUSIONS: The administration of sildenafil diminished morphine withdrawal signs in morphine-dependent mice. We hypothesize that the mechanism involves enhanced cyclic guanosine monophosphate (cGMP) activity, but further studies are recommended for a better understanding.