Curcumin attenuates memory impairments and long-term potentiation deficits by damping hippocampal inflammatory cytokines in lipopolysaccharide-challenged rats.

Neuroinflammation is a key pathological event triggering neurodegenerative process, resulting in neurologic sequelae. Curcumin (cur) has recently received increasing attention due to its anti-inflammatory properties. Therefore, we investigated the protective effects of curcumin on lipopolysaccharide (LPS)-induced memory impairments, long-term potentiation (LTP) deficits, hippocampal inflammatory cytokines, and neuronal loss in male rats. Rats were randomly divided into four groups as follows: (1) Vehicle; (2) cur; (3) LPS; and (4) cur/LPS. Following curcumin pretreatment (50 mg/kg, per oral via gavage, 14 consecutive days), animals received a single dose of LPS (1 mg/kg, intraperitoneally) or saline. Twenty-four hours after LPS/or saline administration, passive avoidance test (PAT), hippocampal LTP, inflammatory cytokines (TNFα, IL-1ß), and neuronal loss were assessed in hippocampal tissue of rats. Our results indicated that pretreatment with curcumin in LPS-challenged rats attenuates memory impairment in PAT, which was accompanied by significant increase in the field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. Hence, pretreatment with curcumin in LPS-treated rats decreased hippocampal concentration of tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß), as well as reduced neuronal loss in the hippocampal tissue. This study provide evidence that pretreatment with curcumin attenuates LPS-induced memory impairment and LTP deficiency, which may be partly related to the amelioration of inflammatory cytokines and neuronal loss in the hippocampal tissue.

Minocycline attenuates cholinergic dysfunction and neuro-inflammation-mediated cognitive impairment in scopolamine-induced Alzheimer's rat model.

OBJECTIVE: Minocycline, a semisynthetic tetracycline-derived antibiotic, has various pharmacological effect such as anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects. The current study investigated the involvement of neuro-inflammatory, oxidative stress, and cholinergic markers in neuroprotection by minocycline against scopolamine-induced brain damage. METHODS: Minocycline was administered (oral, 10, 15, and 30 mg/kg, daily) to groups of amnesic rats for 21 days. Passive avoidance memory and spatial learning and memory were assessed. Following that, oxidative stress, cholinergic function, and neuro-inflammation markers were evaluated in the brain tissue. RESULTS: According to our biochemical data, treatment of the scopolamine-injured rats with minocycline decreased the levels of malondialdehyde and acetylcholinesterase (AChE) as well as mRNA expression of AChE and neuro-inflammation markers (tumor necrosis factor-α, interleukin (IL)-1ß, IL-6). It also increased the total thiol levels and superoxide dismutase activity as well as mRNA expression of cholinergic receptor M1 (ChRM1). Moreover, minocycline modified distance and latencies in Morris water maze, prolonged latency to enter the black zone and light time while decreasing time spent and frequency of entries to darkness. CONCLUSION: Taken together, the data indicate that treatment with minocycline improved memory dysfunction mediated possibly through restoring AChE and ChRM1 levels, oxidant/antioxidant balance, as well as inhibiting inflammatory responses.

Early-life manipulation of the serotonergic system exacerbates the harmful effects of sleep deprivation on cognitive functions.

Serotonin is a monoamine neurotransmitter that plays a main role in regulating physiological and cognitive functions. Serotonergic system dysfunction is involved in the etiology of various psychiatric and neurological disorders. Therefore, the present study was designed to investigate the effects of early-life serotonin depletion on cognitive disorders caused by sleep deprivation. Serotonin was depleted by para-chlorophenylalanine (PCPA, 100 mg/kg, s.c.) at postnatal days 10-20, followed by sleep deprivation-induced through the multiple platform apparatus for 24 h at PND 60. After the examination of the novel object recognition and passive avoidance memories, the hippocampi and prefrontal cortex were dissected to examine the brain-derived neurotrophic factor (BDNF) mRNA expression by PCR. Our findings showed that postnatal serotonin depletion and sleep deprivation impaired the novel object recognition and passive avoidance memories and changed the BDNF levels. In the same way, the serotonin depletion in early life before sleep deprivation exacerbated the harmful effects of sleep deprivation on cognitive function and BDNF levels. It can be claimed that the serotonergic system plays a main role in the modulation of sleep and cognitive functions.

Cacao consumption improves passive avoidance memory impairment in a rat model of Alzheimer's disease: the role of hippocampal synaptic plasticity and oxidative stress.

Introduction: Alzheimer's disease (AD) causes progressive loss of cognitive function and synaptic plasticity, which is the most common form of dementia. The present study was designed to scrutinize the effects of cacao on passive avoidance memory function and to identify the roles of hippocampal synaptic plasticity and oxidative stress in an AD rat model induced by unilateral intracerebroventricular (UICV) injection of amyloid-beta (Aß). Methods: Oral administration of cacao (500 mg/kg/ day) was given for 2 consecutive months. A memory retention test was conducted 24 h after passive avoidance training was completed. Subsequently, the amplitude of population spike (PS) and slope of field excitatory postsynaptic potentials (fEPSPs) were assessed at hippocampal long-term potentiation (LTP) in perforant pathway-dentate gyrus (PP-DG) synapses. Moreover, total thiol group (TTG) and malondialdehyde (MDA) concentrations were evaluated in the plasma. Furthermore, compact Aß plaques were detected in the hippocampal DG by performing Congo red staining. Results: As a result of AD induction, passive avoidance memory was impaired; also, reduced fEPSP slopes, PS amplitudes, and content of TTG, and increase in MDA levels in the rats were observed. In contrast, cacao treatment ameliorated passive avoidance memory impairment, improved hippocampal LTP impairment, modulated oxidative-antioxidative status, and delayed Aß plaques production in AD rats. Disscussion: Conclusively, cacao alleviates Aß-induced cognitive deficit, probably by the amelioration of hippocampal LTP impairment, modulation of oxidative-antioxidative status, and inhibition of Aß plaque accumulation.

Protective effects of selegiline against amyloid beta-induced anxiety-like behavior and memory impairment.

BACKGROUND: Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various aspects of memory performance, anxiety, and oxidative stress in an AD rat model induced by intracerebroventricular injection of amyloid beta1-42 (Aß1-42). METHODS: Oral administration of SEL at a dose of 0.5 mg/kg/day was performed for 30 consecutive days. Following the 30 days, several tests, including the open-field, elevated plus-maze, novel object recognition, Morris water maze, and passive avoidance learning were conducted to assess locomotor activity, anxiety-like behavior, recognition memory, spatial memory, and passive avoidance memory, respectively. RESULTS: The results indicate that the induction of AD in rats led to recognition memory, spatial memory, and passive avoidance memory impairments, as well as increased anxiety. Additionally, the AD rats exhibited a decrease in total antioxidant capacity and an increase in total oxidant status levels, suggesting an imbalance in oxidative-antioxidant status. However, the administration of SEL improved memory performance, reduced anxiety, and modulated oxidative-antioxidant status in AD rats. CONCLUSIONS: These findings provide evidence that SEL may alleviate anxiety-like behavior and cognitive deficits induced by Aß through modulation of oxidative-antioxidant status.

Interaction effect of crocin and citalopram on memory and locomotor activity in rats: an insight into BDNF and synaptophysin levels in the hippocampus.

Selective serotonin reuptake inhibitors (SSRIs) are widely used drugs for the treatment of depression. Citalopram is one of the most prescribed SSRIs that is useful for the treatment of depression, obsessive-compulsive disorder, and anxiety disorders. On the other hand, crocin (active constitute of saffron) has pro-cognitive and mood enhancer effects. Also, both citalopram and crocin affect the function and expression of brain-derived neurotrophic factor (BDNF) and synaptophysin, two molecular factors that are involved in cognitive functions and mood. In the present study, we aim to investigate the interaction effect of citalopram and crocin on rats' performance in the open field test (locomotor activity and anxiety-like behavior) and the shuttle box (passive avoidance memory). Citalopram was injected at the doses of 10, 30, and 50 mg/kg, and crocin was injected at the dose of 50 mg/kg; all administrations were intraperitoneal. Real-time PCR was used to assess the expression level of BDNF and synaptophysin in the hippocampus. The results showed that citalopram (30 and 50 mg/kg) impaired passive avoidance memory and decreased BDNF and synaptophysin expression in the hippocampus, while crocin reversed memory impairment, and BDNF and synaptophysin expression in the hippocampus of rats received citalopram 30 mg/kg. Also, crocin partially showed these effects in rats that received citalopram 50 mg/kg. The results of the open field test were unchanged. In conclusion, we suggested that BDNF and synaptophysin may be involved in the effects of both citalopram and crocin.

Uncovering the protective potential of vanillic acid against traumatic brain injury-induced cognitive decline in male rats: Insights into underlying mechanisms.

Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and there is still no specific drug available to treat cognitive deficits in survivors. Vanillic acid (VA), a bioactive phenolic compound, has shown protective effects in various models of neurodegeneration; however, its impact on TBI outcomes remains elusive. Therefore, this study aimed to elucidate the possible role of VA in ameliorating TBI-induced cognitive decline and to reveal the mechanisms involved. TBI was induced using the Marmarou impact acceleration model to deliver an impact force of 300 g, and treatment with VA (50 mg/kg; P.O.) was initiated 30 minutes post-TBI. The cognitive performance, hippocampal long-term potentiation (LTP), oxidative stress markers, neurological function, cerebral edema, and morphological changes were assessed at scheduled points in time. TBI resulted in cognitive decline in the passive avoidance task, impaired LTP in the perforant path-dentate gyrus (PP-DG) pathway, increased hippocampal oxidative stress, cerebral edema, neurological deficits, and neuronal loss in the rat hippocampus. In contrast, acute VA administration mitigated all the aforementioned TBI outcomes. The data suggest that reducing synaptic plasticity impairment, regulating oxidative and antioxidant defense, alleviating cerebral edema, and preventing neuronal loss by VA can be at least partially attributed to its protection against TBI-induced cognitive decline.

Geraniol improves passive avoidance memory and hippocampal synaptic plasticity deficits in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most progressive and irreversible neurodegenerative disease that leads to synaptic loss and cognitive decline. The present study was designed to evaluate the effects of geraniol (GR), a valuable acyclic monoterpene alcohol, with protective and therapeutic effects, on passive avoidance memory, hippocampal synaptic plasticity, and amyloid-beta (Aß) plaques formation in an AD rat model induced by intracerebroventricular (ICV) microinjection of Aß1-40. Seventy male Wistar rats were randomly into sham, control, control-GR (100 mg/kg; P.O. (orally), AD, GR-AD (100 mg/kg; P.O.; pretreatment), AD-GR (100 mg/kg; P.O.; treatment), and GR-AD-GR (100 mg/kg; P.O.; pretreatment & treatment). Administration of GR was continued for four consecutive weeks. Training for the passive avoidance test was carried out on the 36th day and a memory retention test was performed 24 h later. On day 38, hippocampal synaptic plasticity (long-term potentiation; LTP) was recorded in perforant path-dentate gyrus (PP-DG) synapses to assess field excitatory postsynaptic potentials (fEPSPs) slope and population spike (PS) amplitude. Subsequently, Aß plaques were identified in the hippocampus by Congo red staining. The results showed that Aß microinjection increased passive avoidance memory impairment, suppressed of hippocampal LTP induction, and enhanced of Aß plaque formation in the hippocampus. Interestingly, oral administration of GR improved passive avoidance memory deficit, ameliorated hippocampal LTP impairment, and reduced Aß plaque accumulation in the Aß-infused rats. The results suggest that GR mitigates Aß-induced passive avoidance memory impairment, possibly through alleviation of hippocampal synaptic dysfunction and inhibition of Aß plaque formation.

The effect of ghrelin injection in the CA1 region of hippocampus on the MK801- induced memory impairment in wistar rats.

N-Methyl-D-Aspartate (NMDA) receptors are critically involved in the learning and memory formation and dizocilpine (MK-801) is an antagonist of NMDA receptor. Ghrelin plays a crucial role in learning and memory processes. The present study was conducted to the evaluation of ghrelin effect on passive avoidance memory impairment induced by MK801. In this experimental study, 24 male wistar rats were randomly distributed into 3 groups of 8 each. Passive avoidance tests of animals were evaluated using Shuttle Box apparatus. One week after the surgery, ghrelin (3 nmol) was injected intra-hippocampally, 5 min before the MK-801administration. MK-801 (0.15 mg/kg) was injected intraperitoneally (i.p.), 10 min before the test session. Pre-test injection of MK-801 significantly decreased STL (step through latency) at 24 h and 48 h (P < 0.001) and 10 days (P < 0.01) and increased TDC (time spent in dark compartment) at 24 h, 48 h and 10 days (P < 0.001) after training in comparison with control group. Pre-test injection of ghrelin + MK-801 significantly increased STL at 24 h (P < 0.01), 48 h and 10 days (P < 0.001) and decreased TDC at 24 h, 48 h and 10 days (P < 0.001) after training in comparison with MK-801 received group. It is concluded that pre-test injection of MK-801 impaired passive avoidance memory. Administration of ghrelin before MK-801 ameliorated memory impairment induced by MK-801. It is assumed that this compensative effect of ghrelin was mediated by NMDA receptor.

The effect of GABA-B receptors in the basolateral amygdala on passive avoidance memory impairment induced by MK-801 in rats.

MK-801 (dizocilpine) is a potent non-competitive N-methyl-[D]-aspartate (NMDA) receptor antagonist that affects cognitive function, learning, and memory. As we know, NMDA receptors are significantly involved in memory function, as well as GABA (Gamma-Aminobutyric acid) receptors. In this study, we aimed to discover the effect of GABA-B receptors in the basolateral amygdala (BLA) on MK-801-induced memory impairment. We used 160 male Wistar rats. The shuttle box was used to evaluate passive avoidance memory and locomotion apparatus was used to evaluate locomotor activity. MK-801 (0.125, 0.25, and 0.5 µg/rat), baclofen (GABA-B agonist, 0.0001, 0.001, and 0.01 µg/rat) and phaclofen (GABA-B antagonist, 0.0001, 0.001, and 0.01 µg/rat) were injected intra-BLA, after the training. The results showed that MK-801 at the dose of 0.5 µg/rat, baclofen at the doses of 0.001 and 0.01 µg/rat, and phaclofen at the doses of 0.001 and 0.01 µg/rat, impaired passive avoidance memory. Locomotor activity did not alter in all groups. Furthermore, the subthreshold dose of both baclofen (0.0001 µg/rat) and phaclofen (0.0001 µg/rat) restored the impairment effect of MK-801 (0.5 µg/rat) on memory. Also, both baclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 µg/rat) and phaclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 and 0.25 µg/rat) on passive avoidance memory. In conclusion, our results indicated that BLA GABA-B receptors can alter the effect of NMDA inactivation on passive avoidance memory.

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

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

Ghrelin Is Effective on Passive Avoidance Memory by Altering the Expression of NMDAR and HTR1a Genes in the Hippocampus of Male Wistar Rats.

BACKGROUND: Memory-dependent psychological behaviors have an important role in life. Memory strengthening in adulthood to prevent its defects in aging is a significant issue. The ghrelin endogenous hormone improves memory by targeting glutamatergic and serotonergic circuits. Also, citicoline, a memory strengthening drug in aging, is not recommended to adults due to its side effects. The current study aims to test that ghrelin treatment, like citicoline, would improve passive avoidance memory via expression of the genes encoding the N-methyl-D-aspartate receptor (NMDAR1) and the serotonin receptor 1A (HTR1α) involved in this process. METHODS: Five groups of adult male rats received (1) saline (as control), (2) 0.5 mg/kg citicoline, or (3-5) 0.3, 1.5, and 3 nmol/µl ghrelin). The rats received the drugs via intra-hippocampal injection. Passive avoidance memory was determined using a shuttle box device. The latency to enter the dark chamber before (IL) and after (RL) injection and the total duration of the animal's presence in the light compartment (TLC) were evaluated. Then, the gene expression rates of NMDAR1 and HTR1α were measured by the Real-Time PCR. RESULTS: Ghrelin and citicoline had some similar and significant effects on passive avoidance memory, and both increased NMDAR1 and decreased HTR1α expression. CONCLUSION: Ghrelin, like citicoline, improves passive avoidance learning by altering the NMDAR1 and HTR1α expression in the hippocampus.

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

OBJECTIVES: This study aimed at investigating the effect of serotonergic 5-HT4 receptor agonist/antagonist on memory consolidation deficit induced by ACPA (a potent, selective CB1 cannabinoid receptor agonist) in the pre-limbic (PL) cortex. MATERIALS AND METHODS: We used the step-through passive avoidance test to evaluate memory consolidation of male Sprague-Dawley (SD) rats. Bilateral post-training microinjections of the drugs were done in a volume of 0.6 µl/rat into the PL area (0.3 µl per side). RESULTS: The results showed a significant interaction between RS67333 hydrochloride (5-HT4 receptor agonist) or RS23597-190 hydrochloride (5-HT4 receptor antagonist) and ACPA on consolidation of aversive memory. RS67333 hydrochloride (0.5 µg/rat) enhanced consolidation of memory and its co-administration at the ineffective dose of 0.005 µg/rat with ineffective (0.001 µg/rat) or effective (0.1 µg/rat) doses of ACPA improved and prevented impairment of memory caused by ACPA, respectively. In other words, RS67333 had a bidirectional effect on ACPA-caused amnesia. While RS23597-190 hydrochloride had no effect on memory at the doses used (0.005, 0.01, 0.1, or 0.5 µg/rat); but its concomitant use with an effective dose of ACPA (0.1 µg/rat) potentiated amnesia. None of the drugs had an effect on locomotor activity. CONCLUSION: This study revealed that activation or deactivation of the 5-HT4 receptors in the PL may mediate the IA memory impairment induced by ACPA indicating a modulatory role for the 5-HT4 serotonergic receptors.

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

BACKGROUND: Evidence shows the vital role of sleep in the modulation of cognitive functions. Sleep deprivation (SD) can disrupt learning and memory processes. SD also affects pain perception and locomotor activity. Furthermore, alpha lipoic acid (ALA) may induce antioxidant and neuroprotective effects. ALA affects memory processes, pain subthreshold, and locomotor activity. The goal of the present study was to investigate the effect of REM (rapid-eye movement) SD and ALA on social and passive avoidance memory, locomotor activity, and pain perception. METHODS: Multiple-platform apparatus was used to induce REM SD for 24 h. Three-chamber paradigm test, the shuttle box, locomotion apparatus, and hot plate were used to assess social interaction memory, passive avoidance memory, locomotor activity, and pain perception, respectively. ALA was injected intraperitoneally at the doses of 35 and 70 mg/kg. RESULTS: 24 h REM SD impaired both types of memory. In addition, ALA (35 mg/kg) reversed REM SD-induced memory impairments. However, ALA (70 mg/kg) impaired social memory with no effect on REM SD-induced memory impairments. ALA (70 mg/kg) also decreased pain subthreshold in REM SD rats. CONCLUSION: REM SD impairs social interaction and passive avoidance memory. Furthermore, ALA may exhibit a dose-dependent manner in some cognitive tasks. ALA can induce a therapeutic effect at one dose, and an impairment effect at another dose (lower or higher), while the cognitive task and the conditions are equal.

Effects of exposure to enriched environment during adolescence on passive avoidance memory, nociception, and prefrontal BDNF level in adult male and female rats.

Previous studies demonstrated that an enriched environment (EE) exposure improves cognitive functions, synaptic plasticity, neurogenesis, and induction of brain-derived neurotrophic factor (BDNF) in multiple brain regions of laboratory animal models. Also, studies on the sex-dependent effects of exposure to EE during adolescence on adult cognitive functions are less. Therefore, the present experiment was aimed to assess the effects of EE during adolescence on passive avoidance learning and memory, nociception, and prefrontal cortex (PFC) BDNF mRNA levels in the adult male and female rats. Our results indicated that housing in the EE during adolescence improves passive avoidance memory and increases nociceptive response against thermal stimulus in both sexes. Findings of our study also showed an increased BDNF level in the PFC of female animals. As a result, sex differences can affect the expression of BDNF mRNA in the PFC. Further research concerning the precise mechanisms underlying sex hormone-dependent production of BDNF in PFC is critical.

Sex and Time-of-Day Impact on Anxiety and Passive Avoidance Memory Strategies in Mice.

In humans, anxiety and cognitive processes are age, gender, and time of day dependent. The purpose of the present study was to assess whether the time of day and sex have an influence on anxiety and emotional memory in adult mice. Light-dark and passive avoidance (PA) tests were performed at the beginning and at the end of the light cycle, defined as Zeitgeber time (ZT) ZT0-2.5 and ZT9.5-12, respectively. A baseline difference in anxiety was not found, but on the 24 h retention trial of the PA test, females presented longer latencies to enter into the dark compartment at the ZT0-2.5 time point of the day. The data from the second test day (PA reversal trial) indicated that some animals associated the dark compartment with an aversive stimulus (shock), while others associated the aversive stimulus with crossing from one compartment to another. At the ZT9.5-12, female mice mainly related the aversive stimulus to transferring from one compartment to another, while male mice associated darkness with the aversive stimulus. There was a negative correlation between the frequency of light-dark transitions in the light-dark test and the PA latency on the 24 h retention trial in males tested at ZT0-2.5. The PA latency on the reversal and 24 h retention trials negatively correlated with a risk assessment behavior in male mice tested on ZT0-2.5 and ZT9.5-12, respectively. In conclusion, our data reveal that the impact of motor activity and risk assessment behavior on PA memory formation and applied behavioral strategies are time of day and sex dependent.

Effects of precondition α2-adrenoceptor agents on memory- and anxiety-related processes in the transient cerebral ischemic rats.

Neurological evidence for the neuroprotective function of α2-adrenoceptors in the cerebral ischemia is inconsistent. It is not examined how pretreatment with a single dose of α2-adrenoceptor agents can affect motor function and anxiety- and memory-related responses in the cerebral ischemic animals. The transient forebrain ischemia model was provided, using a bilateral common carotid arterial occlusion (two-vessel occlusion, 2VO) in male Wistar rats. The 2VO rats impaired motor functions in the Rota-rod and wire grip tests and also decreased the step-through latency and the percentage of time spent on the open arms (%OAT), the percentage of entries into the open arms (%OAE) as well as locomotion in the elevated plus maze (EPM), indicating a memory deficit and anxiety-like behavior. Intraperitoneal single administration of yohimbine (0, 0.001, 0.01, and 0.1 mg/kg) before the 2VO did not alter these parameters while the higher and middle doses of clonidine (0.01 and 0.1 mg/kg) prevented the memory deficit and hypo-locomotion and its middle dose abrogated Rota-rod dysfunction and anxiety-like response. Meanwhile, both drugs did not influence on the measured behaviors in the sham groups by themselves. Moreover, yohimbine (0.001 mg/kg) abolished the beneficial effects of clonidine (0.01 and 0.1 mg/kg) on motor function in the Rota-rod and memory retention and also at its middle dose on the %OAT and locomotion in the 2VO rats. Our findings show a neuroprotective role for clonidine in motor function and memory- and anxiety-related behaviors of 2VO rats and the importance of α2-adrenoceptors in these processes.

Cross state-dependent memory retrieval between morphine and norharmane in the mouse dorsal hippocampus.

State-dependent memory (SDM) describes a phenomenon that memory is efficiently restored only when the brain state during restoration matches the state during encoding. Some psychoactive drugs such as morphine, ethanol, and cocaine evoke SDM. The scope of this study was to investigate the cross SDM between morphine and norharmane injected into the dorsal hippocampus of male NMRI mice, and the involvement of µ-opioid receptors (MORs) in the SDM of the drugs. Bilateral cannulae were implanted into the CA1 regions (intra-CA1), and memory retrieval was measured by the step-down apparatus. Results showed that pre-test microinjection of morphine (1 µg/mouse, intra-CA1) reversed amnesia induced by pre-training administration of the same dose of morphine, indicating morphine SDM. Moreover, norharmane (10 µg/mouse) also exerted a SDM. Pre-test microinjection of naloxone (0.5 µg/mouse) abolished amnesia induced by morphine or norharmane, and impaired SDM produced by each drug. The results demonstrated the contribution of MORs in the SDM induced by morphine as well as norharmane. Pre-test administration of morphine (1 µg/mouse, intra-CA1) also inhibited amnesia induced by pre-training intra-CA1 microinjection of norharmane (10 µg/mouse) and vice versa, suggesting a cross SDM between the drugs. In conclusion, it seems that there may be a cross SDM between morphine and norharmane, and MORs have a critical role in this phenomenon.

Enhanced Expression of Secreted α-Klotho in the Hippocampus Alters Nesting Behavior and Memory Formation in Mice.

The klotho gene family consists of α-, ß-, and γ-Klotho, which encode type I single-pass transmembrane proteins with large extracellular domains. α-Klotho exists as a full-length membrane-bound and as a soluble form after cleavage of the extracellular domain. Due to gene splicing, a short extracellular Klotho form can be expressed and secreted. Inactivation of α-Klotho leads to a phenotype that resembles accelerated aging, as the expression level of the α-Klotho protein in the hippocampal formation of mice decreases with age. Here, we show that intrahippocampal viral expression of secreted human α-Klotho alters social behavior and memory formation. Interestingly, overexpression of secreted human α-Klotho in the CA1 changed the nest-building behavior and improved object recognition, object location and passive avoidance memory. Moreover, α-Klotho overexpression increased hippocampal synaptic transmission in response to standardized stimulation strengths, altered paired-pulse facilitation of synaptic transmission, and enhanced activity-dependent synaptic plasticity. These results indicate that memory formation benefits from an augmented level of secreted α-Klotho.

Effect of gallic acid on chronic restraint stress-induced anxiety and memory loss in male BALB/c mice.

OBJECTIVES: Long-term exposure to stress leads to memory deficits and certain mood disorders such as depression and anxiety. We aimed to study the effect of gallic acid (GA) on chronic restraint stress (CRS) induced anxiety and memory deficits in male BALB/c mice. MATERIALS AND METHODS: Ninety male BALB/c mice were assigned to nine groups including caged control (CC): food-water deprived (FWD), under chronic restraint stress (CRS), CRS+ gallic acid (5, 10, and 20 mg/kg), and gallic acid (5, 10, and 20 mg/kg). Behavioral assays were performed after 21 days of daily treatment with CRS and GA. Serum and brain levels of malondialdehyde (MDA) and total antioxidant capacity (TCA) and serum corticosterone level were also measured. RESULTS: Treatment of CRS mice with GA significantly improved passive avoidance memory in the shuttle box and ameliorated anxiety-like behaviors in the elevated plus maze (EPM) and open filed test (OFT). GA treatment significantly reduced elevated levels of serum and brain MDA and increased brain TCA. CRS and GA did not affect serum corticosterone levels. Treatment of healthy mice with GA had some adverse effects and induced some anxiety and oxidative stress. CONCLUSION: GA exerted protective effects against stress-induced mood and memory deficit disorders.