Impaired Inhibitory Avoidance Research Articles

Rottlerin, BDNF, and the impairment of inhibitory avoidance memory.

As a eukaryotic elongation factor 2 kinase (eEF2K) inhibitor and a mitochondrial uncoupler, oncologists have extensively studied rottlerin. Neuroscientists, however, have accumulated scarce data on the role of rottlerin in affective and cognitive functions. Only two prior studies have, respectively, documented its antidepressant-like effect and how it impairs psychostimulant-supported memory. Whether or not rottlerin would affect aversive memory remains unknown. Hence, we sought to investigate the effects of rottlerin on aversive memory in the inhibitory avoidance (IA) task in mice. Male C57BL/6J mice were trained to acquire the IA task. Rottlerin (5 mg/kg, i.p. or 3 μg bilaterally in the hippocampus) or the vehicle was administered before footshock training (acquisition), after footshock training (consolidation), after the memory reactivation (reconsolidation), and before the test (retrieval) in the IA task. Systemic and intrahippocampal rottlerin impaired the acquisition, consolidation, and retrieval of IA memory, without affecting the reconsolidation process. Rottlerin (5 mg/kg, i.p.) induced a fast-onset and long-lasting increase in the brain-derived neurotrophic factor (BDNF) protein levels in the mouse hippocampus. Systemic injection of 7,8-dihydroxyflavone (7,8-DHF, 30 mg/kg), a BDNF tropomyosin receptor kinase B (TrkB) agonist impaired IA memory consolidation, and treatment with K252a (5 μg/kg), a Trk receptor antagonist, reversed the suppressing effect of rottlerin on IA memory consolidation. Rottlerin impairs IA memory consolidation through the enhancement of BDNF signaling in the mouse hippocampus. Excessive brain BDNF levels can be detrimental to cognitive function. Rottlerin is likely to affect the original memory-associated neuroplasticity. Thus, it can be combined with exposure therapy to facilitate the forgetting of maladaptive aversive memory, such as post-traumatic stress disorder (PTSD).

Pyriproxyfen Exposure Impairs Cognitive Parameters and Alters Cortisol Levels in Zebrafish.

Pyriproxyfen is one of the most used larvicides and insecticides; it acts as an analog of juvenile insect hormone (a growth regulator). It is highly toxic during all stages of mosquito development, suppresses metamorphosis, and interferes in insect reproduction and proliferation. Pyriproxyfen and its main metabolite have been shown to affect brain development in rodents. This compound is employed mainly to eliminate outbreaks of the genus Aedes, even in potable water. Despite the increasing number of toxicological studies about larvicides and insecticides—with an indication of continuous use—there have been few studies about the effects of pyriproxyfen in non-target species such as fish. This study evaluated the effects of pyriproxyfen on behavioral, cognitive, and endocrine parameters in zebrafish. We exposed adult zebrafish to different pyriproxyfen (Pestanal®) concentrations (0.125, 0.675, and 1.75 mg/l) for 96 h. We analyzed behavioral parameters, memory, cortisol levels, and gene expression of glucocorticoid receptor (gr) and corticotrophin-releasing factor (crf) after pyriproxyfen exposure. This exposure did not alter locomotion (distance or mean speed), anxiety-like behavior (latency to enter to the top zone of the tank or time in the top zone of the tank), and social or aggressive behavior. However, there was impaired inhibitory avoidance memory at all tested pyriproxyfen concentrations. Cortisol levels were reduced in exposed groups when compared to control or vehicle. However, gr and crf gene expression in pyriproxyfen-treated animals were unaltered when compared to control or vehicle groups. Taken together, these findings indicate that pyriproxyfen may induce cognitive impairment and altered cortisol levels in zebrafish, a non-target species.

Ketamine effects on anxiety and fear-related behaviors: Current literature evidence and new findings

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, presents a rapid and sustained antidepressant effect in clinical and preclinical studies. Regarding ketamine effects on anxiety, there is a widespread discordance among pre-clinical studies. To address this issue, the present study reviewed the literature (electronic database MEDLINE) to summarize the profile of ketamine effects in animal tests of anxiety/fear. We found that ketamine anxiety/fear-related effects may depend on the anxiety paradigm, schedule of ketamine administration and tested species. Moreover, there was no report of ketamine effects in animal tests of fear related to panic disorder (PD). Based on that finding, we evaluated if treatment with ketamine and another NMDA antagonist, MK-801, would induce acute and sustained (24 hours later) anxiolytic and/or panicolytic-like effects in animals exposed to the elevated T-maze (ETM). The ETM evaluates, in the same animal, conflict-evoked and fear behaviors, which are related, respectively, to generalized anxiety disorder and PD. Male Wistar rats were systemically treated with racemic ketamine (10, 30 and 80 mg/kg) or MK-801 (0.05 and 0.1 mg/kg) and tested in the ETM in the same day or 24 hours after their administration. Ketamine did not affect the behavioral tasks performed in the ETM acutely or 24 h later. MK-801 impaired inhibitory avoidance in the ETM only at 45 min post-injection, suggesting a rapid but not sustained anxiolytic-like effect. Altogether our results suggest that ketamine might have mixed effects in anxiety tests while it does not affect panic-related behaviors.

Pentylenetetrazol and Morphine Interaction in a State-dependent Memory Model: Role of CREB Signaling.

Introduction:State-dependent (STD) memory is a process, in which the learned information can be optimally retrieved only when the subject is in the state similar to the encoding phase. This phenomenon has been widely studied with morphine. Several studies have reported that Pentylenetetrazole (PTZ) impairs memory in experimental animal models. Due to certain mechanistic interactions between morphine and PTZ, it is hypothesized that PTZ may interfere with the morphine-STD. The cyclic adenosine monophosphate Response Element-Binding (CREB) is considered as the main downstream marker for long-term memory. This study was designed to determine the possible interaction between PTZ and morphine STD and the presumable changes in CREB mRNA.Methods:In an Inhibitory Avoidance (IA) model, posttraining morphine (2.5, 5, and 7.5 mg/ kg-i.p.) was used. The pre-test morphine was evaluated for morphine-induced STD memory. Moreover, the effect of a pre-test PTZ (60 mg/kg-i.p.) was studied along with morphine STD. Locomotion testing was carried out using open-field. Eventually, using real-time-PCR, the CREB mRNA changes in the hippocampus were evaluated.Results:Posttraining MOR (7.5 mg/kg-i.p.) impaired IA memory (P<0.001). The pre-test injection of similar doses of morphine recovered the morphine-induced memory impairment (P<0.001). The pre-test PTZ impaired the IA memory recall (P<0.001); however, the pre-test PTZ along with morphine STD potentiated the morphine-induced STD (P<0.001). Alterations in CREB mRNA were observed in all groups. No difference was seen in the locomotor activity.Conclusion:Presumably, the certain interactive effect of PTZ on morphine-induced STD is mediated through gamma-aminobutyric acid and opioid systems via CREB signaling.

Iron Overload Impairs Autophagy: Effects of Rapamycin in Ameliorating Iron-Related Memory Deficits.

Over the years, iron accumulation in specific brain regions has been observed in normal aging and related to the pathogenesis of neurodegenerative disorders. Many neurodegenerative diseases may involve cognitive dysfunction, and we have previously shown that neonatal iron overload induces permanent cognitive deficits in adult rats and exacerbates age-associated memory decline. Autophagy is a catabolic pathway involved in the removal of toxic protein aggregates, which are a hallmark of neurodegenerative events. In the present study, we investigated whether iron accumulation would interfere with autophagy and also sought to determine the effects of rapamycin-induced stimulation of autophagy in attenuating iron-related cognitive deficits. Male Wistar rats received a single daily oral dose of vehicle or iron carbonyl (30 mg/kg) at postnatal days 12-14. In adulthood, they received daily intraperitoneal injections of vehicle or rapamycin (0.25 mg/kg) for 14 days. Results showed that iron given in the neonatal period impaired inhibitory avoidance memory and induced a decrease in proteins critically involved in the autophagy pathway, Beclin-1 and LC3, in the hippocampus. Rapamycin in the adulthood reversed iron-induced memory deficits, decreased the ratio phospho-mTOR/total mTOR, and recovered LC3 II levels in iron-treated rats. Our results suggest that iron accumulation, as observed in neurodegenerative disorders, hinders autophagy, which might play a role in iron-induced neurotoxicity. Rapamycin, by inducing authophagy, was able to ameliorate iron-induced cognitive impairments. These findings support the use of rapamycin as a potential neuroprotective treatment against the cognitive decline associated to neurodegenerative disorders.

Effects Following Intracerebroventricular Injection of Immunosuppressant Cyclosporine A On Inhibitory Avoidance Learning and Memory in Mice

Background: Protein phosphatase-2B or calcineurin (CN) is the main phosphatase and a critical regulator of cellular pathways for learning, memory, and plasticity. Cyclosporine A(CyA), a phosphatase and peptidyl-prolyl cis/trans isomerase inhibitor, is a common immune suppressant extensively used in tissue transplantation. To further clarify the role of CN in different stages of learning and memory, the aim of the present study was to evaluate the role of CyA in an inhibitory avoidance (IA) model in mice.Materials and Methods: Using intracerebroventricular (ICV) injection of different doses of CyA (0.5, 5, and 50 nM) at different periods (pre-/post-training and pre-test), the effect of the drug was evaluated in a step-down IA paradigm. The latency of step-down (sec) was considered a criterion for memory performance. Results: The pre-training injections of CyA (0.5, 5 nM), however not of 50 nM, impaired IA learning acquisition. The post-training injection of high-dose CyA (50 nM) impaired memory consolidation. The pre-test ICV CyA injection did not impair memory retrieval; the ICV injection of CyA caused no change in locomotion. Conclusion: These findings suggest that CyA selectively interferes with acquisition, retention, but not retrieval, of information processing in mice. Given the crucial role of CN in common signaling pathway of memory performance and cognition, it could be a probable therapeutic target in the treatment of a wide variety of neurological conditions involving memory. [GMJ.2018;7:e1044]

Effects Following Intracerebroventricular Injection of Immunosuppressant Cyclosporine A On Inhibitory Avoidance Learning and Memory in Mice

Background: Protein phosphatase-2B or calcineurin (CN) is the main phosphatase and a critical regulator of cellular pathways for learning, memory, and plasticity. Cyclosporine A(CyA), a phosphatase and peptidyl-prolyl cis/trans isomerase inhibitor, is a common immune suppressant extensively used in tissue transplantation. To further clarify the role of CN in different stages of learning and memory, the aim of the present study was to evaluate the role of CyA in an inhibitory avoidance (IA) model in mice.&#x0D; Materials and Methods: Using intracerebroventricular (ICV) injection of different doses of CyA (0.5, 5, and 50 nM) at different periods (pre-/post-training and pre-test), the effect of the drug was evaluated in a step-down IA paradigm. The latency of step-down (sec) was considered a criterion for memory performance.&#x0D; Results: The pre-training injections of CyA (0.5, 5 nM), however not of 50 nM, impaired IA learning acquisition. The post-training injection of high-dose CyA (50 nM) impaired memory consolidation. The pre-test ICV CyA injection did not impair memory retrieval; the ICV injection of CyA caused no change in locomotion.&#x0D; Conclusion: These findings suggest that CyA selectively interferes with acquisition, retention, but not retrieval, of information processing in mice. Given the crucial role of CN in common signaling pathway of memory performance and cognition, it could be a probable therapeutic target in the treatment of a wide variety of neurological conditions involving memory. [GMJ.2018;7:e1044]

Effects Following Intracerebroventricular Injection of Immunosuppressant Cyclosporine A On Inhibitory Avoidance Learning and Memory in Mice.

Background: Protein phosphatase-2B or calcineurin (CN) is the main phosphatase and a critical regulator of cellular pathways for learning, memory, and plasticity. Cyclosporine A(CyA), a phosphatase and peptidyl-prolyl cis/trans isomerase inhibitor, is a common immune suppressant extensively used in tissue transplantation. To further clarify the role of CN in different stages of learning and memory, the aim of the present study was to evaluate the role of CyA in an inhibitory avoidance (IA) model in mice. Materials and Methods: Using intracerebroventricular (ICV) injection of different doses of CyA (0.5, 5, and 50 nM) at different periods (pre-/post-training and pre-test), the effect of the drug was evaluated in a step-down IA paradigm. The latency of step-down (sec) was considered a criterion for memory performance. Results: The pre-training injections of CyA (0.5, 5 nM), however not of 50 nM, impaired IA learning acquisition. The post-training injection of high-dose CyA (50 nM) impaired memory consolidation. The pre-test ICV CyA injection did not impair memory retrieval; the ICV injection of CyA caused no change in locomotion. Conclusion: These findings suggest that CyA selectively interferes with acquisition, retention, but not retrieval, of information processing in mice. Given the crucial role of CN in common signaling pathway of memory performance and cognition, it could be a probable therapeutic target in the treatment of a wide variety of neurological conditions involving memory.

Exposure to GSM 900-MHz mobile radiation impaired inhibitory avoidance memory consolidation in rat: Involvements of opioidergic and nitrergic systems

The use of mobile phones is increasing, and the main health concern is the possible deleterious effects of radiation on brain functioning. The present study aimed to examine the effects of exposure to a global system for mobile communication (GSM) with mobile phones on inhibitory avoidance (IA) memory performance as well as the involvement of endogenous opioids and nitric oxide (NO) in this task. Male Wistar rats, 10–12 weeks old, were used. The results showed that four weeks of mobile phone exposure impaired IA memory performance in rats. The results also revealed that post-training, but not pre-training, as well as pre-test intracerebroventricular (i.c.v.) injections of naloxone (0.4, 4 and 40 ng/rat), dose-dependently recovered the impairment of IA memory performance induced by GSM radiation. Additionally, the impairment of IA memory performance was completely recovered in the exposed animals with post-training treatment of naloxone (40 ng/rat) plus pre-test i.c.v. injections of L-arginine (100 and 200 nmol/rat). However, pre-test i.c.v. injections of L-NAME (10 and 20 nmol/rat), impaired IA memory performance in the animals receiving post-training naloxone (40 ng/rat). In the animals receiving post-training naloxone treatment, the impairment of IA memory performance due to pre-test i.c.v. injections of L-NAME was recovered by the pre-test co-administration of L-arginine. It was concluded that the recovery from impairment of IA memory in GSM-exposed animals with post-training naloxone treatment was the result of blockade of the opioidergic system in early memory consolidation as well as activation of the nitrergic system in the retrieval phase of memory.

Memory retrieval of inhibitory avoidance requires histamine H1 receptor activation in the hippocampus

Retrieval represents a dynamic process that may require neuromodulatory signaling. Here, we report that the integrity of the brain histaminergic system is necessary for retrieval of inhibitory avoidance (IA) memory, because rats depleted of histamine through lateral ventricle injections of α-fluoromethylhistidine (a-FMHis), a suicide inhibitor of histidine decarboxylase, displayed impaired IA memory when tested 2 d after training. a-FMHis was administered 24 h after training, when IA memory trace was already formed. Infusion of histamine in hippocampal CA1 of brain histamine-depleted rats (hence, amnesic) 10 min before the retention test restored IA memory but was ineffective when given in the basolateral amygdala (BLA) or the ventral medial prefrontal cortex (vmPFC). Intra-CA1 injections of selective H1 and H2 receptor agonists showed that histamine exerted its effect by activating the H1 receptor. Noteworthy, the H1 receptor antagonist pyrilamine disrupted IA memory retrieval in rats, thus strongly supporting an active involvement of endogenous histamine; 90 min after the retention test, c-Fos-positive neurons were significantly fewer in the CA1s of a-FMHis-treated rats that displayed amnesia compared with in the control group. We also found reduced levels of phosphorylated cAMP-responsive element binding protein (pCREB) in the CA1s of a-FMHis-treated animals compared with in controls. Increases in pCREB levels are associated with retrieval of associated memories. Targeting the histaminergic system may modify the retrieval of emotional memory; hence, histaminergic ligands might reduce dysfunctional aversive memories and improve the efficacy of exposure psychotherapies.

Intra-CA1 administration of FK-506 (tacrolimus) in rat impairs learning and memory in an inhibitory avoidance paradigm.

Calcineurin (CN) is a main phosphatase and a critical regulator of cellular pathways for learning, memory, and plasticity. The FK-506 (tacrolimus), a phosphatase inhibitor, is a fungal-derived agent and a common immune suppressant extensively used for tissue transplantation. To further clarify the role of CN in different stages of learning and memory the main aim of this study was to evaluate the role of FK-506 in an inhibitory avoidance model. Using different doses of FK-506 (0.5, 5, and 50 nM) in the CA1 of hippocampus at different times (before, after the training and also before the test), the effect of drug was evaluated in a step-through inhibitory avoidance paradigm. The latency of entering to the dark compartment was considered as a criterion for memory. The pre-training intra-CA1 injections of FK-506 impaired inhibitory avoidance (IA) learning acquisition. In addition, the post-training intra-CA1 injections of FK-506 at 1, 2, and 3 hr relative to training impaired memory consolidation. Moreover, the pre-test intra-CA1 injections of FK-506 impaired memory retrieval. These findings suggest that the FK-506 selectively interferes with acquisition, retention, and retrieval of information processing in CA1 of hippocampus. Given the crucial role of CN in common signaling pathway of higher functions such as memory performance and cognition, in future it would be a probable therapeutic target in the treatment of a wide verity of neurological conditions involving memory.

Cross state-dependency of learning between morphine and WIN55, 212-2 in mouse dorsal hippocampus

Both morphine and cannabinoids impair memory and induce state-dependent learning. Furthermore, early studies indicated the existence of functional interactions between cannabinoid and opioid systems in the modulation of behavioral and physiological responses. Therefore, in the current study, cross state-dependent learning between WIN55, 212-2 (a cannabinoid CB1/CB2 receptor agonist) and morphine (µ-opioid agonist) administration in mice dorsal hippocampus was investigated using a step-down inhibitory avoidance task. Animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-down type inhibitory avoidance task, and tested 24 h after training to measure their step-down latency. Post-training or pre-test administration of morphine (6 mg/kg) and WIN55, 212-2 (0.6 and 0.9 µg/mouse) impaired inhibitory avoidance memory and induced amnesia. Moreover, the amnesia induced by the post-training injections of morphine (6 mg/kg) or WIN55, 212-2(0.9 µg/mouse) was restored by either pre-test injections of morphine (6 mg/kg) or WIN55, 212-2(0.9 µg/mouse). Furthermore, pre-test co-administration of ineffective doses of morphine (3 mg/kg) with WIN55, 212-2 (0.3 µg/mouse) restored the amnesia induced by post-training injections of WIN55, 212-2(0.9 µg/mouse) or morphine (6 mg/kg). Noteworthy, the response induced by the pre-test injection of morphine or WIN55, 212-2 was antagonized with naloxone. Our data strongly revealed a cross state-dependent learning between morphine and WIN55, 212-2 in mice where µ-opioid receptors of dorsal hippocampus play an important role.

Infusion of galanin into the mid-caudal portion of the dorsal raphe nucleus has an anxiolytic effect on rats in the elevated T-maze

Galanin and 5-HT coexist in dorsal raphe nucleus (DRN) neurons. Microinjection of galanin into the DRN reduces the firing rate of serotonin neurons. Serotonergic neurons projecting from the DRN to the amygdala facilitate learned anxiety producing an anxiogenic effect, while those projecting from the periaqueductal grey affect innate anxiety producing a panicolytic effect. We tested the hypothesis that injection of galanin into rat DRN would induce anxiolytic/panicogenic effects in the elevated T-maze (ETM), a model that allows for the evaluation of both of these effects. Galanin infusion into the mid-caudal DRN, but not into the rostral DRN, impaired inhibitory avoidance, suggesting an anxiolytic effect. The effective dose of galanin (0.3nmol) did not modify locomotor activity in the open field. Contrary to expectations, microinjection of galanin into the DRN did not facilitate the latency of one-way escape in the ETM. Pretreatment with a galanin antagonist, M40, attenuated galanin-induced impairment of inhibitory avoidance. The results show that microinjection of a low dose of galanin only into the mid-caudal DRN has an anxiolytic effect. This effect seems to be mediated, at least in part, by galanin receptors. Further investigation is necessary to identify the receptor subtypes and the DRN subregion involved in the anxiolytic effect of galanin.

Effects of time of estrogen deprivation on anxiety-like behavior and GABAA receptor plasticity in ovariectomized rats

Ovariectomized animals have frequently been used to study the effects of estrogen deficiency on mood disorders, particularly anxiety disorder. However, a range of results including anxiolytic, anxiogenic, and no behavioral effects have been reported. One discrepancy was the different in behavioral testing time following ovariectomized; therefore, the aim of this study was to examine the effects of time of estrogen deprivation on anxiety-like behavior and on GABAA receptor subunit gene expressions in ovariectomized rats. The GABAA receptor was of special interest as it had been shown to be influenced by estrogen. In this study, adult female Wistar rats were ovariectomized and randomly assigned into 2 groups: ovariectomized-rat (Ovx) and ovariectomized-rat treated with estrogen (E2) at the dosage of 1μg/kg BW. At 7, 14, 21 and 28 days after ovariectomy, the rats were tested with elevated T-maze (ETM) and open field. We found that after ovariectomy, the Ovx showed signs of anxiety as demonstrated by the increased in inhibitory avoidance latency in the ETM with significant effect at day 21 and even higher at day 28. On the other hand, the escape latency was not differed between each time point. These behavioral data implied that the anxiety in term of generalized anxiety disorder as interpreted from impaired inhibitory avoidance in the ETM was affected by estrogen depletion; while, the anxiety disorder in term of panic disorder as shown by escape latency was unaffected. For gene expression analysis, the GABAA receptor α2-, α3- and α4-subunits in Ovx groups were significantly increased in the midbrain compared to E2 groups; whereas, in the amygdala, the gene expressions were not different between Ovx and E2 groups. In conclusion, these results indicated that ovariectomized as early as 21 day can induce anxiety and the altered GABAA receptor subunit may be partially responsible for anxiety following estrogen deprivation.

Interaction between gamma-aminobutyric acid type A (GABAA) receptor agents and scopolamine in the nucleus accumbens on impairment of inhibitory avoidance memory performance in rat

We designed this study to investigate effects of intra-nucleus accumbens (intra-NAc) infusions of GABAA receptors agonist (muscimol) and antagonist (bicuculline) by themselves and their interaction with scopolamine on inhibitory avoidance (IA) memory performance. This study used a step-through IA task to assess memory in male Wistar rats. The results showed that post-training intra-NAc infusions of muscimol at doses of 0.01 and 0.02μg/rat significantly impaired IA memory performance, while bicuculline (0.1, 0.2 and 0.4μg/rat) had no effect. Post-training intra-NAc infusions of scopolamine at dose of 0.5μg/rat impaired IA memory performance by itself, and in combination with an ineffective dose of muscimol increased impairment of IA memory performance. The results also showed that post-training intra-NAc infusions of bicuculline prevented the impairing effect of higher doses of scopolamine on IA memory performance. Pre-test intra-NAc infusions of muscimol (0.01 and 0.02μg/rat) and bicuculline (0.001, 0.01 and 0.1μg/rat) impaired IA memory performance. The results also revealed that pre-test intra-NAc infusions of scopolamine (0.25 and 0.5μg/rat) impaired IA memory performance, and its co-infusions with an ineffective dose of muscimol (0.005μg/rat) increased impairment of IA memory performance. Interestingly, pre-test intra-NAc infusions of bicuculline impaired performance by itself, but did not prevent the impairing effect of scopolamine. It can be concluded that GABAA and muscarinic receptors of the NAc may have an interaction in modulation of IA memory performance, which may result from affecting output neurons in the NAc directly or indirectly via cholinergic and GABAergic interneurons.

Activation of dopamine D1 receptors in the medial septum improves scopolamine-induced amnesia in the dorsal hippocampus

In the present study, we investigated the influence of intra-medial septum (intra-MS) injections of dopamine D1 receptor agents on amnesia induced by intra-CA1 injections of a muscarinic acetylcholine receptor antagonist, scopolamine. This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that in the animals that received post-training intra-MS injections of saline, intra-CA1 administrations of scopolamine (0.75, 1, and 2μg/rat) decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-MS injections of a dopamine D1 receptor agonist, SKF38393 at doses of 0.1, 0.15, and 0.3μg/rat had no effect, but at dose of 0.5μg/rat impaired IA memory consolidation. Interestingly, intra-MS injections of SKF38393 (0.15, 0.3 and 0.5μg/rat) significantly prevented amnesia induced by intra-CA1 injections of scopolamine (1μg/rat). Intra-MS injections of a dopamine D1 receptor antagonist, SCH23390 (0.5 and 0.75μg/rat) by itself impaired IA memory consolidation, and also at dose of 0.75μg/rat increased amnesia induced by intra-CA1 administrations of an ineffective dose of scopolamine (0.5μg/rat). Post-training intra-MS injections of ineffective doses of SCH23390 (0.1, 0.3 and 0.5μg/rat) prevented an effective dose of SKF38393 response to the impaired effect of scopolamine. These results suggest that dopamine D1 receptors in the MS via projection neurons to the hippocampus affect impairment of memory consolidation induced by intra-CA injections of scopolamine.

Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory

Mammalian target of rapamycin (mTOR), a central regulator of protein synthesis in neurons, has been implicated in synaptic plasticity and memory. Here we show that mTOR inhibition by rapamycin in the basolateral amygdala (BLA) or dorsal hippocampus (DH) impairs both formation and reconsolidation of memory for inhibitory avoidance (IA) in rats. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after IA training or retrieval. Memory retention was tested at different time points after drug infusion. Rapamycin impaired long-term IA retention when given before or immediately after training or retrieval into the BLA. When infused into the DH, rapamycin produced memory impairment when given before training or immediately after retrieval. The impairing effects of post-retrieval rapamycin required memory retrieval and were not reversed by a reminder shock. The results provide the first evidence that mTOR in the BLA and DH might play a role in IA memory reconsolidation.

Effect of the acute and chronic estrogen on anxiety in the elevated T-maze

Despite the extensive studies on the influences of estrogen (E2) on anxiety-like behaviors, there is still conflicting evidence regarding the specific effects of E2 on anxiety. These discrepancies may be a result of different replacement regimens. The goals of this study were to evaluate anxiety-like behavior in ovariectomized rats (Ovx) using the elevated T-maze (ETM) test for the following variables: (1) the effects of acute versus chronic E2 dosing, (2) the effects of chronic E2 at different doses and, (3) the effects of Tamoxifen (Tam) co-administered with E2. Rats in the acute E2 dosing group (aE2) showed reduced inhibitory avoidance responses with prolong escape latencies compared to Ovx; while rats in the chronic E2 dosing group (cE2) showed reduced inhibitory avoidance responses only. These results suggest that E2 contains anxiolytic effects when given once or repeatedly. Moreover, when various doses of E2 (1–100μg/kg) were chronically given to the Ovx rats, all doses produced impaired inhibitory avoidance responses compared to Ovx, suggesting that chronic replacement of E2 had no dose-dependent effect on anxiety-like behavior. Interestingly, in the 3-week delay replacement regimen, the low dose E2 (1μg/kg, s.c.) group displayed no anxiolytic effects as their inhibitory avoidance responses in the ETM were not different from their Ovx counterparts. On the contrary, the Ovx group that received Tam+E2 (Tam 1mg/kg, PO and E2 1μg/kg, s.c.) had reduced inhibitory avoidance responses compared to other groups. These findings indicate that when Tam is co-administered with chronic low dose estrogen, it can act as an estrogen receptor agonist and result in anti-anxiety effects. Therefore, it is likely that the anxiolytic-like behavior relative to generalized anxiety disorder can be conserved when estrogen is given acutely or chronically; while the anxiolytic-like behavior relative to panic disorder can be conserved only when estrogen is given acutely.

Contextual learning requires synaptic AMPA receptor delivery in the hippocampus

The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience-dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. By combining viral-mediated in vivo gene delivery with in vitro patch-clamp recordings, we found that the inhibitory avoidance task, a hippocampus-dependent contextual fear-learning paradigm, delivered GluR1-containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus. To block the synaptic delivery of endogenous AMPARs, we expressed a fragment of the GluR1-cytoplasmic tail (the 14-aa GluR1 membrane-proximal region with two serines mutated to phospho-mimicking aspartates: MPR-DD). MPR-DD prevented learning-driven synaptic AMPAR delivery in CA1 neurons. Bilateral expression of MPR-DD in the CA1 region of the rat impaired inhibitory avoidance learning, indicating that synaptic GluR1 trafficking in the CA1 region of the hippocampus is required for encoding contextual fear memories. The fraction of CA1 neurons that underwent synaptic strengthening positively correlated with the performance in the inhibitory avoidance fear memory task. These data suggest that the robustness of a contextual memory depends on the number of hippocampal neurons that participate in the encoding of a memory trace.

Activation of cannabinoid CB1 receptors in the central amygdala impairs inhibitory avoidance memory consolidation via NMDA receptors

In the present study, we investigated the influence of bilateral intra-central amygdala (intra-CeA) microinjections of N-methyl-d-aspartate (NMDA) receptor agents on amnesia induced by a cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA). This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that intra-CeA administration of ACPA (2ng/rat) immediately after training decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-CeA microinjections of NMDA (0.0001, 0.001 and 0.01μg/rat) did not affect IA memory consolidation. However co-administration of NMDA with ACPA (2ng/rat) prevented the impairment of IA memory consolidation that was induced by ACPA. Although post-training intra-CeA administration of the NMDA receptor antagonist, d-(−)-2-amino-5-phosphonopentanoic acid (d-AP5; 0.01, 0.05 and 0.1μg/rat) alone had no effect, its co-administration with an ineffective dose of ACPA (1ng/rat) impaired IA memory consolidation. Post-training intra-CeA microinjection of an ineffective dose of d-AP5 (0.01μg/rat) prevented an NMDA response to the impaired effect of ACPA. These results suggest that amnesia induced by intra-CeA administration of ACPA is at least partly mediated through an NMDA receptor mechanism in the Ce-A.