Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits

Cyclophosphamide (CYP) is an anti-neoplastic agent as well as an immunosuppressive agent. In order to elucidate the alteration in adult hippocampal function following acute CYP treatment, hippocampus-related behavioral dysfunction and changes in adult hippocampal neurogenesis in CYP-treated (intraperitoneally, 40 mg/kg) mice (8–10-week-old ICR) were analyzed using hippocampus-dependent learning and memory tasks (passive avoidance and object recognition memory test) and immunohistochemical markers of neurogenesis (Ki-67 and doublecortin (DCX)). Compared to the vehicle-treated controls, mice trained at 12 h after CYP injection showed significant memory deficits in passive avoidance and the object recognition memory test. The number of Ki-67- and DCX-positive cells began to decrease significantly at 12 h post-injection, reaching the lowest level at 24 h after CYP injection; however, this reverted gradually to the vehicle-treated control level between 2 and 10 days. We suggest that the administration of a chemotherapeutic agent in adult mice interrupts hippocampal functions, including learning and memory, possibly through the suppression of hippocampal neurogenesis.     

Cognitive aspects of congenital learned helplessness and its reversal by the monoamine oxidase (MAO)-B inhibitor deprenyl

Cognitive processes are assumed to change with learned helplessness, an animal model of depression, but little is known about such deficits. Here we investigated the role of cognitive and related functions in selectively bred helpless (cLH, n = 10), non-helpless (cNLH, n = 12) and wild type (WT, n = 8) Sprague Dawley rats. The animals were exposed to an open field for 10 min on each of two test days. On the third day, an object exploration paradigm was carried out. The animals were later tested for helplessness. Both cLH and cNLH rats were more active than WTs on the first day in the open field. Over trials, cNLH and WT rats lowered their activity less than cLH rats. This resistance-to-habituation co-varied with a resistance to develop helplessness. In cLH rats, higher ‘anxiety’ or less time spent in the center of the open field co-varied with severe helplessness. In WTs, a greater reactivity to novel objects and to a spatially relocated object predicted lower levels of helplessness. In cLH rats (n = 4–5 per group), chronic treatment with a high dose of the monoamine oxidase (MAO)-B inhibitor deprenyl (10 mg/kg; i.p.), an anti-Parkinson, nootropic and antidepressant drug, attenuated helplessness. Remarkably, helplessness reversal required the experience of repeated test trials, reminiscent of a learning process. Chronic deprenyl (10 mg/kg; i.p.) did not alter locomotion/exploration or ‘anxiety’ in the open field. In conclusion, helplessness may be related to altered mechanisms of reinforcement learning and working memory, and to abnormalities in MAO-A and/or MAO-B functioning.     

SLV330, a cannabinoid CB1 receptor antagonist,ameliorates deficits in the T-maze,object recognition and Social Recognition Tasks in rodents

Cannabinoid CB₁ receptor (CB₁R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB₁R antagonist SLV330 (doses ranging from 0.3 to 10 mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease) and nicotine were used as reference compounds.SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1 mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3 mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1 mg/kg, p.o.) and the AChEI donepezil (0.1 mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3 mg/kg (p.o.).In conclusion, the CB₁R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.     

Enhanced inhibitory avoidance learning prevents the long-term memory-impairing effects of cycloheximide,a protein synthesis inhibitor

Interference with activity of numerous cerebral structures produces memory deficiencies; in many instances, however, when animals are over-trained such interference becomes innocuous. Systemic administration of protein synthesis inhibitors impairs long-term retention; this effect has been interpreted to mean that protein synthesis is required for memory consolidation, though little is known about the effect of protein synthesis inhibitors on memory of enhanced learning in the rat. To further analyze the protective effect of enhanced learning against amnesic treatments, groups of Wistar rats were trained in a one-trial step-through inhibitory avoidance task, using different intensities of foot-shock during training. Cycloheximide (CXM; 2.8 mg/kg), an inhibitor of protein synthesis, was injected either 30 min before training or immediately after training. Twenty-four hours after training retention latencies were recorded. Our data showed that both pre- and post-training administration of CXM produced amnesia in those groups that had been trained with relatively low foot-shock intensities, but no impairment in retention was observed when relatively high intensities of foot-shock were administered. These and similar results lead us to conclude that protein synthesis inhibitors may interfere with memory consolidation, but their effect disappears when animals are submitted to an enhanced learning experience, calling into question the idea that protein synthesis is required for memory consolidation.     

Post-training administration of corticosterone enhances consolidation of contextual fear memory and hippocampal long-term potentiation in rats

This study was designed to examine the effect of corticosterone on consolidation of contextual fear memory and hippocampal long-term potentiation (LTP) in rats. In Experiment 1, dose–response effects of corticosterone on consolidation of contextual fear memory were determined. Immediately after training in contextual fear conditioning task, rats received different doses of corticosterone. Testing 24 h later, it revealed that corticosterone enhanced memory consolidation in an inverted U shape as evidenced in increased freezing behavior of corticosterone-treated animals. The most effective dose was 3 mg/kg. In Experiment 2, LTP was examined in rats whose memory consolidation has been enhanced with corticosterone. The rats were trained as the above and received corticosterone (3 mg/kg) immediately after training. Immediately or up to one day after retention test, rats were anesthetized with urethane for LTP experiments. For LTP induction, three episodes of high frequency stimuli, 30 s apart, were delivered to the perforant path, each consisting of 10 stimuli at 250 Hz. LTP was assessed by measuring the increase in the initial slope of the population excitatory post-synaptic potentials and the amplitude of the population spikes. Data indicated that animals whose memory has been enhanced by corticosterone, also displayed enhanced hippocampal LTP. The above findings suggest that glucocorticoids may enhance contextual fear memory consolidation via enhancing hippocampal LTP.     

The NK3 receptor agonist senktide ameliorates scopolamine-induced deficits in memory for object, place and temporal order

Senktide, a potent neurokinin-3 receptor (NK₃-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schäble et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK₃-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK₃-R agonists and their activating influence on ACh suggest a possible role of the NK₃-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK₃-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous – s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object–place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object–place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine-induced memory impairments and indicate that the promnestic action of NK₃-R agonists is mediated by muscarinic cholinergic mechanisms.     

The role of working memory and visual processing in prototype category learning

To investigate whether working memory and visual processing have the same role or different roles in A/B and A/not A prototype category learning, the present study adopted an A/B or A/not A category learning task in control and dual conditions. The results of Experiment 1 showed that an additional dual visual working memory task rather than a dual verbal working memory task reduced accuracy of the A/B task, whereas no dual tasks influenced accuracy of the A/not A task. The results of Experiment 2 revealed that an additional dual visual processing task impaired accuracy of the A/B task, whereas the dual visual processing task did not influence accuracy of the A/not A task. These results indicate that visual working memory and visual processing play different roles in A/B and A/not A prototype category learning, and support that these two types of prototype category learning are mediated by different memory systems.     

Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of memory for emotionally arousing events through interactions with the noradrenergic system of the basolateral complex of the amygdala (BLA). We previously reported that intra-BLA administration of a β-adrenoceptor agonist immediately after inhibitory avoidance training enhanced memory consolidation and increased hippocampal expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc). In the present experiments corticosterone (3 mg/kg, i.p.) was administered to male Sprague-Dawley rats immediately after inhibitory avoidance training to examine effects on long-term memory, amygdala norepinephrine levels, and hippocampal Arc expression. Corticosterone increased amygdala norepinephrine levels 15 min after inhibitory avoidance training, as assessed by in vivo microdialysis, and enhanced memory tested at 48 h. Corticosterone treatment also increased expression of Arc protein in hippocampal synaptic tissue. The elevation in BLA norepinephrine appears to participate in corticosterone-influenced modulation of hippocampal Arc expression as intra-BLA blockade of β-adrenoceptors with propranolol (0.5 μg/0.2 μL) attenuated the corticosterone-induced synaptic Arc expression in the hippocampus. These findings indicate that noradrenergic activity at BLA β-adrenoceptors is involved in corticosterone-induced enhancement of memory consolidation and expression of the synaptic-plasticity-related protein Arc in the hippocampus.     

Posttraining infusion of cholinergic drugs into the ventral subiculum modulated memory in an inhibitory avoidance task: Interaction with the bed nucleus of the stria terminalis

The ventral subiculum (vSUB), a hippocampal efferent target implicated in learning and stress coping, receives cholinergic input and sends glutamatergic output to the bed nucleus of the stria terminalis (BNST). This study examined the roles of vSUB muscarinic activation and its interaction with BNST N-methyl-d-aspartate and noradrenergic receptors in formation of aversive memory. Male Wistar rats with cannulae implanted into the vSUB or BNST were trained on a step-through inhibitory avoidance task. Shortly after training, they received cholinergic drugs infused into the vSUB and/or glutamatergic or noradrenergic drugs infused into the BNST. Results of the 1-day retention tests showed that intra-vSUB infusion of oxotremorine (0.01 μg) or scopolamine (0.3 or 3.0 μg) enhanced or impaired retention, respectively. Both effects were dose- and time-dependent, and 0.001 μg oxotremorine attenuated the amnesia induced by 3.0 μg scopolamine. The oxotremorine-induced memory enhancement was blocked by intra-BNST infusion of dl-2-amino-5-phosphonovaleric acid or propranolol at a dose not affecting retention; the amnesia induced by scopolamine was blunted by intra-BNST infusion of glutamate or norepinephrine at a dose with a negligible effect on retention. These data suggest that in an inhibitory avoidance task muscarinic activation of the vSUB modulated memory formation by interacting with the BNST glutamatergic and noradrenergic functions.     

Involvement of dorsal hippocampal α-adrenergic receptors in the effect of scopolamine on memory retrieval in inhibitory avoidance task

The present study evaluated the possible role of α-adrenergic receptors of the dorsal hippocampus on scopolamine-induced amnesia and scopolamine state-dependent memory in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-through type inhibitory avoidance task, and tested 24 h after training to measure step-through latency. Results indicate that post-training or pre-test intra-CA1 administration of scopolamine (1 and 2 μg/rat) dose-dependently reduced the step-through latency, showing an amnestic response. Amnesia produced by post-training scopolamine (2 μg/rat) was reversed by pre-test administration of the scopolamine that is due to a state-dependent effect. Interestingly, pre-test intra-CA1 microinjection of α1-adrenergic agonist, phenylephrine (1 and 2 μg/rat) or α2-adrenergic agonist, clonidine improved post-training scopolamine (2 μg/rat)-induced retrieval impairment. Furthermore, pre-test intra-CA1 microinjection of phenylephrine (0.25, 0.5 and 1 μg/rat) or clonidine (0.25, 0.5 and 1 μg/rat) with an ineffective dose of scopolamine (0.25 μg/rat), synergistically improved memory performance impaired by post-training scopolamine. On the other hand, pre-test injection of α1-receptors antagonist prazosin (1 and 2 μg/rat) or α2-receptors antagonist yohimbine (1 and 2 μg/rat) prevented the restoration of memory by pre-test scopolamine. It is important to note that pre-test intra-CA1 administration of the same doses of prazosin or yohimbine, alone did not affect memory retrieval. These results suggest that α1- and α2-adrenergic receptors of the dorsal hippocampal CA1 regions may play an important role in scopolamine-induced amnesia and scopolamine state-dependent memory.     

Trace administration of vitamin E can retrieve and prevent UV-irradiation- and metal exposure-induced memory deficits in nematode Caenorhabditis elegans

Vitamin E (α-tocopherol), a lipid-soluble anti-oxidant, prevents the uncontrolled propagation of lipid peroxidation by free radicals. Nevertheless, there is weak or no evidence of a protective effect of previous vitamin E intake on cognitive function in humans. In the present study, we explored the thermosensation model to investigate the possible effects of vitamin E administration on memory behaviors in Caenorhabditis elegans. Administration of 100 and 200 μg/mL of vitamin E had no significant effects on the memory for different time intervals, whereas relatively high concentration (400 μg/mL) of vitamin E exposure shortened the extinction period of the association paradigm (food at 20 °C). Following the UV-irradiation, post-treatment with 200 μg/mL of vitamin E not only retrieved the UV-irradiation-induced memory deficits, but also enhanced the memory functions in UV-irradiating animals. Post-treatment with trace vitamin E could also ameliorate the memory deficits in metal (Al or Pb) exposed worms. In addition, pre-treatment with 200 μg/mL of vitamin E could effectively prevent the occurrence of memory deficits induced by metal exposure and UV-irradiation. Therefore, the close association may exist between trace dietary vitamin E intake and memory behaviors, and a specific response mechanism may be activated after the administration of vitamin E in stress-exposed animals. Moreover, treatment with 200 μg/mL of vitamin E could restore the memory deficits formed in the ncs-1 mutant worms, suggesting that exogenous treatment with trace vitamin E can largely mimic the function of NCS-1 in regulating the memory for thermosensation.     

Cognitive discernible factors between schizophrenia and schizoaffective disorder

BackgroundSchizophrenia (SZ) and schizoaffective disorders (SA) are associated with cognitive deficits. Generally, a schizoaffective diagnosis is associated with better prognosis on the level of social integration. It is also well established that cognition is an important factor for good social outcome in schizophrenia. We hypothesized that, although patients suffering from SA share symptoms with SZ, they can be differentiated on the basis of neurocognitive function and that SA perform better in several domains.MethodPerformances of two groups SA (N = 13) and SZ (N = 44) were compared on several visual-motor tasks using CANTAB [Motor Screening (MOT), Reaction Time (RTI), Paired Associates Learning Task (PAL), and Stockings of Cambridge items (SOC)]. The two groups were matched for symptom severity. ANOVA with repeated measures was employed to determine whether any difference in cognitive scores during a 2-year period was significantly related to the diagnostic status.ResultsA significant and durable difference was observed between SZ and SA on motor screening and explicit memory tests where SA performed better.ConclusionNeurocognitive tests may be relevant for distinguishing schizoaffective from schizophrenia, chiefly via tests tapping into visuo-spatial and visuo-motor coordination abilities (e.g., paired associated learning and motor screening).     

Chronic oral methylphenidate induces post-treatment impairment in recognition and spatial memory in adult rats

Recent pre-clinical research has indicated that chronic treatment with methylphenidate (Ritalin^®) in young animals can result in lasting and potentially detrimental alterations in brain function that can persist into adulthood. Chronic methylphenidate-induced neuronal alterations may result in behavior and cognitive deficits that include increases in behavioral responses and impairment in recognition memory. This study compared the cognitive consequences following chronic treatment with two doses (5 and 10 mg/kg) of methylphenidate on recognition and spatial memory in adult male Long-Evans rats using an established oral dosing procedure. The animals were then tested in the Object Recognition test at 14 days post treatment and the Object Placement test at 21 days post treatment. The results indicate that repeated exposure to oral methylphenidate impaired the performance of rats in these tests. The current findings add to recent research demonstrating negative consequences in rats pre-treated with methylphenidate, and extend previous findings to include deficits in spatial recognition memory.     

Experiential avoidance in body dysmorphic disorder

Experiential avoidance (i.e., the attempt to avoid certain internal experiences including bodily sensations, thoughts, emotions, memories, and urges) has been studied in various psychological disorders. However, research examining experiential avoidance in individuals with body dysmorphic disorder (BDD) is limited and inconsistent. The present study compared experiential avoidance in individuals with primary BDD (n = 23) to healthy controls (n = 22). Standardized measures were used to assess baseline clinical characteristics as well as experiential avoidance. Compared to healthy controls, individuals with BDD presented with significantly greater experiential avoidance (p < .001, d = −2.51). In BDD, experiential avoidance was positively correlated with depressive symptoms (p < .01) and avoidant coping strategies (p < .01). Clinician sensitivity to experiential avoidance may serve to improve the course of treatment for BDD.     

Vasopressin/oxytocin-related peptides influence long-term memory of a passive avoidance task in the cuttlefish,Sepia officinalis

The vasopressin (VP)/oxytocin (OT)-related peptides constitute a large superfamily found in a wide range of both vertebrate and invertebrate species. While intensive literature reports that these neuropeptides influence behavior, especially learning and memory, in numerous species from diverse vertebrate groups, their roles in behavioral regulation have never been studied in invertebrates. Here, we investigated the role of two VP/OT superfamily peptides, octopressin (OP) and cephalotocin (CT), on long-term memory (LTM) formation of a passive avoidance task in a cephalopod mollusc, the cuttlefish, Sepia officinalis. Subadult cuttlefish were intravenously injected, in a dose range of 3–60 μg/kg, 1 h after the training phase (consolidation design); retention performance was tested 24 h post-training. We found that administration of OP at low dose (3 μg/kg) enhanced LTM, whereas a dose of 60 μg/kg attenuated it. No effect of OP on LTM was observed for the 15 μg/kg dose. Conversely, an enhancement of retention performance was observed at all doses of CT tested. This study is the first to demonstrate the behavioral effects of VP/OT superfamily peptides in an invertebrate species. The valuable role of VP/OT-like peptides on memory processes offers new evolutionary perspectives on peptidergic transmission and neuromodulation.     

Impaired retention is responsible for temporal order memory deficits in mild cognitive impairment

Temporal order memory, or remembering the order of events, is critical for everyday functioning and is difficult for patients with mild cognitive impairment (MCI). It is currently unclear whether these patients have difficulty acquiring and/or retaining such information and whether deficits in these patients are in excess of “normal” age-related declines. Therefore, the current study examined age and disease-related changes in temporal order memory as well as whether memory load played a role in such changes. Young controls (n = 25), older controls (n = 34), and MCI patients (n = 32) completed an experimental task that required the reconstruction of sequences that were 3, 4, or 5 items in length both immediately after presentation (i.e., immediate recall) and again after a 10-min delay (i.e., delayed recall). During the immediate recall phase, there was an effect of age largely due to reduced performance at the two longest span lengths. Older controls and MCI patients only differed during the five span (controls > MCI). During the delayed recall, however, there were significant effects of both age and MCI regardless of span length. In MCI patients, immediate recall was significantly correlated with measures of executive functioning, whereas delayed recall performance was only related to other memory tests. These findings suggest that MCI patients experience initial temporal order memory deficits at the point when information begins to exceed working memory capacity and become dependent on medial temporal lobe functioning. Longer-term deficits are due to an inability to retain information, consistent with the characteristic medial temporal lobe dysfunction in MCI.     

Reacquisition of heroin and cocaine place preference involves a memory consolidation process sensitive to systemic and intra-ventral tegmental area naloxone

To investigate the effect of naloxone on a putative memory consolidation process underlying reacquisition of heroin and cocaine conditioned place preference, four studies were conducted in male Sprague–Dawley rats using a common procedure involving: place conditioning (0.3 or 1 mg/kg heroin or 20 mg/kg cocaine; ×4 sessions), extinction (vehicle × 4 sessions), and reconditioning (0 or 1 mg/kg heroin or 20 mg/kg cocaine; ×1 session). Systemic naloxone injections (0, 1 and 3 mg/kg) or bilateral intra-ventral tegmental area (VTA) naloxone methiodide infusions (2 nmol in 0.5 μl × side) were administered at different times following reconditioning. Post-reconditioning administration of naloxone dose-dependently blocked, attenuated and had no effect on reacquisition of heroin CPP when administered immediately, 1 h and 6 h after reconditioning, respectively. The highest dose of naloxone also blocked reacquisition of cocaine CPP, and did not produce a conditioned place aversion in heroin-naïve and heroin pre-treated animals. Post-reconditioning infusions in the VTA, but not in adjacent structures, blocked reacquisition of heroin CPP when administered immediately, but not 6 h, after reconditioning. These data suggest that reacquisition of drug-cues associations involves a memory consolidation process sensitive to manipulations of the endogenous opioid system, and indicate that opioid receptors in the VTA may be critically involved in the re-emergence of drug seeking behavior.     

Body checking and avoidance in ethnically diverse female college students

Although body checking and avoidance behaviors are common in women with eating disorders, minimal research has examined the nature or correlates of these behaviors in ethnically diverse female college students without eating disorders. Self-identified European American (n = 268), Asian American (n = 163), Latina (n = 146), and African American (n = 73) women completed self-report measures of body checking and avoidance, thin-ideal internalization, eating pathology, and clinical impairment. Results indicated that European and Asian American women reported significantly more body checking and avoidance than African American and Latina women. Generally, correlates of body checking and avoidance were consistent across ethnic groups: Regression analyses indicated that type of ethnicity predicted body checking and avoidance; and ethnicity, body checking, and body avoidance predicted eating pathology and clinical impairment. These associations suggest that body checking and avoidance are not benign behaviors in diverse nonclinical women.     

Increased stress-induced intra-hippocampus corticosterone rise associated with memory impairments in middle-aged mice

The present study investigates the relationships between hippocampal corticosterone concentrations and memory retrieval performance in stress and non-stress conditions, in both young (6 month-old) and middle-aged (16 month-old) mice. For this purpose, the time-course evolution of stress-induced corticosterone rise in the dorsal hippocampus (dHPC) was investigated in both young and middle-aged mice. In parallel, the evolution of memory retrieval patterns was assessed using a contextual serial discrimination task (CSD). Finally, metyrapone (corticosterone synthesis inhibitor) was administered in order to evaluate the stress-induced impact of corticosterone rise on contextual memory retrieval in middle-aged animals.Results showed that: (i) non-stressed middle-aged mice exhibited a memory retrieval pattern opposite to that of non-stressed young animals, but similar to that of stressed young mice; (ii) the impact of stress on memory performance was transient (90 min) in young, as compared to middle-aged mice (120 min); (iii) dHPC basal (non-stress) corticosterone level was significantly increased by ageing; (iv) acute stress induced a rapid (15 min) and transient (90 min) dHPC corticosterone rise in young mice, while exhibiting greater magnitude and duration (120 min) in middle-aged animals; and (v) both the stress-induced endocrinal and memory effects were blocked by metyrapone in young and middle-aged mice.Finally, to our knowledge, the present work is the first study to directly measure the corticosterone rise in the hippocampus following exposure to stress and to directly correlate the corticosterone changes in the hippocampus with memory performance in both young and middle-aged mice.     

Nociceptin and its metabolite attenuate U0126-induced memory impairment through a nociceptin opioid peptide (NOP) receptor-independent mechanism

Nociceptin binds to nociceptin opioid peptide (NOP) receptors. We reported that although high doses of nociceptin impaired memory function and that these effects were mediated via NOP receptors, low doses of nociceptin attenuated the memory impairment, and these attenuating effects were not mediated via NOP receptors. Even very low doses of nociceptin were biologically active and suggested a certain binding site for this peptide, but the mechanism underlying this attenuating effect has not yet been elucidated. In the present study, we investigated the effect of an intrahippocampal injection (i.h.) of nociceptin on memory impairment induced by U0126, a MEK inhibitor, and Rp-cAMPS, a PKA inhibitor in a step-down type passive avoidance test. U0126 (2.63 nmol/mouse, i.h.) impaired memory formation and training-dependent phosphorylation of ERK2 in the hippocampus. Co-administration of nociceptin (10 fmol/mouse) significantly attenuated memory impairment, while it did not attenuate the inhibition of training-dependent phosphorylation of ERK2 induced by U0126. On the other hand, nociceptin did not attenuate memory impairment induced by Rp-cAMPS (0.448 nmol/mouse, i.h.). Nociceptin (1 fmol/mouse) also attenuated U0126 (5.26 nmol/mouse)-induced memory impairment in NOP receptor knockout mice. Nociceptin was reported to metabolize into fragments (1–13) and (14–17) in vivo, which showed pharmacological activities without affecting NOP receptors. Our findings showed that nociceptin (14–17) (1 fmol/mouse) also attenuated U0126-induced memory impairment, while nociceptin (1–13) (0.1–10 fmol/mouse) did not attenuate memory impairment. These results suggest a novel action site or mechanism for the attenuating effects of nociceptin and its metabolite, and the sequence of nociceptin (14–17) is a critical structure.