Object Recognition Task In Rats Research Articles

Propofol protects rats against intra-cerebroventricular streptozotocin-induced cognitive dysfunction and neuronal damage.

Cognitive dysfunction is a severe issue of Alzheimer's disease. Thus, the present study was conducted to enumerate the protective effect of propofol (PPL) in rats against intra-cerebroventricular streptozotocin (STZ)-induced cognitive dysfunction and neuronal damage. The effect of PPL was investigated to evaluate behavioural changes in STZ-induced cognitive dysfunction in Wistar rats using Object Recognition Task (ORT) for nonspatial, Morris Water Maze (MWM) for spatial and locomotor activity. The effect of PPL was also investigated on acetylcholine (ACh) esterase (AChE) activity and oxidative stress markers, e.g., nitrite, malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). The level of pro-inflammatory cytokines, e.g., tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, was also studied in the PPL-treated group. The effect of PPL on the level of neurotransmitters, e.g., dopamine (DA), serotonin (5-HT), and norepinephrine (NE) and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels were also estimated in frozen hippocampal tissues by high-performance liquid chromatography. Histopathology analysis of neurons in the hippocampus of rats was performed using haematoxylin and eosin (H&E) staining. Propofol showed significant improvement in the spatial and nonspatial memory deficit of rats in the MWM test and ORT in rats. It also causes improvement in locomotor activity of rats by preserving ACh via inhibition of AChE. It also potentiates the expression of DA, 5-HT, and NE with a simultaneous reduction in the level of metabolites (DOPAC, HVA, and 5-HIAA). PPL showed a reduction of oxidative stress in rats by restoring the level of nitrite, SOD, MDA, and GSH near to normal. In the PPL-treated group, the level of TNF-α, IL-1β, and IL-6 was found reduced in a dose-dependent manner. In histopathology analysis of neurons in the hippocampus of the STZ rats, PPL causes dose-dependent reduction of pyknosis in the nucleus, which confirmed the protective effect of PPL. The present study demonstrated that PPL could significantly attenuate cognitive dysfunction and neuronal damage in STZ-induced rats.

Nootropic effects of LSD: Behavioral, molecular and computational evidence

The therapeutic use of classical psychedelic substances such as d-lysergic acid diethylamide (LSD) surged in recent years. Studies in rodents suggest that these effects are produced by increased neural plasticity, including stimulation of the mTOR pathway, a key regulator of metabolism, plasticity, and aging. Could psychedelic-induced neural plasticity be harnessed to enhance cognition? Here we show that LSD treatment enhanced performance in a novel object recognition task in rats, and in a visuo-spatial memory task in humans. A proteomic analysis of human brain organoids showed that LSD affected metabolic pathways associated with neural plasticity, including mTOR. To gain insight into the relation of neural plasticity, aging and LSD-induced cognitive gains, we emulated the experiments in rats and humans with a neural network model of a cortico-hippocampal circuit. Using the baseline strength of plasticity as a proxy for age and assuming an increase in plasticity strength related to LSD dose, the simulations provided a good fit for the experimental data. Altogether, the results suggest that LSD has nootropic effects.

Synthesis and Biological Evaluation of Fused Tricyclic Heterocycle Piperazine (Piperidine) Derivatives As Potential Multireceptor Atypical Antipsychotics

Herein, a novel series of multireceptor ligands was developed as polypharmacological antipsychotic agents using the designed multiple ligand approach between dopamine receptors and serotonin receptors. Among them, compound 47 possessed unique pharmacological features, exhibiting high affinities for D2, D3, 5-HT1A, 5-HT2A, and 5-HT6 receptors and low efficacy at the off-target receptors (5-HT2C, histamine H1, and adrenergic α1 receptor). Compound 47 showed dose-dependent inhibition of apomorphine- and MK-801-induced motor behavior, and the conditioned avoidance response with low cataleptic effect. Moreover, compound 47 resulted nonsignificantly serum prolactin levels and weight gain change compared with risperidone. Additionally, compound 47 possessed a favorable pharmacokinetic profile with oral bioavailability of 58.8% in rats. Furthermore, compound 47 displayed procognition properties in a novel object recognition task in rats. Taken together, compound 47 may constitute a novel class of atypical antipsychotic drugs for schizophrenia.

Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders.

Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.

In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist

S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties.In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10mg/kg i.p.).Acute oral administration of S 38093 at 0.1mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1mg/kg i.p.Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10mg/kg p.o. also decreased the barbital-induced sleeping time in rats.Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents.

The role of transient receptor potential vanilloid type 1 in unimodal and multimodal object recognition task in rats.

The role of transient receptor potential vanilloid type 1 (TRPV1) channels in learning and memory processes has recently been recognized. In the present study, the role of this receptor in the multisensory integration process was investigated. This study was done using 96 male Wistar rats, which were kept in a reverse 12-12h dark/light cycle. Unimodal and multimodal object recognition task was performed by four variations of the spontaneous object recognition (SOR) test including standard SOR, tactile SOR, visual SOR, and cross-modal visual-tactile SOR (CMOR). AMG9810 (selective TRPV1 antagonist) was injected into the right lateral cerebral ventricle prior to sample and choice phases of SOR. A discrimination ratio was calculated to assess the preference of the animal for the novel object. Results demonstrated that administration of AMG9810 prior to the sample phase, as encoding phase, and prior to the choice phase, as retrieval phase, impaired discrimination between the novel and the familiar objects in all standard SOR, tactile SOR, visual SOR, and CMOR tasks (all p<0.05). The results of this study showed that TRPV1 receptors might be implicated in both unimodal and cross-modal encoding of information in rats.

Embelin Attenuates Intracerebroventricular Streptozotocin-Induced Behavioral, Biochemical, and Neurochemical Abnormalities in Rats.

Embelin, the main active constituent of Embelia ribes, has been reported to possess various pharmacological actions, including anti-inflammatory, antioxidant, anticonvulsant, and neuroprotective. The present study was designed to investigate neuroprotective mechanisms and therapeutic potential of embelin against intracerebroventricular streptozotocin (ICV-STZ)-induced experimental sporadic dementia in rats. STZ was infused bilaterally at the dose of (3mg/kg/1μl/1min) ICV on day first and third. Spatial and non-spatial memory was evaluated using Morris water maze and object recognition task in rats. Embelin (2.5, 5, and 10mg/kg, i.p.) was administrated for 14days from seventh day onwards after first ICV-STZ infusion in rats. On day 22, rats were sacrificed and hippocampal brain regions were used to identify biochemical, neurochemical, and neuroinflammatory alterations. STZ-infused rats showed significant learning and memory deficit which was associated with an increase in oxidative stress (lipid peroxidation and nitrite), compromised antioxidant defense (reduced glutathione), neurotransmitter alterations (AChE, dopamine, noradrenaline, 5-hydroxytryptamine, gama amino butyric acid, and glutamate), and elevation in neuroinflammatory cytokine (IL-1 β, IL-6, and TNF-α) levels. Embelin dose dependently attenuated STZ-induced cognitive deficit and biochemical alterations and restored hippocampal neurochemical levels. The observed protective effect might be attributed to the antioxidant and anti-inflammatory potential of embelin and its ability to restore hippocampal neurochemistry. Thus, the outcomes of the current study suggest therapeutic potential of embelin in cognitive disorders such as sporadic Alzheimer's disease (SAD).

Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats

Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6–12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP.

Discovery and optimization of Lu AF58801, a novel, selective and brain penetrant positive allosteric modulator of alpha-7 nicotinic acetylcholine receptors: Attenuation of subchronic phencyclidine (PCP)-induced cognitive deficits in rats following oral administration

In this Letter, we describe a chemical lead optimization campaign starting from a novel, weak α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) hit from a HTS screen. Exploration of the structure–activity relationships for α7 PAM potency, intrinsic hepatic clearance, the structure–property relationships for lipophilicity, and thermodynamic solubility, led to the identification of Lu AF58801: a potent, orally available, brain penetrant PAM of the α7 nicotinic acetylcholine receptor, showing efficacy in a novel object recognition task in rats treated subchronically with phencyclidine (PCP).

Role of Medial Prefrontal Cortex Serotonin 2A Receptors in the Control of Retrieval of Recognition Memory in Rats

Often, retrieval cues are not uniquely related to one specific memory, which could lead to memory interference. Controlling interference is particularly important during episodic memory retrieval or when remembering specific events in a spatiotemporal context. Despite a clear involvement of prefrontal cortex (PFC) in episodic memory in human studies, information regarding the mechanisms and neurotransmitter systems in PFC involved in memory is scarce. Although the serotoninergic system has been linked to PFC functionality and modulation, its role in memory processing is poorly understood. We hypothesized that the serotoninergic system in PFC, in particular the 5-HT2A receptor (5-HT2AR) could have a role in the control of memory retrieval. In this work we used different versions of the object recognition task in rats to study the role of the serotoninergic modulation in the medial PFC (mPFC) in memory retrieval. We found that blockade of 5-HT2AR in mPFC affects retrieval of an object in context memory in a spontaneous novelty preference task, while sparing single-item recognition memory. We also determined that 5-HT2ARs in mPFC are required for hippocampal-mPFC interaction during retrieval of this type of memory, suggesting that the mPFC controls the expression of memory traces stored in the hippocampus biasing retrieval to the most relevant one.

Vibrissal paralysis unveils a preference for textural rather than positional novelty in the one-trial object recognition task in rats

In order to explore the role of active whisking in object novelty detection, the performance of rats having bilateral vibrissal paralysis was compared to that of non-lesioned animals in three modified versions of the one-trial object recognition task performed in the dark. Vibrissal paralysis was induced by crushing the buccal and mandibular branches of the facial nerve. Lesioned animals were not different from non-lesioned ones in terms of weight-gain, locomotive activity, motivation to explore, and ability to become habituated to a given environment. Only lesioned animals were unable to discriminate a change in object texture as novelty cue in the first task, designed to test textural novelty detection. In the second task, designed to test positional novelty detection, both lesioned and non-lesioned subjects were able to discriminate a change in object position as novelty cue. In the third task, designed to force the subjects to choose between two conflicting novelty cues (texture and position), non-lesioned subjects displayed a clear-cut preference for textural novelty while subjects having bilateral vibrissal paralysis preferred positional novelty. According to these results, active whisking is necessary for textural, but not for positional novelty detection. Moreover, these results indicate that textural novelty in non-lesioned animals seems to overcome positional novelty if these are in competition in an object recognition memory task.

Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats

Cognitive deficits are a major clinical unmet need in schizophrenia. The psychotomimetic drug phencyclidine (PCP) is widely applied in rodents to mimic symptoms of schizophrenia, including cognitive deficits. Previous studies have shown that sub-chronic PCP induces an enduring episodic memory deficit in female Lister Hooded rats in the novel object recognition (NOR) task. Here we show that positive modulation of AMPA receptor (AMPAR) mediated glutamate transmission alleviates cognitive deficits induced by sub-chronic PCP treatment. Female Lister hooded rats were treated sub-chronically with either vehicle (0.9% saline) or PCP (2 mg/kg two doses per day for 7 days), followed by a 7 days washout period. 30 min prior to the acquisition trial of the NOR task animals were dosed with either vehicle, CX546 (10, 40 or 80 mg/kg) or CX516 (0.5, 2.5, 10, 40 or 80 mg/kg). Our results show that sub-chronic PCP treatment induced a significant decrease in the discrimination index (DI) and both ampakines CX546 and CX516 were able to reverse this disruption of object memory in rats in the novel object recognition task. These data suggest that positive AMPAR modulation may represent a mechanism for treatment of cognitive deficits in schizophrenia.

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.

P.2.d.008 Evaluation of cognition enhancing properties of agomelatine in the object recognition task in rats

P.2.d.008 Evaluation of cognition enhancing properties of agomelatine in the object recognition task in rats

Comparison of single vs. multiple administrations of the AMPA receptors modulator S 18986 in the object recognition task in rats

The present study aimed at defining the best scheme of administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-positive modulator (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986) [once daily (o.d.) administration of 1 mg/kg for 3 days vs. three times daily (t.i.d.) administration of 0.3 mg/kg for 3 days] to get an optimal procognitive activity in the object recognition task in rats. Memory performance [Recognition Index (RI)] of rats was significantly improved 1 h (RI = 41%, P < 0.01) and 3 h (RI = 46%, P < 0.001) following oral administration of S 18986 (1 mg/kg, o.d.) when compared with animals receiving the vehicle (RI = 6%). When the interval between administration and testing was increased to 6 h and 9 h, no statistically significant improvement in memory performance was observed (RI = 42% for 6 h and RI = 18% for 9 h vs. 20% for the vehicle group). When S 18986 was administered at 0.3 mg/kg t.i.d., no statistically significant improvement in memory performance was observed (RI = 36%). These findings show a long-lasting efficacy of the AMPA receptor allosteric modulator in the object recognition task despite a short half-life in plasma and in brain (approximately 1 h). Accordingly, multiple administrations of S 18986 are not required to obtain a maximal efficacy in this paradigm, because a o.d. schedule of administration leads to a powerful procognitive activity.

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective alpha7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the alpha7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801- or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective alpha7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.

The object recognition task in rats and mice: A simple and rapid model in safety pharmacology to detect amnesic properties of a new chemical entity

Introduction The aim of the present study was to evaluate the potential usefulness of the object recognition learning paradigm to detect the potential amnesic properties of a new drug for use in the characterisation of its safety pharmacology profile. Methods and Results In the first experiment, the time-dependent decay of object recognition memory was characterised in Sprague–Dawley rats and C57Bl/6J mice. Under our experimental conditions, it takes between 3 and 4 post-training hours for the rats and between 1 and 2 post-training hours for the mice to forget the respective value of the objects. In the second experiment, the effects of scopolamine (0.03–1 mg/kg) were investigated in both rats and mice when administered 30 min prior to training in the object recognition task. Memory retention was tested 2 h after training in rats and 1 h after training in mice. Scopolamine impairs the object recognition memory at doses of 0.1, 0.3, and 1 mg/kg in rats and at doses of 0.3 and 1 mg/kg in mice. In the last experiment, effects of two benzodiazepines (alprazolam and diazepam) were assessed in the mouse model of object recognition task. Diazepam and alprazolam were intraperitoneally administered 30 min prior to training and memory retention was tested 10 min and 1 h after training. At 0.2 mg/kg, both benzodiazepines impair object recognition memory when testing is performed 1 h after training. However, when testing is performed 10 min after training, both benzodiazepines at 0.2 mg/kg failed to disrupt memory processes. Discussion Taken together, these results show that the object recognition task can easily be performed in rats and mice for safety pharmacology studies related to CNS function. Because of the ageing population and the increasing number of drugs prescribed to elderly patients, it becomes important to evaluate the potential side effects of a new chemical entity on memory function during evaluation of its safety profile. The object recognition task, which is simple, rapid, and reliable, should be of great use in safety pharmacology to detect amnesic properties of new compounds.

P.1.c.040 Long-lasting cognitive enhancing effects of S 18986, a positive modulator of AMPA receptors, in the object recognition task in rats

Pallet arrays enable cells to be separated while they remain adherent to a surface and provide a much greater range of cell selection criteria relative to that of current technologies. However there remains a need to further broaden cell selection criteria to include dynamic intracellular signaling events. To demonstrate the feasibility of measuring cellular protein behavior on the arrays using high resolution microscopy, the surfaces of individual pallets were modified to minimize the impact of scattered light at the pallet edges. The surfaces of the three-dimensional pallets on an array were patterned with a coating such as fibronectin using a customized stamping tool. Micropatterns of varying shape and size were printed in designated regions on the pallets in single or multiple steps to demonstrate the reliability and precision of patterning molecules on the pallet surface. Use of a fibronectin matrix stamped at the center of each pallet permitted the localization of H1299 and mouse embryonic fibroblast (MEF) cells to the pallet centers and away from the edges. Compared to pallet arrays with fibronectin coating the entire top surface, arrays with a central fibronectin pattern increased the percentage of cells localized to the pallet center by 3–4-fold. Localization of cells to the pallet center also enabled the physical separation of cells from optical artifacts created by the rough pallet side walls. To demonstrate the measurement of dynamic intracellular signaling on the arrays, fluorescence measurements of high spatial resolution were performed using a RhoA GTPase biosensor. This biosensor utilized fluorescence resonance energy transfer (FRET) between cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) to measure localized RhoA activity in cellular ruffles at the cell periphery. These results demonstrated the ability to perform spatially resolved measurements of fluorescence-based sensors on the pallet arrays. Thus, the patterned pallet arrays should enable novel cell separations in which cell selection is based on complex cellular signaling properties.

CGMP, but not cAMP, in rat hippocampus is involved in early stages of object memory consolidation

The present study investigates the role of cGMP and cAMP on the memory performance in the object recognition task in rats. The analogue 8-Br-GMP or 8-Br-cAMP was administered bilaterally into the hippocampus (0, 1, 3 and 10 μg in 0.5 μl saline/site) immediately after the exposure to two identical objects. After 24 h, saline-treated animals spent equal times exploring a new and the familiar object demonstrating that they did not recognize the familiar one. However, a dose-dependent improvement in object recognition was found after injection of 8-Br-cGMP. In contrast, 8-Br-cAMP did not improve the memory performance at the doses tested. These results indicate that hippocampal cGMP but not cAMP is involved in early stages of consolidation of object memory.

Effects of S 18986-1, a novel cognitive enhancer, on memory performances in an object recognition task in rats

( S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986-1) is a new compound that facilitates post-synaptic responses by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated synaptic responses and thus promotes long-term potentiation and potentiates ( S)-AMPA-induced release of noradrenaline in rat brain slices. In the present study, the effects of S 18986-1 were evaluated on cognitive functions by using a one-trial object-recognition test in the Wistar rat, a test which measures a form of episodic memory in rodents. Recognition was measured by the ability of treated rats to discriminate between a familiar and a new object after a 24-h retention delay. Oral administrations with S 18986-1 (0.3 to 100 mg/kg) 1 h before each session of the test improved object recognition at concentrations as low as 0.3 mg/kg. Under the same conditions, the nootropic drug aniracetam was active at a dose of 10 mg/kg by i.p. route. S 18986-1 was still effective on the object-recognition test when it was administered 4 h before each of the three sessions. Furthermore, subchronic oral pretreatment (7 days) with S 18986-1 (0.3 to 30 mg/kg) also increased the recognition of the familiar object indicating that the animals failed to develop tolerance to repeated administrations with S 18986-1. Finally, the recognition of the familiar object was improved when S 18986-1 was administered before the recognition trial whereas the rats failed to recognise the familiar object when S 18986-1 was administered before the sample presentation trial only. Taken together, the results indicated that S 18986-1 facilitated a form of episodic memory in the rat, by improving the recognition of a familiar information (retention). Furthermore, S 18986-1 was long-acting and demonstrated a good oral bioavailability. These data confer on S 18986-1, a potential role in improving episodic memory impaired in neurodegenerative diseases and during aging.