Deficits In Novel Object Recognition Research Articles

Asenapine improves phencyclidine-induced object recognition deficits in the rat: evidence for engagement of a dopamine D1 receptor mechanism

Cognitive deficits are common in schizophrenia. Asenapine is an atypical antipsychotic approved by the US Food and Drug Administration in adults for treatment of schizophrenia or acute treatment, as monotherapy or adjunct therapy to lithium or valproate, of manic or mixed episodes of bipolar I disorder. Based on the receptor pharmacology of asenapine, the current study assessed the efficacy and mechanism of action of asenapine to improve a subchronic phencyclidine (PCP)-induced deficit in visual recognition memory using the novel object recognition (NOR) paradigm in the rat, a paradigm of relevance to cognition in schizophrenia. Female-hooded Lister rats received vehicle or PCP (2mg/kg, i.p.) for 7days, followed by a 7-day washout. On the test day, rats were given asenapine (0.001-0.1mg/kg, s.c.) alone or in combination with the D(1) receptor antagonist SCH-23390 (0.05mg/kg, i.p.) or 5-HT(1A) receptor antagonist WAY100635 (1mg/kg, i.p.). Time spent exploring two identical objects during a 3-min acquisition trial (followed by a 1-min intertrial interval) and then a familiar and a novel object for another 3min (retention trial) were recorded onto videotape and scored blind. In the retention trial, vehicle- but not PCP-treated animals explored the novel object significantly more than the familiar object (p < 0.001). Asenapine (0.01-0.075mg/kg) reversed PCP-induced deficits in NOR (p < 0.01-0.001) in a dose-related manner. This effect was antagonised by SCH-23390 but not by WAY100635. These results demonstrate a role for D(1) but not 5-HT(1A) receptor mechanisms in mediating the cognitive effects of asenapine in this rodent model.

PD168077, a D4 receptor agonist, reverses object recognition deficits in rats: potential role for D4 receptor mechanisms in improving cognitive dysfunction in schizophrenia

This study investigated the effects of the dopamine D(4) receptor agonist, PD168077, on recognition memory using a novel object recognition task, which detects disruption and improvement of recognition memory in rats by measuring their ability to discriminate between familiar and novel objects. When acquisition and test were 6 h apart (experiment 1), control rats failed to discriminate between familiar and novel objects at test. Rats given low doses of PD168077 (0.3; 1.0 mg/kg) also failed to discriminate between the objects, while rats given higher doses (3.0; 10.0 mg/kg) explored the novel object more than the familiar object, indicating retained memory of the familiar object. Thus, at higher doses, PD168077 improved recognition memory in rats. Experiment 2 tested whether PD168077 would attenuate deficits in novel object recognition induced by sub-chronic phencyclidine. Testing was 1 min after acquisition, such that vehicle pre-treated rats differentiated between the novel and familiar objects: however, sub-chronic phencyclidine-treated rats failed to discriminate between the two, indicating disruption of recognition memory. PD168077 (10 mg/kg) restored the ability of phencyclidine-treated rats to differentiate between the novel and familiar objects, indicating improved recognition memory. The results suggest that D(4) receptor activation can improve cognitive dysfunction in an animal model relevant to schizophrenia.

The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat

Current antipsychotics are ineffective at treating the negative and cognitive symptoms of schizophrenia, so there is a substantial need to develop more effective therapeutics for this debilitating disorder. The type II metabotropic glutamate receptor (mGluR2/3) is a novel, potential therapeutic target requiring evaluation in appropriate preclinical models of schizophrenia. This study evaluated the potent, selective mGluR2/3 agonist, LY379268, on the behavioural deficits induced by rearing rat pups in social isolation from weaning, a neurodevelopmental model of schizophrenia, to investigate its antipsychotic potential. Male Lister Hooded rats were weaned on post-natal day 23-25 and either group-housed (3-4 per cage) or isolation-reared for 6 weeks. At subsequent weekly intervals, animals received acute systemic injection of either vehicle or LY379268 (1 mg/kg; i.p.) 30 min prior to recording locomotor activity in a novel arena, novel object recognition, pre-pulse inhibition of acoustic startle and conditioned emotional response paradigms. Isolation rearing induced locomotor hyperactivity, deficits in novel object recognition, conditioned emotional behaviour and attenuated the magnitude of the initial acoustic startle response in the PPI paradigm compared to that of group-housed controls. LY379268 reversed the isolation-induced locomotor hyperactivity, the object recognition deficit, and restored startle responses in isolated animals, whilst having no effect on conditioned emotional response impairments. These data show that LY379268 can reverse some, but not all, post-weaning social isolation-induced changes which have translational relevance to core symptom defects in schizophrenia and support a potential therapeutic role of mGluR2/3 agonists in its treatment.

Lack of Neurotensin type1 receptor facilitates contextual fearmemory depending on the memory strength

Early studies suggest that selective α2C-adrenoceptor (AR)-antagonism has anti-psychotic-like and pro-cognitive properties. However, this has not been demonstrated in an animal model of schizophrenia with a neurodevelopmental construct. The beneficial effects of clozapine in refractory schizophrenia and associated cognitive deficits have, among others, been associated with its α2C-AR modulating activity. Altered brain-derived neurotrophic factor (BDNF) has been linked to schizophrenia and cognitive deficits. We investigated whether the α2C-AR antagonist, ORM-10921, could modulate sensorimotor gating and cognitive deficits, as well as alter striatal BDNF levels in the social isolation reared (SIR) model of schizophrenia, comparing its effects to clozapine and the typical antipsychotic, haloperidol, the latter being devoid of α2C-AR-activity. Moreover, the ability of ORM-10921 to augment the effects of haloperidol on the above parameters was also investigated. Animals received subcutaneous injection of either ORM-10921 (0.01 mg/kg), clozapine (5 mg/kg), haloperidol (0.2 mg/kg), haloperidol (0.2 mg/kg) + ORM-10921 (0.01 mg/kg) or vehicle once daily for 14 days, followed by assessment of novel object recognition (NOR), prepulse inhibition (PPI) of startle response and striatal BDNF levels. SIR significantly attenuated NOR memory as well as PPI, and reduced striatal BDNF levels vs. social controls. Clozapine, ORM-10921 and haloperidol + ORM-10921, but not haloperidol alone, significantly improved SIR-associated deficits in PPI and NOR, with ORM-10921 also significantly improving PPI deficits vs. haloperidol-treated SIR animals. Haloperidol + ORM-10921 significantly reversed reduced striatal BDNF levels in SIR rats. α2C-AR-antagonism improves deficits in cognition and sensorimotor gating in a neurodevelopmental animal model of schizophrenia and bolsters the effects of a typical antipsychotic, supporting a therapeutic role for α2C-AR-antagonism in schizophrenia.

Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine2A Receptor Inverse Agonist

Subchronic administration of the N-methyl-d-aspartate receptor antagonist, phencyclidine (PCP), in rodents has been shown to produce impairment in novel object recognition (NOR), a model of visual learning and memory. We tested the hypothesis that the selective 5-HT(2A) inverse agonists, pimavanserin and (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4-piperidinemethanol (M100907), would potentiate subeffective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Female rats received vehicle or PCP (2 mg/kg b.i.d.) for 7 days, followed by a 7-day washout. Pimavanserin (3 mg/kg) or M100907 (1 mg/kg) alone, or four atypicial APDs, risperidone (0.05-0.1 mg/kg), melperone (1-3 mg/kg), olanzapine (1-2 mg/kg), or N-desmethylclozapine (1-2 mg/kg), and the typical APD, haloperidol (0.05-0.1 mg/kg), were administered alone, or in combination with pimavanserin or M100907, before NOR testing. The exploration times of objects during 3-min acquisition and retention trials, separated by a 1-min interval, were compared by analysis of variance. Vehicle-, but not PCP-treated, animals, explored the novel object significantly more than the familiar in the retention trial (p < 0.05-0.01). Pretreatment with the higher doses of the atypical APDs, but not pimavanserin, M100907, or haloperidol alone, reversed the effects of PCP. The effect of risperidone was blocked by haloperidol pretreatment. Coadministration of pimavanserin or M100907, with ineffective doses of the atypical APDs, but not haloperidol, also reversed the PCP-induced deficit in NOR. These results support the importance of 5-hydroxytryptamine(2A) receptor blockade relative to D(2) receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia.

Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT6 and 5-HT2A receptor mechanisms

This study examined the efficacy of sertindole in comparison with a selective 5-HT(6) and a 5-HT(2A) receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats. In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT(2A) receptor antagonist M100.907 or the selective 5-HT(6) receptor antagonist SB-742457. The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT(6) receptor in vivo binding in striatum, although contribution from binding to 5-HT(2A) receptors in vivo in cortex may also provide an important mechanism. The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.

Endogenous κ Opioid Activation Mediates Stress-Induced Deficits in Learning and Memory

We hypothesized that mice subjected to prolonged stress would demonstrate decreased performance in a learning and memory task attributable to the endogenous activation of the kappa opioid receptor (KOR). C57BL/6J mice were tested using the novel object recognition (NOR) assay at various time points after exposure to repeated forced swim stress (FSS). Unstressed mice demonstrated recognition of the novel object at the end of a procedure using three 10-min object interaction phases, with a recognition index (RI) for the novel object of 71.7+/-3.4%. However, 1 h after exposure to FSS, vehicle-pretreated mice displayed a significant deficit in performance (RI=58.2+/-4.1%) compared with unstressed animals. NOR was still significantly reduced 4 but not 24 h after FSS. Treatment with the KOR-selective antagonist norbinaltorphimine (10 mg/kg, i.p.) prevented the decline in learning and memory performance. Moreover, direct activation of the KOR induced performance deficits in NOR, as exogenous administration of the KOR agonist U50,488 [(+/-)-trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide] (0.3 mg/kg, i.p.) suppressed NOR (RI=56.0+/-3.9%). The effect of FSS on NOR performance was further examined in mice lacking the gene for the endogenous KOR agonist dynorphin (Dyn). Dyn gene-disrupted mice exposed to FSS did not show the subsequent learning and memory deficits (RI=66.8+/-3.8%) demonstrated by their wild-type littermates (RI=49.7+/-2.9%). Overall, these results suggest that stress-induced activation of the KOR may be both necessary and sufficient to produce subsequent deficits in novel object recognition.

Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition

The Tg2576 transgenic mouse is an extensively characterized animal model for Alzheimer's disease (AD). Similar to AD, these mice suffer from progressive decline in several forms of declarative memory including contextual fear conditioning and novel object recognition (NOR). Recent work on this and other AD animal models suggests that initial cognitive deficits are due to synaptic dysfunction that, with the correct intervention, are fully treatable. We recently reported that acute calcineurin (CaN) inhibition with FK506 ameliorates one form of declarative memory (contextual fear conditioning) impairment in 5 months old Tg2576. This study tested whether acute CaN inhibition rescues deficits in an additional form of declarative memory, spontaneous object recognition, by employing the NOR paradigm. Furthermore, we determined whether FK506 rescue of NOR deficits depends on the retention interval employed and therefore is restricted to short-term, intermediate-term, or long-term memory (STM, ITM or LTM, respectively). In object recognition, Tg2576 are unimpaired when NOR is tested as a STM task and CaN inhibition with FK506 does not influence NOR STM performance in Tg2576 or WT mice. Tg2576 were impaired in NOR compared to WT mice when a 4 or 24 h retention interval was employed to model ITM and LTM, respectively. Acute CaN inhibition prior to and during the training session reversed these deficits in Tg2576 mice with no effect on WT performance. Our findings demonstrate that aberrant CaN activity mediates object recognition deficits in 5 months old Tg2576 when NOR is employed as a test for ITM and LTM. In human AD, CaN inhibition may lead the way for therapeutics to improve declarative memory performance as demonstrated in a mouse model for AD.

The Behavioral and Neurochemical Effects of a Novel d-Amino Acid Oxidase Inhibitor Compound 8 [4H-Thieno [3,2-b]pyrrole-5-carboxylic Acid] and d-Serine

Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC(50), 145 nM) and rat (IC(50), 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by approximately 96% and brain DAAO activity by approximately 80%. This marked decrease in DAAO activity resulted in a significant (p < 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.

Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat

Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment. The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration. CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05). Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.

Amelioration of recognition memory impairment associated with iron loading or aging by the type 4-specific phosphodiesterase inhibitor rolipram in rats

Increasing evidence indicates that iron deposition in the brain might play a role in cognitive dysfunction associated with neurodegenerative disorders and aging. Previous studies have not examined whether iron-induced memory deficits can be attenuated by acute treatments with memory-enhancing agents. Phosphodiesterase type 4 (PDE4) inhibitors such as rolipram (ROL) ameliorate memory impairments in several rodent models of amnesia and have been proposed as candidate cognitive-enhancing drugs. Here we show that a single posttraining systemic injection of ROL dose-dependently attenuates the impairment of memory for novel object recognition (NOR) in rats given neonatal iron loading, a model of iron-induced cognitive impairment. Posttraining administration of ROL also recovered NOR deficits associated with aging in rats. These findings provide the first evidence that stimulation of an intracellular second messenger signaling pathway can attenuate iron-induced memory impairment, and support the view that PDE4 inhibitors might ameliorate cognitive dysfunction associated with aging and neurodegenerative disorders.

Interferon-α-induced deficits in novel object recognition are rescued by chronic exercise

The anti-viral drug interferon-alpha (IFN-α) is widely-known to induce psychiatric and cognitive effects in patients. Previous work has shown that physical exercise can have a positive effect against brain insult. We investigated the effects of a clinically-comparable treatment regime of IFN-α on cognitive function in male Wistar rats and assessed the impact of chronic treadmill running on the deficits generated by IFN-α. We found that IFN-α induced significant impairments in performance on both spatial novelty and object novelty recognition. Chronic forced exercise did not protect against IFN-α-induced learning deficits in reactivity to spatial change, but did restore the capacity for novel object recognition in IFN-α-treated animals.

P.1.085 The effect of bupropion on the activity of dopamine transporter in depression — preliminary results

Current antipsychotic medication is largely ineffective against the negative and cognitive symptoms of schizophrenia. One promising therapeutic development is to design new molecules that balance actions on dopamine D2 and D3 receptors to maximise benefits and limit adverse effects. This study used two rodent paradigms to investigate the action of the dopamine D3-preferring D3/D2 receptor partial agonist cariprazine. In adult male rats, cariprazine (0.03–0.3 mg/kg i.p.), and the atypical antipsychotic aripiprazole (1–3 mg/kg i.p.) caused dose-dependent reversal of a delay-induced impairment in novel object recognition (NOR). Treating neonatal rat pups with phencyclidine (PCP) and subsequent social isolation produced a syndrome of behavioural alterations in adulthood including hyperactivity in a novel arena, deficits in NOR and fear motivated learning and memory, and a reduction and change in pattern of social interaction accompanied by increased ultrasonic vocalisations (USVs). Acute administration of cariprazine (0.1 and 0.3 mg/kg) and aripiprazole (3 mg/kg) to resultant adult rats reduced neonatal PCP-social isolation induced locomotor hyperactivity and reversed NOR deficits. Cariprazine (0.3 mg/kg) caused a limited reversal of the social interaction deficit but neither drug affected the change in USVs or the deficit in fear motivated learning and memory. Results suggest that in the behavioural tests investigated cariprazine is at least as effective as aripiprazole and in some paradigms it showed additional beneficial features further supporting the advantage of combined dopamine D3/D2 receptor targeting. These findings support recent clinical studies demonstrating the efficacy of cariprazine in treatment of negative symptoms and functional impairment in schizophrenia patients.

5-HT 1A and 5-HT 2A receptor gene expression in schizophrenia

Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D2, D3, D4, serotonin (5-HT)1A, and 5-HT2A receptors (Rs), full agonism at α4β2 nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5-HT2B, 5-HT6, and 5-HT7Rs. Most atypical APDs are 5-HT2A inverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)-as well as amphetamine-induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP-induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co-administration of a sub-effective dose (SED) of RP5063 with SEDs of a 5-HT7R antagonist, a 5-HT1BR antagonist, a 5-HT2AR inverse agonist, or an α4β2 nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre-treatment with a 5-HT1AR, a D4R, antagonist, but not an α4β2 nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co-administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP-treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia.

Circulating l-arginine metabolites and platelet nitric oxide synthase in schizophrenics

Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D2, D3, D4, serotonin (5-HT)1A, and 5-HT2A receptors (Rs), full agonism at α4β2 nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5-HT2B, 5-HT6, and 5-HT7Rs. Most atypical APDs are 5-HT2A inverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)-as well as amphetamine-induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP-induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co-administration of a sub-effective dose (SED) of RP5063 with SEDs of a 5-HT7R antagonist, a 5-HT1BR antagonist, a 5-HT2AR inverse agonist, or an α4β2 nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre-treatment with a 5-HT1AR, a D4R, antagonist, but not an α4β2 nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co-administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP-treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia.