Profiling attention and cognition enhancing drugs in a rat touchscreen-based continuous performance test.

RATIONALE: A novel rodent continuous performance test (CPT) was developed as one of the goals of the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium to improve its translatability to the CPT test used in human subjects. OBJECTIVES: The objective of the study is to investigate the effects of attention and cognition enhancing drugs in rodent CPT. METHODS: A single cohort of rats were trained to asymptotic performance in the test. Pharmacological test sessions were then performed twice per week in a full crossover design with the following drugs tested: methylphenidate (0.3, 1, and 3 mg/kg), the α4ß2 nicotinic agonist ABT-594 (0.0023, 0.007 and 0.023 mg/kg), modafinil (8, 16, and 32 mg/kg), atomoxetine (0.3, 1, and 3 mg/kg), donepezil (0.1, 0.3, and 1 mg/kg), and memantine (1.25, 2.5, and 5 mg/kg). RESULTS: The stimulant-like drugs methylphenidate, ABT-594, and modafinil were found to increase measures of impulsivity and overall responding with generally no positive effects on d', a putative measure of attention, with the exception of ABT-594 which improved d' at the highest dose tested. Atomoxetine and the memory-enhancing drugs donepezil and memantine, on the other hand, were found to reduce measures of impulsivity and responding and had either negligible or worsening effects on d'. CONCLUSIONS: Our results suggest rodent CPT can detect changes in impulsivity resulting from drugs known to improve attention in rodents and humans. However, additional work is needed to assess the sensitivity and validity of this assay for assessing effects on attention.

Anticonvulsant effects of structurally diverse GABA(B) positive allosteric modulators in the DBA/2J audiogenic seizure test: Comparison to baclofen and utility as a pharmacodynamic screening model.

The GABA(B) receptor has been indicated as a promising target for multiple CNS-related disorders. Baclofen, a prototypical orthosteric agonist, is used clinically for the treatment of spastic movement disorders, but is associated with unwanted side-effects, such as sedation and motor impairment. Positive allosteric modulators (PAM), which bind to a topographically-distinct site apart from the orthosteric binding pocket, may provide an improved side-effect profile while maintaining baclofen-like efficacy. GABA, the major inhibitory neurotransmitter in the CNS, plays an important role in the etiology and treatment of seizure disorders. Baclofen is known to produce anticonvulsant effects in the DBA/2J mouse audiogenic seizure test (AGS), suggesting it may be a suitable assay for assessing pharmacodynamic effects. Little is known about the effects of GABA(B) PAMs, however. The studies presented here sought to investigate the AGS test as a pharmacodynamic (PD) screening model for GABA(B) PAMs by comparing the profile of structurally diverse PAMs to baclofen. GS39783, rac-BHFF, CMPPE, A-1295120 (N-(3-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide), and A-1474713 (N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide) all produced robust, dose-dependent anticonvulsant effects; a similar profile was observed with baclofen. Pre-treatment with the GABA(B) antagonist SCH50911 completely blocked the anticonvulsant effects of baclofen and CMPPE in the AGS test, indicating such effects are likely mediated by the GABA(B) receptor. In addition to the standard anticonvulsant endpoint of the AGS test, video tracking software was employed to assess potential drug-induced motor side-effects during the acclimation period of the test. This analysis was sensitive to detecting drug-induced changes in total distance traveled, which was used to establish a therapeutic index (TI = hypoactivity/anticonvulsant effects). Calculated TIs for A-1295120, CMPPE, rac-BHFF, GS39783, and A-1474713 were 5.31x, 5.00x, 4.74x, 3.41x, and 1.83x, respectively, whereas baclofen was <1. The results presented here suggest the DBA/2J mouse AGS test is a potentially useful screening model for detecting PD effects of GABA(B) PAMs and can provide an initial read-out on target-related motor side-effects. Furthermore, an improved TI was observed for PAMs compared to baclofen, indicating the PAM approach may be a viable therapeutic alternative to baclofen.

Cross-site strain comparison of pharmacological deficits in the touchscreen visual discrimination test.

The low rate of success for identifying effective treatments for cognitive dysfunction has prompted recent efforts to improve pharmaceutical discovery and development. In particular, investigators have emphasized improving translation from pre-clinical to clinical research. A specific area of focus has been touchscreen technology; this computer-automated behavioral testing method provides an objective assessment of performance that can be used across species. As part of a larger multi-site study with partners from the Innovative Medicines Initiative (IMI), two US sites, AbbVie and Pfizer, conducted a cross-site experiment with a common protocol for the visual discrimination (VD) task using identical testing equipment, stimuli, and rats of the same strains, sex, and age from the same supplier. As most touchscreen-based rodent experiments have used Lister-Hooded rats that are not readily available outside of Europe, a strain comparison with male Long-Evans rats was conducted as part of the study. Rats were trained for asymptotic performance, and test sessions were performed once per week in a full crossover design with cognition-impairing drugs. Drugs tested were phencyclidine and S-ketamine (N-methyl-D-aspartate (NMDA) antagonists), D-amphetamine (indirect dopamine agonist), and scopolamine (muscarinic antagonist). Satellite brain and plasma samples were taken to confirm appropriate exposures. Results indicate that both rat strains show similar patterns of impairment, although Lister-Hooded rats were more sensitive than Long-Evans rats to three out of four drugs tested. This suggests that researchers should fully explore dose-response relationships in their strain of choice and use care in the interpretation of reversal of cognitive impairment.

Nicotinic modulation of auditory evoked potential electroencephalography in a rodent neurodevelopmental model of schizophrenia.

Schizophrenia is a chronic disease that has been hypothesized to be linked to neurodevelopmental abnormalities. Schizophrenia patients exhibit impairments in basic sensory processing including sensory gating deficits in P50 and mismatch negativity (MMN). Neuronal nicotinic acetylcholine receptor (nAChR) agonists have been reported to attenuate these deficits. Gestational exposure of rats to methylazoxymethanol acetate (MAM) at embryonic day 17 leads to developmental disruption of the limbic-cortical system. MAM exposed offspring show neuropathological and behavioral changes that have similarities with those seen in schizophrenia. In this study, we aimed to assess whether N40 auditory sensory gating (the rodent form of P50 gating) and MMN deficits as measures of auditory evoked potential (AEP) electroencephalography (EEG) are present in MAM rats and whether nAChR agonists could attend the deficit. E17 male MAM and sham rats were implanted with cortical electrodes at 2 months of age. EEG recordings evaluating N40 gating and MMN paradigms were done comparing effects of vehicle (saline), nicotine and the α7 agonist ABT-107. Deficits were seen for MAM rats compared to sham animals in both N40 auditory sensory gating and MMN AEP recordings. There was a strong trend for N40 deficits to be attenuated by both nicotine (0.16mg/kg i.p. base) and ABT-107 (1.0mg/kg i.p. base). MMN deficits were significantly attenuated by ABT-107 but not by nicotine. These data support the MAM model as a useful tool for translating pharmacodynamic effects in clinical medicine studies of novel therapeutic treatments for schizophrenia.

Predictive validity of a MK-801-induced cognitive impairment model in mice: implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically.

Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS.

Discriminative-stimulus effects of NS9283, a nicotinic α4ß2* positive allosteric modulator, in nicotine-discriminating rats.

RATIONALE: Neuronal α4ß2* nicotinic acetylcholine receptors mediate cognition, pain, and the discriminative and reinforcing effects of nicotine. In addition to traditional orthosteric agonists, α4ß2* positive allosteric modulators (PAMs) have recently been identified. With increased subtype selectivity relative to agonists, PAMs administered alone or in combination with low-dose α4ß2* agonists may be used as powerful tools for increasing our understanding of α4ß2* pharmacology. OBJECTIVES: The present experiments tested the nicotine discriminative-stimulus effects of the α4ß2* PAM NS9283 (A-969933) in the presence and absence of low-dose nicotine or nicotinic subtype-selective agonist. METHODS: Rats were trained to discriminate 0.4 mg/kg nicotine from saline in a two-lever drug discrimination paradigm. In subsequent generalization tests, rats were administered nicotine, the α4ß2*-preferring agonist ABT-594, and NS9283, alone or in two-drug combinations. RESULTS: Nicotine and ABT-594 showed dose-dependent nicotine generalization. NS9283 alone resulted in a non-significant increase in nicotine-appropriate lever selection. Combination of non-effective doses of nicotine or ABT-594 with escalating doses of NS9283 resulted in a complete conversion to 100 % nicotine-appropriate choice in the case of nicotine combination and incomplete, though significant, generalization for ABT-594. CONCLUSIONS: The α4ß2* PAM NS9283 alone did not produce nicotine-like discriminative effects, but did demonstrate dose-related increases in nicotine lever choice when combined with a non-effective dose of nicotine or the α4ß2* agonist ABT-594. This finding provides confirmation of the positive allosteric modulating effect of NS9283 in a functional in vivo paradigm. NS9283 is a potentially valuable tool for studying the role of α4ß2* receptors in various nicotinic acetylcholine receptor-related functions.

Preclinical evaluation of non-imidazole histamine H3 receptor antagonists in comparison to atypical antipsychotics for the treatment of cognitive deficits associated with schizophrenia.

Cognitive deficits associated with schizophrenia (CDS) are implicated as a core symptom cluster of the disease and are associated with poor daily life functioning. Unfortunately, current antipsychotic agents provide little alleviation of CDS, representing a critical unmet therapeutic need. Here we investigated the effects of ABT-239 and A-431404, non-imidazole histamine H(3) receptor (H(3)R) antagonists, in animal models with relevance to CDS. As N-methyl-d-aspartate receptor hypofunction is considered an important factor in the pathogenesis of schizophrenia, acute administration of ketamine or MK-801 was used to induce cognitive impairments. The assays employed in the current studies were spontaneous alternation in cross-maze, used as an indication of working memory, and inhibitory avoidance (IA), used to assess long-term memory retention. Risperidone and olanzapine were also tested to directly compare the effects of H(3)R antagonists to two widely used antipsychotics. ABT-239 and A-431404, but not risperidone and olanzapine, attenuated ketamine-induced deficits on spontaneous alternation in cross-maze, while none of these compounds affected alternation performance on their own. ABT-239 and A-431404 also attenuated MK-801-induced impairments in IA; no effects were observed when given alone. Risperidone and olanzapine, however, failed to attenuate MK-801-induced deficits in IA and produced dose-dependent impairments when given alone. ABT-239 was also investigated in methylazoxymethanol acetate (MAM) treated rats, a neurodevelopmental model for schizophrenia. Chronic, but not acute, treatment with ABT-239 significantly improved spontaneous alternation impairments in MAM rats tested in cross-maze. In summary, these results suggest H(3)R antagonists may have the potential to ameliorate CDS.

Pharmacological properties and procognitive effects of ABT-288, a potent and selective histamine H3 receptor antagonist.

Blockade of the histamine H(3) receptor (H(3)R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H(3)R antagonist 2-[4'-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H(3)Rs (K(i) = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001-0.03 mg/kg), social recognition memory in adult rats (0.03-0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1-1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H(3)R occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, ABT-288 is a selective H(3)R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.

The scopolamine model as a pharmacodynamic marker in early drug development.

RATIONALE: Drug development is a high-risk and high failure enterprise, and studies that provide an early read on the pharmacodynamic activity of novel compounds could save time and money, increasing the efficiency of the drug development process. OBJECTIVE: Preclinical and clinical experiments were designed to examine the utility of the scopolamine-induced cognitive impairment model in predicting pharmacodynamic signals of putatively procognitive compounds, utilizing the acetylcholinesterase inhibitor donepezil for illustration. METHODS/RESULTS: In normal healthy rats, scopolamine (0.3 mg/kg) significantly impaired performance on the two-platform water maze and on the T-maze. The deficits in water maze performance were reversed by donepezil at 0.5 and 1.0 mg/kg. There was a trend towards reversal of scopolamine-induced deficits in performance on the T-maze with 1.0 mg/kg donepezil. In normal healthy humans, scopolamine (0.3 and 0.5 mg) reliably impaired performance on the Cognitive Drug Research test battery composite scores (power of attention, continuity of attention, quality of working memory, quality of episodic secondary memory, and speed of memory) in a dose- and time-dependent manner. Donepezil (10 mg) significantly attenuated the scopolamine-induced impairment in cognition on power of attention, continuity of attention, quality of working memory, and speed of memory. CONCLUSIONS: These findings suggest that reversal of scopolamine-induced cognitive impairment is a viable model for predicting pharmacodynamic signals of procognitive compounds in both animals and humans. The utility of the scopolamine-induced cognitive impairment model is discussed and illustrated at various decision points in drug development, with a focus on Go/No Go decisions.

Effects of α7 nicotinic acetylcholine receptor agonists on antipsychotic efficacy in a preclinical mouse model of psychosis.

RATIONALE: Antipsychotics normalize responses in the DBA/2 mouse model of prepulse inhibition (PPI), a preclinical model of sensorimotor gating deficits. The α7 nicotinic acetylcholine receptor (nAChR) as a molecular target is considered an attractive approach for improvement of cognitive deficits in schizophrenia (CDS). Assessment of clinical efficacy of novel agents in CDS involves treating patients already on antipsychotic medications. OBJECTIVE: We evaluated the effects of the combination of α7 nAChR agonists ABT-107 (0.1-10.0 mg/kg i.p.), A-582941 (0.04-4.0 mg/kg i.p.), and PNU282987 (1.0-10.0 mg/kg i.p.) with risperidone (0.1-1.0 mg/kg i.p.) or haloperidol (0.3-3.0 mg/kg i.p.), representative atypical and typical antipsychotic agents in the DBA/2 mouse PPI model. The same α7 agonists were given alone or in combination with a dose of antipsychotic medication that induces a minimal level of catalepsy in rats, an assay with predictive validity for the induction of extrapyramidal symptoms. RESULTS: The α7 nAChR agonists ABT-107, A-582941, and PNU282987 had no effect in DBA/2 mouse PPI when given alone yet increased the effects of haloperidol and risperidone. The α7 nAChR agonists did not cause catalepsy in rats, nor did they enhance antipsychotic-induced catalepsy. CONCLUSIONS: When given in combination with either a typical or atypical antipsychotic, α7 nAChR agonists did not impair efficacy in the DBA/2 J mouse PPI model. The efficacy but not the motoric side effects of antipsychotics was enhanced, suggesting that adjunctive therapy of α7 nAChR agonists not only could be useful for the treatment of cognitive deficits associated with schizophrenia but also could enhance the efficacy against positive symptoms.

Acute inhibition of 11beta-hydroxysteroid dehydrogenase type-1 improves memory in rodent models of cognition.

Mounting evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11ß-hydroxysteroid dehydrogenase type-1 (HSD1) regulates conversion of glucocorticoids from inactive to active forms. HSD1 knock-out mice have improved cognition, and the nonselective inhibitor carbenoxolone improved verbal memory in elderly men. Together, these data suggest that HSD1 inhibition may be a potential therapy for cognitive deficits, such as those associated with AD. To investigate this, we characterized two novel and selective HSD1 inhibitors, A-918446 and A-801195. Learning, memory consolidation, and recall were evaluated in mouse 24 h inhibitory avoidance. Inhibition of brain cortisol production and phosphorylation of cAMP response element-binding protein (CREB), a transcription factor involved in cognition, were also examined. Rats were tested in a short-term memory model, social recognition, and in a separate group cortical and hippocampal acetylcholine release was measured via in vivo microdialysis. Acute treatment with A-801195 (10-30 mg/kg) or A-918446 (3-30 mg/kg) inhibited cortisol production in the ex vivo assay by ∼ 35-90%. Acute treatment with A-918446 improved memory consolidation and recall in inhibitory avoidance and increased CREB phosphorylation in the cingulate cortex. Acute treatment with A-801195 significantly improved short-term memory in rat social recognition that was not likely due to alterations of the cholinergic system, as acetylcholine release was not increased in a separate set of rats. These studies suggest that selective HSD1 inhibitors work through a novel, noncholinergic mechanism to facilitate cognitive processing.

Structural abnormalities revealed by magnetic resonance imaging in rats prenatally exposed to methylazoxymethanol acetate parallel cerebral pathology in schizophrenia.

Schizophrenia is a highly familial, neurodevelopmental disorder that is associated with several neuropsychiatric, psychological, and neuropathological features. Although pharmacological animal models of dopaminergic and glutamatergic dysfunction have helped advance our understanding of the disease biology, there is a clear need for translational models that capture the neuropathological and functional manifestations associated with the intermediate phenotype and the clinical illness. Neuroimaging of preclinical neurodevelopmental approaches such as methylazoxymethanol acetate (MAM) exposure may afford a powerful translational tool to establish endpoints with greater congruency across animals and humans. Using in vivo volumetric magnetic resonance imaging (MRI), manganese-enhanced MRI, and diffusion tensor imaging (DTI), we investigated morphological and cytoarchitectural changes of brain structures in MAM-exposed rats, a neurodevelopmental model of schizophrenia. Compared to saline-exposed controls, MAM-exposed rats showed significant enlargement of lateral and third ventricles as well as reduced hippocampal volumes, which is consistent with findings observed in schizophrenia. In addition, DTI revealed that diffusion fractional anisotropy retrieved from corpus callosum and cingulum were significantly decreased in MAM-exposed rats, suggesting that demyelination occurred in these white-matter fiber tracts. Imaging findings were confirmed by conducting histological analysis using hematoxylin and eosin and Luxol fast blue stainings. In summary, structural abnormalities resulting from a MAM environmental challenge parallel cerebral pathology observed in schizophrenia. The MAM model incorporating noninvasive imaging techniques may therefore serve as an improved translational research tool for assessing new treatments for schizophrenia.

Behavioral characterization of a mutant mouse strain lacking D-amino acid oxidase activity.

D-amino acid oxidase (DAO), an enzyme that degrades d-serine, has been suggested as a susceptibility factor for schizophrenia. Here we sought to understand more about the behavioral consequence of lacking DAO and the potential therapeutic implication of DAO inhibition by characterizing a mouse strain (ddY/DAO(-)) lacking DAO activity. We found that the mutant mice showed enhanced prepulse inhibition responses (PPI). Intriguingly, DAO-/- mice had increased sensitivity to the PPI-disruptive effect induced by the competitive NMDA antagonist, SDZ 220-581. In the 24-h inhibitory avoidance test, DAO-/- mice were not different from DAO+/+ mice during the recall. In Barnes Maze, we found that DAO-/- mice had a shortened latency to enter the escape tunnel. Interestingly, although these mice were hypoactive when tested in a protected open field, they showed a profound increase of activity on the edge of the unprotected open field of the Barnes Maze even with the escape tunnel removed. This increased edge activity does not appear to be related to a reduced level of anxiety given that there were no significant genotype effects on the measures of anxiety-like behaviors in two standard animal models of anxiety, elevated plus maze and novelty suppressed feeding. Our data suggest that DAO-/- mice might have altered functioning of NMDARs. However, these results provide only modest support for manipulations of DAO activity as a potential therapeutic approach to treat schizophrenia.

Vogel conflict test: sex differences and pharmacological validation of the model.

Anxiety disorders affect approximately 20% of the population, and women are twice as likely as men to develop anxiety disorders. Despite these findings, little is known about the effects of gender on tolerability and therapeutic efficacy of anxiolytic drugs. Sex differences are also observed in rodents, even though the majority of preclinical behavioral studies are conducted on males. The aim of this study was to investigate sex differences in anxiety-like behavior using the Vogel conflict test and the pharmacological responsiveness to a variety of psychoactive drugs in rats. Pharmacological treatments clinically used for the treatment of anxiety were tested in male and female rats. Overall, female rats accepted fewer punished responses, had lower levels of water intake even when matched for weight, and had a lower pain threshold for electrical footshock than males. Diazepam and chlordiazepoxide displayed anxiolytic-like effects in both genders. In contrast, buspirone, propranolol, fluoxetine and paroxetine showed activity only in male rats. Morphine had no anxiolytic-like activity in either gender. Analysis of the estrous cycle did not reveal any effect of cycle stage on behavioral or drug responses. This investigation highlights the importance of using female subjects in the preclinical research of anxiety and the screening of anxiolytic compounds in the drug development process.

Treating the cognitive deficits of schizophrenia with alpha4beta2 neuronal nicotinic receptor agonists.

Schizophrenic patients exhibit debilitating impairments of intellectual function. Typical and atypical antipsychotic medications are largely ineffective at treating the cognitive deficits of schizophrenia (CDS), and efforts to discover compounds that treat these symptoms are ongoing. Considerable tobacco use in schizophrenic patients, genetic linkage, and receptor binding studies suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in schizophrenia. Neuronal alpha4beta2 nAChRs are widely distributed in the mammalian brain, and are implicated in normal cognitive functioning in animal models. Ligands of various selectivity and potency have been used to study the role of the alpha4beta2 subtype in schizophrenia. For instance, studies in rodents show that alpha4beta2 agonists improve sensory gating, an information processing function that is deficient in schizophrenia. Pharmacological studies in animals also suggest that alpha4beta2 nAChRs are involved in other cognitive domains that are impaired in schizophrenia, including speed of processing, working memory, visual learning and memory, and social cognition. The non-selective nAChR agonist nicotine has been shown to improve CDS in several human clinical studies, and recent trials have been undertaken to evaluate the efficacy of more alpha4beta2 selective compounds. It remains to be determined whether alpha4beta2 agonists will provide greater efficacy than nicotine for CDS or reducing tobacco use in patients. Pre-clinical evidence to date suggests that agonists of the nicotinic alpha4beta2 subtype could be useful in improving cognitive function in schizophrenic patients.

ABT-594 improves performance in the 5-choice serial reaction time task under conditions of increased difficulty, sub-chronic dosing, and in poorly-performing subjects.

Several studies have tested nicotinic receptor ligands in the 5-Choice Serial Reaction Time Task (5-CSRTT) with varying results. Some investigators have increased attentional demands by modifying task parameters or using aged or poor performing rats to observe treatment effects. This study examined the alpha4beta2 nicotinic agonist ABT-594 in the 5-CSRTT using a variety of manipulations to determine optimal conditions for observing enhancement. ABT-594 had no effect in drug-naïve adult rats that self-initiated trials. Constant trial presentation decreased accuracy and omissions, with the latter significantly attenuated by acute administration of ABT-594 (0.019-0.062 micromol/kg). Sub-chronic treatment (0.019 micromol/kg) initially impaired drug-naïve subjects, but significant improvements in accuracy and decreased omissions were observed after 5 days of dosing. In 18-22 month-old rats, attentional demands were altered by interspersing blocks of trials with different stimulus durations. Acute ABT-594 (0.062 micromol/kg) enhanced accuracy performance in poor performing rats (<70% accuracy) but not in those that performed well (>80% accuracy), while omissions were decreased in both groups. Sub-chronic treatment with (0.019 micromol/kg) decreased omissions in all rats, but enhanced accuracy primarily in poor performing rats. These experiments demonstrate that an alpha4beta2 nicotinic agonist can enhance attention, but accuracy effects may only be observed under specific conditions. Moreover, a reduction in omissions was more reliably observed than improvements in accuracy, resulting in a net increase in signals successfully detected.

Mice expressing the Swedish APP mutation on a 129 genetic background demonstrate consistent behavioral deficits and pathological markers of Alzheimer's disease.

Mutant Tg2576 mice which possess the human "Swedish" APP mutation have been shown to demonstrate both Abeta plaque pathology and memory deficits in behavioral tasks. These mice are routinely maintained on a mixed C57BL/6xSJL genetic background which exhibits a high frequency of retinal degeneration allele and high variability in many behavioral assays. The same APP mutation is also available maintained on a 129 genetic background, providing more genetic homogeneity, but little data are published regarding the effects of the mutation on this background. We investigated whether transgenic mice expressing the Swedish mutation on the 129 background show similar behavioral deficits and Abeta pathology as those on the mixed background. Mice on the 129 background were tested at 6-7, 11-12, or 18-19 months of age in locomotor activity, Y-maze spontaneous alternation, and contextual fear conditioning. Differences were detected between WT and Tg mice in locomotor activity at 6-7 and 18-19 months, Y-maze at 6-7 and 11-12 months, and fear conditioning at 6-7, 11-12, and 18-19 months. In contrast, Tg mice on the mixed B6/SJL background tested at 6-7 months only demonstrated significant impairment in the contextual fear conditioning assay and in the Y-maze in one of 2 cohorts tested. Despite the behavioral differences observed, similar Abeta pathology was observed between Tg mice on the two genetic backgrounds. These results indicate that mice on the 129 genetic background may generate more consistent and robust behavioral differences, providing a useful model for testing therapeutic agents for Alzheimer's disease.

Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders.

The purinergic P2X(7) receptor is a ligand-gated ion channel found on peripheral macrophages and microglia in the nervous system. Activation of P2X(7) receptors results in the rapid release of interleukin-1 beta (IL-1 beta). Cytokines like IL-1 beta are suggested to be involved in the pathophysiology of depression. The aim of this study was to behaviorally profile P2X(7) receptor knockout (KO) mice in behavioral models of depression- and anxiety-like behaviors. P2X(7) receptor KO and wild type (WT) mice were tested in multiple models including; forced swim test, tail suspension test, elevated plus maze, novelty suppressed feeding, spontaneous locomotor activity, and food intake. P2X(7) receptor KO mice exhibited an antidepressant-like profile in tail suspension test and forced swim test; an effect that was not associated with changes in spontaneous locomotor activity. In addition, P2X(7) receptor KO mice showed higher responsivity to a subefficacious dose of the antidepressant drug imipramine (15 mg/kg) in forced swim test. No significant differences between genotypes were observed in models of anxiety. These data support the relevance of pro-inflammatory cytokines in depressive-like states, and suggest that P2X(7) receptor antagonists could be of potential interest for the treatment of affective disorders.

A-366833: a novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane alpha4beta2 nicotinic acetylcholine receptor selective agonist: Synthesis, analgesic efficacy and tolerability profile in animal models.

5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) is a novel nicotinic acetylcholine receptor (nAChR) ligand that binds to the agonist-binding site ([3H]-cytisine) with Ki value of 3.1 nM and exhibits agonist selectivity at alpha4beta2 nAChR relative to the alpha3beta4 nAChR subtype. The analgesic effects of A-366833 were examined across a variety of animal models including the mouse model of writhing pain (abdominal constriction), the rat models of acute thermal (hot box), persistent chemical (formalin) and neuropathic (spinal nerve ligation, SNL) pain. In the abdominal constriction model, A-366833 was effective at doses ranging from 0.062 to 0.62 micromol/kg (i.p.). In addition, A-366833 demonstrated significant effects in acute thermal pain (6.2-19.0 micromol/kg, i.p.), formalin (1.9-19 micromol/kg i.p.) and SNL (1.9-19 micromol/kg i.p.) models. The systemic effects of A-366833 were attenuated by pretreatment with mecamylamine (5 micromol/kg i.p.) in both the formalin and SNL models, suggesting that the analgesic effects of A-366833 in models of persistent nociceptive and neuropathic pain are mediated by activation of nAChRs. Pharmacokinetic investigations of A-366833 in rat revealed moderate brain:plasma distribution, half-life of 1.5h and excellent oral bioavailability of 73%. Comparison of peak plasma levels at the minimal effective doses across rat models of acute thermal pain, formalin and SNL with the maximal exposure that does not evoke emesis in ferret revealed therapeutic margins ranging from 6- to 22-fold. These studies indicate that compounds like A-366833 with improved agonist selectivity at alpha4beta2 vs. alpha3beta4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects.

Effects of antipsychotics and selective D3 antagonists on PPI deficits induced by PD 128907 and apomorphine.

Rats treated with apomorphine and amphetamine display sensorimotor gating impairments, as measured by prepulse inhibition (PPI), and these impairments can be reversed by antipsychotic treatment. However, it remains unknown whether the dopamine (DA) D(3) receptor plays a role in mediating these effects on PPI, as none of these DA agonists or antipsychotics are exclusively selective at either D(2) or D(3) receptors. To address this question, the current study was designed to investigate whether antipsychotic drugs and selective D(3) antagonists could block the PPI-disruptive effects of PD 128907 (a preferential D(3) agonist) and apomorphine. We found that the effect of PD 128907 on PPI in rats could be antagonized by risperidone, clozapine, and the selective D(3) antagonists SB 277011 and A-691990, but not by raclopride or haloperidol, while the apomorphine-induced PPI deficit could be reversed by risperidone, clozapine and haloperidol, but not by SB 2770111 and A-691990. These results suggest that the D(3) receptor does not mediate apomorphine-induced disruption of PPI in rats, however, given the findings that PD 128907 elicited a PPI-disruptive effect that was blocked by selective D(3) antagonists, a role of D(3) receptor in mediating PPI in rats cannot be ruled out. The possible mechanisms of D(3) receptor involvement in PPI are discussed.