Probiotics: Potential novel therapeutics for microbiota-gut-brain axis dysfunction across gender and lifespan.

Probiotics are live microorganisms, which when administered in adequate amounts, present a health benefit for the host. While the beneficial effects of probiotics on gastrointestinal function are generally well recognized, new animal research and clinical studies have found that alterations in gut microbial communities can have a broad range of effects throughout the body. Non-intestinal sites impacted include the immune, endocrine, cardiovascular and the central nervous system (CNS). In particular, there has been a growing interest and appreciation about the role that gut microbiota may play in affecting CNS-related function through the 'microbiota-gut-brain axis'. Emerging evidence suggests potential therapeutic benefits of probiotics in several CNS conditions, such as anxiety, depression, autism spectrum disorders and Parkinson's disease. There may also be some gender-specific variances in terms of probiotic mediated effects, with the gut microbiota shaping and being concurrently molded by the hormonal environment governing differences between the sexes. Probiotics may influence the ability of the gut microbiome to affect a variety of biological processes in the host, including neurotransmitter activity, vagal neurotransmission, generation of neuroactive metabolites and inflammatory response mediators. Some of these may engage in cross talk with host sex hormones, such as estrogens, which could be of relevance in relation to their effects on stress response and cognitive health. This raises the possibility of gender-specific variation with regards to the biological action of probiotics, including that on the endocrine and central nervous systems. In this review we aim to describe the current understanding in relation to the role and use of probiotics in microbiota-gut-brain axis-related dysfunction. Furthermore, we will address the conceptualization and classification of probiotics in the context of gender and lifespan as well as how restoring gut microbiota composition by clinical or dietary intervention can help in supporting health outcomes other than those related to the gastrointestinal tract. We also evaluate how these new learnings may impact industrial effort in probiotic research and the discovery and development of novel and more personalized, condition-specific, beneficial probiotic therapeutic agents.

IgM response against amyloid-beta in aging: a potential peripheral protective mechanism.

BACKGROUND: The immune system plays a major role in the pathogenesis of age-related dementia, including Alzheimer's disease (AD). An insight into age-associated changes in the immune response to amyloid-beta (Aß) in individuals without AD may be beneficial in identifying mechanisms preventing accumulation of Aß. METHODS: We examined the response of human monocyte-derived dendritic cells (DCs), T cells, and peripheral blood mononuclear cells (PBMCs) from healthy aged and young subjects to Aß peptide 1-42, Aß fibrils, and recombinant, nonaggregated tau-4 protein with a view to understand the role of peripheral immunity in AD. RESULTS: Our studies revealed that DCs from healthy aged subjects display weak reactivity towards the Aß peptide and no reactivity towards Aß fibrils and tau compared with their young counterparts. An analysis of old and young PBMCs revealed that there is no significant T-cell memory against Aß peptide, fibrils, or tau. Remarkably, the plasma levels of IgM antibodies specific to Aß peptide 1-42 were significantly increased in aged subjects compared with young subjects, while IgG levels were comparable. Aß peptide-specific IgM and IgG levels were also determined in the plasma of AD subjects compared with age-matched controls to demonstrate that the immune response against Aß is stronger in AD patients. A decline in Aß peptide-specific IgM antibodies was observed in AD patients compared with age-matched controls. In contrast, the levels of IgG as well as interleukin-21, the major cytokine involved in class switching, were increased in AD and patients with mild cognitive impairment, indicating a strong immune response against Aß. CONCLUSIONS: Collectively, low immunogenicity of Aß in healthy controls may prevent inflammation while the generation of specific IgM antibodies may help in the clearance of Aß in healthy subjects.

Pattern separation and goal-directed behavior in the aged canine.

The pattern separation task has recently emerged as a behavioral model of hippocampus function and has been used in several pharmaceutical trials. The canine is a useful model to evaluate a multitude of hippocampal-dependent cognitive tasks that parallel those in humans. Thus, this study was designed to evaluate the suitability of pattern separation task(s) for detecting age-related changes in canines. We also assessed the dogs' ability to show pattern separation and discrimination reversal, which provides a novel extension of the pattern separation learning literature. Our data show that aged dogs are impaired on a complex pattern separation task (six-well task) relative to easier tasks (four-well or six-well pattern discrimination task), and that the age-related deficits are due to loss of perceptual and inhibitory control in addition to the loss of spatial discrimination and pattern separation ability. Our data also suggest that aged animals show pattern separation deficits when the objects are brought progressively closer together while changing the location of both correct and incorrect objects. However, if the location of any one object is fixed the animals tend to use alternate strategies. Overall, these data provide important insight into age-related pattern separation deficits in a higher animal model and offers additional means for evaluating the impact of lifestyle and pharmaceutical interventions on episodic memory in preclinical trials.

H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus.

An increasing number of studies show that an altered epigenetic landscape may cause impairments in regulation of learning and memory-related genes within the aged hippocampus, eventually resulting in cognitive deficits in the aged brain. One such epigenetic repressive mark is trimethylation of H3K9 (H3K9me3), which is typically implicated in gene silencing. Here, we identify, for the first time, an essential role for H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions. Pharmacological inhibition of SUV39H1 using a novel and selective inhibitor decreased levels of H3K9me3 in the hippocampus of aged mice, and improved performance in the objection location memory and fear conditioning tasks and in a complex spatial environment learning task. The inhibition of SUV39H1 induced an increase in spine density of thin and stubby but not mushroom spines in the hippocampus of aged animals and increased surface GluR1 levels in hippocampal synaptosomes, a key index of spine plasticity. Furthermore, there were changes at BDNF exon I gene promoter, in concert with overall BDNF levels in the hippocampus of drug-treated animals compared with control animals. Together, these data demonstrate that SUV39H1 inhibition and the concomitant H3K9me3 downregulation mediate gene transcription in the hippocampus and reverse age-dependent deficits in hippocampal memory. SIGNIFICANCE STATEMENT: Cognitive decline is a debilitating condition associated with not only neurodegenerative diseases but also aging in general. However, effective treatments have been slow to emerge so far. In this study, we demonstrate that epigenetic regulation of key synaptic proteins may be an underlying, yet reversible, cause of this decline. Our findings suggest that histone 3 trimethylation is a probable target for pharmacological intervention that can counteract cognitive decline in the aging brain. Finally, we provide support to the hypothesis that, by manipulating the enzyme that regulates H3K9me3 (using a newly developed specific inhibitor of SUV39H1), it is possible to alter the chromatin state of subjects and restore memory and synaptic function in the aging brain.

Effect of mitochondrial cofactors and antioxidants supplementation on cognition in the aged canine.

A growing body of research has focused on modifiable risk factors for prevention and attenuation of cognitive decline in aging. This has led to an unprecedented interest in the relationship between diet and cognitive function. Several preclinical and epidemiologic studies suggest that dietary intervention can be used to improve cognitive function but randomized controlled trials are increasingly failing to replicate these findings. Here, we use a canine model of aging to evaluate the effects of specific components of diet supplementation which contain both antioxidants and a combination of mitochondrial cofactors (lipoic acid [LA] and acetyl-l-carnitine) on a battery of cognitive functions. Our data suggest that supplementation with mitochondrial cofactors, but not LA or antioxidant alone, selectively improve long-term recall in aged canines. Furthermore, we found evidence that LA alone could have cognitive impairing effects. These results contrast to those of a previous longitudinal study in aged canine. Our data demonstrate that one reason for this difference may be the nutritional status of animals at baseline for the 2 studies. Overall, this study suggests that social, cognitive, and physical activity together with optimal dietary intake (rather than diet alone) promotes successful brain aging.

Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1ß in the aged hippocampus.

In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1ß (IL-1ß). In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1ß impairment. In hippocampal neuronal cultures, IL-1ß increased the expression of the IL-1 receptor type 1 and the accessory coreceptor AcP (proinflammatory), but not of the AcPb (prosurvival) subunit, a reconfiguration that potentiates the responsiveness of neurons to IL-1ß. To evaluate whether synapses develop a similar heightened sensitivity to IL-1ß with age, we used an assay to track long-term potentiation (LTP) in synaptosomes. We found that IL-1ß impairs LTP directly at the synapse and that sensitivity to IL-1ß is augmented in aged hippocampal synapses. The increased synaptic sensitivity to IL-1ß was due to IL-1 receptor subunit reconfiguration, characterized by a shift in the AcP/AcPb ratio, paralleling our culture data. We suggest that the age-related increase in brain IL-1ß levels drives a shift in IL-1 receptor configuration, thus heightening the sensitivity to IL-1ß. Accordingly, selective blocking of AcP-dependent signaling with Toll-IL-1 receptor domain peptidomimetics prevented IL-1ß-mediated LTP suppression and blocked the memory impairment induced in aged mice by peripheral immune challenge (bacterial lipopolysaccharide). Overall, this study demonstrates that increased AcP signaling, specifically at the synapse, underlies the augmented vulnerability to cognitive impairment by IL-1ß that occurs with age.

Exercise enhances memory consolidation in the aging brain.

Exercise has been shown to reduce age-related losses in cognitive function including learning and memory, but the mechanisms underlying this effect remain poorly understood. Memory formation occurs in stages that include an initial acquisition phase, an intermediate labile phase, and then a process of consolidation which leads to long-term memory formation. An effective way to examine the mechanism by which exercise improves memory is to introduce the intervention (exercise), post-acquisition, making it possible to selectively examine memory storage and consolidation. Accordingly we evaluated the effects of post-trial exercise (10 min on a treadmill) on memory consolidation in aged canines both right after, an hour after, and 24 h after acute exercise training in concurrent discrimination, object location memory (OLM), and novel object recognition tasks. Our study shows that post-trial exercise facilitates memory function by improving memory consolidation in aged animals in a time-dependent manner. The improvements were significant at 24 h post-exercise and not right after or 1 h after exercise. Aged animals were also tested following chronic exercise (10 min/day for 14 consecutive days) on OLM or till criterion were reached (for reversal learning task). We found improvements from a chronic exercise design in both the object location and reversal learning tasks. Our studies suggest that mechanisms to improve overall consolidation and cognitive function remain accessible even with progressing age and can be re-engaged by both acute and chronic exercise.

Pyroglutamate-3 amyloid-ß deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models.

Amyloid-ß (Aß) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Aß), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Aß peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Aß deposition in humans and animal models. PyroGlu-3 Aß immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general Aß IR. PyroGlu-3 Aß is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 Aß deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general Aß deposition preceding pyroGlu-3 Aß deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 Aß is a major species of ß-amyloid deposited early in diffuse and focal plaques and cerebral amyloid angiopathy in humans and nonhuman primates, whereas it is deposited later in a subset of focal and vascular amyloid in AD-like transgenic mouse models. Given the proposed decisive role of pyroGlu-3 Aß peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap.

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease.

Caspase-3 activation as a bifurcation point between plasticity and cell death.

Death-mediating proteases such as caspases and caspase-3 in particular, have been implicated in neurodegenerative processes, aging and Alzheimer's disease. However, emerging evidence suggests that in addition to their classical role in cell death, caspases play a key role in modulating synaptic function. It is remarkable that active caspases-3, which can trigger widespread damage and degeneration, aggregates in structures as delicate as synapses and persists in neurons without causing acute cell death. Here, we evaluate this dichotomy, and discuss the hypothesis that caspase-3 may be a bifurcation point in cellular signaling, able to orient the neuronal response to stress down either pathological/apoptotic pathways or towards physiological cellular remodeling. We propose that temporal, spatial and other regulators of caspase activity are key determinants of the ultimate effect of caspase-3 activation in neurons. This concept has implications for differential roles of caspase-3 activation across the lifespan. Specifically, we propose that limited caspase-3 activation is critical for synaptic function in the healthy adult brain while chronic activation is involved in degenerative processes in the aging brain.

Age and distraction are determinants of performance on a novel visual search task in aged Beagle dogs.

Aging has been shown to disrupt performance on tasks that require intact visual search and discrimination abilities in human studies. The goal of the present study was to determine if canines show age-related decline in their ability to perform a novel simultaneous visual search task. Three groups of canines were included: a young group (N = 10; 3 to 4.5 years), an old group (N = 10; 8 to 9.5 years), and a senior group (N = 8; 11 to 15.3 years). Subjects were first tested for their ability to learn a simple two-choice discrimination task, followed by the visual search task. Attentional demands in the task were manipulated by varying the number of distracter items; dogs received an equal number of trials with either zero, one, two, or three distracters. Performance on the two-choice discrimination task varied with age, with senior canines making significantly more errors than the young. Performance accuracy on the visual search task also varied with age; senior animals were significantly impaired compared to both the young and old, and old canines were intermediate in performance between young and senior. Accuracy decreased significantly with added distracters in all age groups. These results suggest that aging impairs the ability of canines to discriminate between task-relevant and -irrelevant stimuli. This is likely to be derived from impairments in cognitive domains such as visual memory and learning and selective attention.

Dietary and behavioral interventions protect against age related activation of caspase cascades in the canine brain.

Lifestyle interventions such as diet, exercise, and cognitive training represent a quietly emerging revolution in the modern approach to counteracting age-related declines in brain health. Previous studies in our laboratory have shown that long-term dietary supplementation with antioxidants and mitochondrial cofactors (AOX) or behavioral enrichment with social, cognitive, and exercise components (ENR), can effectively improve cognitive performance and reduce brain pathology of aged canines, including oxidative damage and Aß accumulation. In this study, we build on and extend our previous findings by investigating if the interventions reduce caspase activation and ceramide accumulation in the aged frontal cortex, since caspase activation and ceramide accumulation are common convergence points for oxidative damage and Aß, among other factors associated with the aged and AD brain. Aged beagles were placed into one of four treatment groups: CON--control environment/control diet, AOX--control environment/antioxidant diet, ENR--enriched environment/control diet, AOX/ENR--enriched environment/antioxidant diet for 2.8 years. Following behavioral testing, brains were removed and frontal cortices were analyzed to monitor levels of active caspase 3, active caspase 9 and their respective cleavage products such as tau and semaphorin7a, and ceramides. Our results show that levels of activated caspase-3 were reduced by ENR and AOX interventions with the largest reduction occurring with combined AOX/ENR group. Further, reductions in caspase-3 correlated with reduced errors in a reversal learning task, which depends on frontal cortex function. In addition, animals treated with an AOX arm showed reduced numbers of cells expressing active caspase 9 or its cleavage product semaphorin 7A, while ENR (but not AOX) reduced ceramide levels. Overall, these data demonstrate that lifestyle interventions curtail activation of pro-degenerative pathways to improve cellular health and are the first to show that lifestyle interventions can regulate caspase pathways in a higher animal model of aging.

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

RATIONALE: 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. OBJECTIVES: 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. METHODS: Female-hooded Lister rats received vehicle or PCP (2 mg/kg, i.p.) for 7 days, followed by a 7-day washout. On the test day, rats were given asenapine (0.001-0.1 mg/kg, s.c.) alone or in combination with the D(1) receptor antagonist SCH-23390 (0.05 mg/kg, i.p.) or 5-HT(1A) receptor antagonist WAY100635 (1 mg/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 3 min (retention trial) were recorded onto videotape and scored blind. RESULTS: In the retention trial, vehicle- but not PCP-treated animals explored the novel object significantly more than the familiar object (p < 0.001). Asenapine (0.01-0.075 mg/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. CONCLUSIONS: 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.

Phencyclidine (PCP)-induced disruption in cognitive performance is gender-specific and associated with a reduction in brain-derived neurotrophic factor (BDNF) in specific regions of the female rat brain.

Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n=8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p<0.05), motor cortex (p<0.01), orbital cortex (p<0.01), olfactory bulb (p<0.05), retrosplenial cortex (p<0.001), frontal cortex (p<0.01), parietal cortex (p<0.01), CA1 (p<0.05) and polymorphic layer of dentate gyrus (p<0.05) of the hippocampus and the central (p<0.01), lateral (p<0.05) and basolateral (p<0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p<0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism.

Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive deficits of relevance to schizophrenia in rodents and their subsequent reversal by first- and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-Choice Serial Reaction Time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel pharmacological agents for improved therapy of cognitive deficits and negative symptoms in schizophrenia.

Subchronic effects of phencyclidine on dopamine and serotonin receptors: implications for schizophrenia.

Changes in representative dopamine (D(1), D(2), and D(4)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors that have been implicated in the pathophysiology and treatment of schizophrenia were autoradiographically quantified after subchronic phencyclidine (PCP) treatment (2 mg/kg for 7 days, bi-daily followed by 7 days drug free). This treatment has consistently induced robust and long-lasting cognitive deficits in adult rats, although the molecular mechanisms contributing to PCP-induced cognitive deficits remain undefined. Repeated PCP treatment significantly decreased labeling of D(1) receptors in the medial and lateral caudate-putamen (22% and 23%, respectively) and increased 5HT(1A) receptor binding in the medial-prefrontal (26%) and dorsolateral-frontal cortex (30%). No changes in D(1) or 5HT(1A) receptors were detected in other brain regions. These findings suggest that downregulation of striatal D(1) receptors and upregulation of cortical 5HT(1A) receptors may contribute to PCP-induced impairment of cognitive functions in rats. Subchronic PCP treatment did not alter levels of D(2), D(4), and 5HT(2A) receptors in all brain regions examined, which suggests a minimal role for these receptors in mediating subchronic actions of PCP in adult rats.

Effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain; comparison with effects of 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC260584) and N-desmethylclozapine.

We have demonstrated that the main metabolite of clozapine, N-desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M(1) receptor agonist effect of N-desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M(1) receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline>xanomeline approximately AC260584>N-desmethylclozapine. The present study suggests that the binding potency of muscarinic M(1) receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.

Improvement of phencyclidine-induced social behaviour deficits in rats: involvement of 5-HT1A receptors.

We have recently shown that sub-chronic phencyclidine (PCP) treatment produces social behaviour deficits in female rats which are reversed by ziprasidone but not haloperidol or clozapine. This investigation was designed to extend the previous findings and identify the role of 5-HT(1A) receptors in mediating the effects of these drugs in this model. Female hooded-Lister rats received vehicle (n=36; intraperitoneal (i.p.)) or PCP (n=22; 2mg/kg, i.p.) twice daily for 7 days, followed by a 7-day washout period. On test days, PCP-treated rats were treated acutely with aripiprazole (5mg/kg, s.c.) or WAY100635 (0.5mg/kg, i.p.) alone and in combination. In a second experiment, PCP-treated rats were treated acutely with either fluoxetine (2.5mg/kg, i.p.) or chlordiazepoxide (CDP) (2.5mg/kg, i.p.) all 30 min prior to testing. For the test, pairs of unfamiliar rats receiving acute doses of drugs described above were placed in the test arena and social behaviours (following, sniffing, climbing over and under, exploration of inanimate object and avoiding) were recorded on video for subsequent blind scoring. The results showed that PCP-induced deficits in social behaviours were reversed by acute treatment with both aripiprazole and fluoxetine but not CDP or WAY100635. Furthermore, pre-treatment with WAY100635 prevented the reversal of social behaviour deficits observed with aripiprazole. These findings suggest that the beneficial effects of drugs such as aripiprazole and fluoxetine on PCP-induced social behaviour deficits, a potential model of negative symptoms of schizophrenia, may be a consequence of modifications of the serotonergic system, in particular through an interaction with 5-HT(1A) receptors.

Efficacy of antipsychotics to reverse phencyclidine-induced social interaction deficits in female rats--a preliminary investigation.

Sub-chronic phencyclidine (PCP) treatment mimics certain aspects of schizophrenia symptomology in rats. However, there is a marked lack of attempts to model negative symptomology such as social behaviour deficits in female rats. This study was conducted to assess whether sub-chronic PCP treatment produces social interaction deficits in female rats and to ascertain if these deficits can be reversed by either typical (haloperidol) or atypical (clozapine and ziprasidone) antipsychotics.