Alpha7 Nicotinic Receptor Agonist Research Articles

Alpha-7 Nicotinic Receptor Agonist Protects Mice Against Pulmonary Emphysema Induced by Elastase.

Pulmonary emphysema is a primary component of chronic obstructive pulmonary disease (COPD), a life-threatening disorder characterized by lung inflammation and restricted airflow, primarily resulting from the destruction of small airways and alveolar walls. Cumulative evidence suggests that nicotinic receptors, especially the α7 subtype (α7nAChR), is required for anti-inflammatory cholinergic responses. We postulated that the stimulation of α7nAChR could offer therapeutic benefits in the context of pulmonary emphysema. To investigate this, we assessed the potential protective effects of PNU-282987, a selective α7nAChR agonist, using an experimental emphysema model. Male mice (C57BL/6) were submitted to a nasal instillation of porcine pancreatic elastase (PPE) (50µl, 0.667IU) to induce emphysema. Treatment with PNU-282987 (2.0mg/kg, ip) was performed pre and post-emphysema induction by measuring anti-inflammatory effects (inflammatory cells, cytokines) as well as anti-remodeling and anti-oxidant effects. Elastase-induced emphysema led to an increase in the number of α7nAChR-positive cells in the lungs. Notably, both groups treated with PNU-282987 (prior to and following emphysema induction) exhibited a significant decrease in the number of α7nAChR-positive cells. Furthermore, both groups treated with PNU-282987 demonstrated decreased levels of macrophages, IL-6, IL-1β, collagen, and elastic fiber deposition. Additionally, both groups exhibited reduced STAT3 phosphorylation and lower levels of SOCS3. Of particular note, in the post-treated group, PNU-282987 successfully attenuated alveolar enlargement, decreased IL-17 and TNF-α levels, and reduced the recruitment of polymorphonuclear cells to the lung parenchyma. Significantly, it is worth noting that MLA, an antagonist of α7nAChR, counteracted the protective effects of PNU-282987 in relation to certain crucial inflammatory parameters. In summary, these findings unequivocally demonstrate the protective abilities of α7nAChR against elastase-induced emphysema, strongly supporting α7nAChR as a pivotal therapeutic target for ameliorating pulmonary emphysema.

The Novel Antipsychotic Drug Cariprazine and Cognition Enhancing Drugs: Indications for their Use as the Add-on Therapy in Schizophrenia.

Schizophrenia and schizoaffective disorder are treated with antipsychotic drugs. Some patients show treatment-resistant forms of psychotic disorders, and in this case, they can be treated with clozapine. Based on the previous reviews on novel antipsychotic drugs, it is important to know whether the add-on therapy with the new drugs can ameliorate the positive and negative schizophrenic scale (PANSS) total score. The aim of this review is to suggest an appropriate treatment for patients with treatment-resistant forms of psychotic disorders. A combination of the currently available antipsychotic drugs with novel antipsychotic or modulating drugs might improve negative schizophrenic symptoms and cognitive function and thereby social functioning and quality of life. The mechanisms of action, the therapeutic effects, and the pharmacokinetic profiles of novel antipsychotic drugs such as cariprazine, brexipiprazole, and lumateperone have been updated. Published case reports of patients with treatment-resistant psychoses have also been discussed in this study. These patients were treated only with clozapine, as a result of which a high PANSS total score was observed. Only the add-on therapy with cariprazine improved the score, and above all, the negative schizophrenic symptoms and cognitive functions were improved. For the ensurance of a constant antipsychotic drug concentration, long-acting injectable antipsychotic drugs might be a choice for the maintenance therapy in schizophrenia. New modulating drugs, such as receptor positive allosteric modulators (N-methyl-D-aspartate receptor; subtype 5 of the metabotropic glutamatergic receptor) and encenicline, an alpha7 nicotinic cholinergic receptor agonist, have been investigated in preclinical and clinical trials. In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know whether combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total score. In schizophrenia, long-acting injectable antipsychotic drugs are safe and tolerable maintenance therapy. In further clinical studies, it should be investigated whether patients with treatment-resistant forms of psychoses can improve negative schizophrenic symptoms and cognitive functions by the add-on therapy with cognitionenhancing drugs.

Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation.

The aim of the trial was to assess whether extending plasma levels of the alpha7-nicotinic acetylcholine receptor (nAChR) agonist 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) over time enhances its cognitive effects in schizophrenia. Both smoking and non-smoking patients were studied, to determine whether effects differ between these two groups. Forty-three smokers and thirty-seven non-smokers who met DSM-IV criteria for schizophrenia were enrolled in a double-blind, randomized, placebo-controlled 1 month trial. DMXB-A 150 mg was formulated with hypromellose to produce extended release over 4 h and administered four times daily. The primary outcome (the Neurocognitive Composite of the MATRICS Consensus Cognitive Battery) and secondary outcomes (the MATRICS Attention-Vigilance Domain and P50 gating), showed no significant effect. Plasma levels were obtained 2.5 h post administration. In non-smokers, levels were similar to those reached transiently with 75-150 mg DMXB-A immediate-release formulations twice daily, which were earlier shown to be effective doses. However, the extended-release formulation produced no cognitive or clinical effect either in non-smokers or smokers. The 10-fold lower DMXB-A plasma levels in smokers suggest that chronic smoking enhances DMXB-A metabolism. Pro-cognitive effects of DMXB-A may result from transient increases in cell signaling that are limited by receptor tachyphylaxis. Future efforts to improve cognition in schizophrenia by enhancing alpha7 nAChR function may require consideration of these pharmacokinetic limitations.

Brief Report: Initial Trial of Alpha7-Nicotinic Receptor Stimulation in Two Adult Patients with Autism Spectrum Disorder.

Abnormalities in CHRNA7, the alpha7-nicotinic receptor gene, have been reported in autism spectrum disorder. These genetic abnormalities potentially decrease the receptor's expression and diminish its functional role. This double-blind, placebo-controlled crossover study in two adult patients investigated whether an investigational receptor-specific partial agonist drug would increase the inhibitory functions of the gene and thereby increase patients' attention. An electrophysiological biomarker, P50 inhibition, verified the intended neurobiological effect of the agonist, and neuropsychological testing verified a primary cognitive effect. Both patients perceived increased attention in their self-ratings. Alpha7-nicotinic receptor agonists, currently the target of drug development in schizophrenia and Alzheimer Disease, may also have positive clinical effects in autism spectrum disorder.

Targeting Functional Biomarkers in Schizophrenia with Neuroimaging.

Many of the most debilitating symptoms for psychiatric disorders such as schizophrenia remain poorly treated. As such, the development of novel treatments is urgently needed. Unfortunately, the costs associated with high failure rates for investigational compounds as they enter clinical trials has led to pharmaceutical companies downsizing or eliminating research programs needed to develop these drugs. One way of increasing the probability of success for investigational compounds is to incorporate alternative methods of identifying biological targets in order to more effectively screen new drugs. A promising method of accomplishing this goal for psychiatric drugs is to use functional magnetic resonance imaging (fMRI). fMRI investigates neural circuits, shedding light on the biology that generates symptoms such as hallucinations. Once identified, relevant neural circuits can be targeted with pharmacologic interventions and the response to these drugs measured with fMRI. This review describes the early use of fMRI in this context, and discusses the alpha7 nicotinic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A), as an example of the potential value of fMRI for psychiatric drug development.

Symptômes négatifs de la schizophrénie : nouvelles approches pharmacologiques

The management of negative symptoms appears to be a major challenge because of functional disability induced by these symptoms and their relative resistance to treatments currently on the market. The aim of this article is to review new approaches that may enable optimal management of these symptoms. First, we describe the methodological difficulties that hindered the development and evaluation of specific treatment, and objectives currently defined to enable the development of new pharmacological approaches. Then we present the monotherapy and adjuvant therapies that have been assessed, including first and second generation antipsychotics, psychostimulants, antidepressants, cholinergic and glutamatergic agents, the oxytocin, hormones and more invasive therapies such as transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT). Other molecules are under development and evaluation such alpha-7 nicotinic receptor agonists.

Rapid and Green Chemistry Catalysis in Synthesis of Hexahydroquinazolinones and Cyclopenta, Cyclohepta[d]Pyrimidinones with Prediction of Biological Activity via PASS INET

Ceric Ammonium Nitrate (CAN), turns out to be commercially available, efficient and mild catalyst for synthesis of polyhydro-2Hcycloalka[d]pyrimidinones and hexahydroquinazolinones in few minutes. Accompanied with Predictions of the activity spectra of some selected compounds using PASS INET. at Pa > 50%, showing high probability of Protein kinase (CK1) inhibitor and Alpha7 nicotinic receptor agonist. However Cycloheptene systems showed some important targets including, Insulin growth factor agonist, and Acetylcholine nicotinic agonist and Tumour necrosis factor agonist.

Selective Alpha7 Nicotinic Receptor Agonist Increases Cardiac Function in Isolated Mouse Hearts by a Non-Nicotinic Mechanism

Selective alpha7 nicotinic receptor agonists, such as GTS-21, are known to have neuroprotective and anti-inflammatory actions, but the effect of these agents on the heart is not known. Therefore, we evaluated the actions of GTS-21 in isolated atria and isolated hearts from C57BL/6 mice. GTS-21 (1-100 μM) caused a concentration-dependent increase in amplitude of contractions and decrease in beating rate in isolated atria. Percent changes in rate and contractile force evoked by 30 μM GTS-21 were −14 ± 2 and +36 ± 11, respectively (n = 4). The onset of responses to GTS-21 was slower than would occur to acetylcholine and norepinephrine, and effects of GTS-21 were not blocked by atropine or atenolol. The impact of GTS-21 on left ventricular function was evaluated next in isolated hearts paced at 400 BPM. Treatment with 30 µM GTS-21 caused significant increases in contractile function: developed pressure (+30 ± 4%); peak systolic pressure (+16 ± 2%); dP/dtmax (+31 ± 6%). Diastolic pressure was also decreased (−60 ± 10%) while the rate of relaxation increased (-dP/dtmax, +36 ± 6%) with no sizable change in coronary perfusion pressure (p < 0.05 for all parameters, n = 4). Surprisingly, responses to GTS-21 were not affected by a selective alpha7 antagonist or the nonselective nicotinic antagonist mecamylamine, and there was no evidence of desensitization. Our data demonstrate that GTS enhances atrial and ventricular contractility and improves LV relaxation with a modest decrease in heart rate. GTS-21 cardiac actions occur by a mechanism that is independent of nicotinic receptors and autonomic nerves. The unique profile of cardiac effects for GTS-21 suggests its potential use in the setting of acute heart failure.

A new isoxazolic compound acts as alpha7 nicotinic receptor agonist in human umbilical vein endothelial cells.

Recent evidence suggests that the alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) participate in the development of angiogenesis and could be a new endothelial target for revascularization in therapeutic angiogenesis. It has been shown that in human umbilical vein endothelial cells (HUVECs) alpha7 nAChR agonists increase the intracellular calcium concentration ([Ca2+]i), thus inducing proliferation and vessel formation which are important stages of angiogenesis. In the present study we evaluated the effect of new isoxazole compounds on the cytosolic Ca2+ signal in HUVECs using the fluorescent Ca2+ indicator Fluo-3AM and probing the involvement of alpha7 nAChR by means of pharmacological tools. HUVECs expressed mainly alpha7 nAChR, since there was no significant difference in the increase in [Ca2+]i induced by nicotine, a non-selective nicotinic agonist, in relation to choline, a selective alpha7 nAChR agonist. The increase in [Ca2+]i induced by 1 mM choline was inhibited significantly (p = 0.014) in cells which had been pre-incubated for 15 min with methyllycaconitine (MLA), a selective alpha7 nAChR antagonist. The studied compounds 1, 2, and 3 induced an increase in [Ca2+]i in a dose-dependent manner. Compound 1 at 10 microM induced a greater increase in [Ca2+]i than compounds 2 and 3. The increase in [Ca2+]i induced by compound 1 was significantly inhibited by MLA (p = 0.013) and completely inhibited by mecamylamine, a non-selective nAChR antagonist, indicating that the isoxazolic compound 1 acts as an alpha7 nAChR agonist.

Motor and Anxiety Effects of PNU-282987, An Alpha7 Nicotinic Receptor Agonist, and Stress in an Animal Model of Alzheimer’s Disease

Behavioral and Psychological Symptoms in Dementia (BPSD) are also seen in Alzheimer's disease (AD), being agitation and anxiety common symptoms. Since cholinergic agonists used to be the first pharmacological intervention in AD and this neurotransmission system have been related to cognitive and behavioral symptoms in this serious disease, we here address the question of a possible therapeutic role of PNU-282987 (PNU), an alpha7 nicotinic agonist, in motor activity and anxiety-like behaviors in an animal model of AD. On the other hand, since stress is an unavoidable condition in our daily activities, which activates physiological systems and deregulates body's homeostasis, we also evaluated the possible precipitating effects of stress in the onset of behavioral deficits in animals with susceptibility to AD. A dose of 0 or 1 mg/kg of PNU was administered to transgenic mice under restrained stress or not, resulting in 4 experimental groups: SAL, PNU, SAL-STR, PNU-STR. The main goal of this study was to evaluate the possible therapeutic role of PNU- 282987 alpha7 nicotinic agonist in motor activity and anxiety-like behaviors, as well as the possible effects of stress in precipitating the onset of behavioral deficits in animals with susceptibility to AD. The present results suggest a differential effect of stress (p=0.011) and PNU (p= 0.009) on anxiety evaluated in an open field depending on genetic vulnerability. Moreover, PNU seems to reverse stress effects in the same apparatus. This was also observed when a more sensitive task such as the zero maze was used.

Effects of an Alpha7 Nicotinic Receptor Agonist and Stress on Spatial Memory in an Animal Model of Alzheimer's Disease

The aim of the present study was to test the effects of PNU-282987 on spatial learning and memory and hippocampal neurogenesis in both intact and chronically stressed transgenic mice. Transgenic mice with susceptibility to Alzheimer's disease (AD) under immobilization stress and not-stressed animals receiving 0 and 1 mg/kg of PNU-282987 (PNU) were evaluated in a water maze task. The effects of PNU and stress on proliferation of new cells in the hippocampus of these animals were also assessed. The latency to escape the platform was significantly higher in transgenic stressed mice compared to those in the wild stressed group, as well as in transgenic animals without PNU compared to control wild group. On retention of the task, differences emerged on stressed wild animals, PNU wild group, and stressed wild mice receiving PNU. However, no significant differences were detected on new cell proliferation. The results of the present study did not show any impact of stress in acquisition of a spatial task both in wild and transgenic mice. No clear effects of PNU on acquisition of a spatial task in transgenic mice with susceptibility to AD were detected. Although PNU and stress effects were detected on retention of the task in wild animals, no changes were noted in transgenic mice.

Differential Immediate and Sustained Memory Enhancing Effects of Alpha7 Nicotinic Receptor Agonists and Allosteric Modulators in Rats

The α7 nicotinic acetylcholine receptor (nAChR) is a potential target for the treatment of cognitive deficits in patients with schizophrenia, ADHD and Alzheimer's disease. Here we test the hypothesis that upregulation of α7 nAChR levels underlies the enhanced and sustained procognitive effect of repeated administration of α7 nAChR agonists. We further compare the effect of agonists to that of α7 nAChR positive allosteric modulators (PAMs), which do not induce upregulation of the α7 nAChR. Using the social discrimination test as a measure of short-term memory, we show that the α7 nAChR agonist A-582941 improves short-term memory immediately after repeated (7× daily), but not a single administration. The α7 nAChR PAMs PNU-120596 and AVL-3288 do not affect short-term memory immediately after a single or repeated administration. This demonstrates a fundamental difference in the behavioral effects of agonists and PAMs that may be relevant for clinical development. Importantly, A-582941 and AVL-3288 increase short-term memory 24 hrs after repeated, but not a single, administration, suggesting that repeated administration of both agonists and PAMs may produce sustained effects on cognitive performance. Subsequent [125I]-bungarotoxin autoradiography revealed no direct correlation between α7 nAChR levels in frontal cortical or hippocampal brain regions and short-term memory with either compound. Additionally, repeated treatment with A-582941 did not affect mRNA expression of RIC-3 or the lynx-like gene products lynx1, lynx2, PSCA, or Ly6H, which are known to affect nAChR function. In conclusion, both α7 nAChR agonists and PAMs exhibit sustained pro-cognitive effects after repeated administration, and altered levels of the α7 nAChR per se, or that of endogenous regulators of nAChR function, are likely not the major cause of this effect.

Alpha7 nicotinic receptor agonists interrupt the interaction between fibrillar amyloid and nicotinic receptor in Alzheimer's brain

Alpha7 nicotinic receptor agonists interrupt the interaction between fibrillar amyloid and nicotinic receptor in Alzheimer's brain

No Efficacy Found for GABA Agent in Improving Cognition in Schizophrenia

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessNo Efficacy Found for GABA Agent in Improving Cognition in SchizophreniaJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:4 Feb 2011https://doi.org/10.1176/pn.46.3.psychnews_46_3_028AbstractFor some time now, there has been reason to believe that raising levels of the neurotransmitter GABA in the brain might help correct some of the cognitive defects that people with schizophrenia experience.For example, GABA is crucial for the regulation of prefrontal cortex function, and postmortem studies have found decreased levels of GABA expression in the prefrontal cortex of individuals with schizophrenia. GABA has been shown to be crucial for normal working memory, and individuals with schizophrenia have been found to have working memory impairments.In addition, a GABA deficiency in the visual cortex has been identified in study subjects with schizophrenia and linked with a visual-perception problem often present in people with schizophrenia (Psychiatric News, May 7, 2010).Moreover, a small pilot study headed by David Lewis, M.D., a professor and chair of psychiatry at the University of Pittsburgh, published in the December 2008 American Journal of Psychiatry found that subjects with schizophrenia performed better on memory and several other cognitive tests after being given a partial GABA agonist called MK-0777 than after being given a placebo.Other scientists have now explored the same drug's potential in this domain in a larger trial. They were not able, however, to confirm the findings of Lewis and his team, they reported online December 9, 2010, in Biological Psychiatry.The lead investigator was Robert Buchanan, M.D., a professor of psychiatry and a schizophrenia expert at the University of Maryland.Sixty clinically stable individuals with DSM-IV-diagnosed schizophrenia were enrolled in a four-week, multicenter, double-blind, placebo-controlled trial. They were randomized to receive either MK-0777 3 mg b.i.d., MK-0777 8 mg b.i.d, or a placebo. Each subject's cognition was evaluated at the start of the study and four weeks later. Cognitive outcomes for the three groups were compared.There were no significant differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery. Participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than subjects getting either MK-0777 dosage.These results “suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia,” Buchanan and his colleagues concluded.Nonetheless, they believe that GABA is still a promising target for improving cognition in people with schizophrenia, they noted, and that a more potent GABA agonist than MK-0777 might be effective. “The rationale for why GABA agents should work is compelling,” Buchanan told Psychiatric News.There are also other promising drugs for improving cognition in people with schizophrenia, he pointed out—the alpha7 nicotinic receptor agonists and glycine T1 reuptake inhibitors, for example.The study was funded by the National Institute of Mental Health.An abstract of “A Randomized Clinical Trial of MK-0777 for the Treatment of Cognitive Impairments in People With Schizophrenia” is posted at <www.biologicalpsychiatryjournal.com/article/S0006-3223(10)01053-X/abstract>. ISSUES NewArchived

Behavioral effects of PNU-282987, an alpha7 nicotinic receptor agonist, in mice

The cholinergic system is closely related to learning and memory processes, and its neurodegeneration seems to be involved in neurodegenerative and neuropsychiatric cognitive disorders in the elderly. Alpha7 nicotinic acetylcholine receptors (nAChRs) have recently been shown to mediate neuroprotection and enhance cognitive performance in a variety of tasks, suggesting that there may be a new target for the pharmacotherapy of cognitive deficiencies. In this study, we investigated the behavioral effects of the acute and sub-chronic administration of 0, 1, 3, and 5 mg/kg of PNU-282987 (PNU) on motor activity, anxiety and learning in open-field and Morris water maze tasks in mice. Our results showed that the highest dose of PNU (5 mg/kg) diminished motor activity in the open-field following 5 and 12 days of administration (acute and sub-chronic, respectively). No effects on the acquisition of the Morris water maze were observed. However, only 1 mg/kg of PNU administered just before training trials over a period of 5 days showed beneficial effects on the retention of the water maze when evaluated 4 h after water maze acquisition. Further studies are needed to clarify the effects on the cognitive performance and potential neuroprotection of these agents in an elderly population with slight or severe deficiency in learning and memory processes, and/or in animal models vulnerable to neurodegenerative disorders.

Characterization of the alpha-7 nicotinic receptor agonist WYE-103914 in models relevant to schizophrenia and interaction with antipsychotics

Characterization of the alpha-7 nicotinic receptor agonist WYE-103914 in models relevant to schizophrenia and interaction with antipsychotics

Evp-6124: Safety, Tolerability And Cognitive Effects Of A Novel A7 Nicotinic Receptor Agonist In Alzheimer'S Disease Patients On Stable Donepezil Or Rivastigmine Therapy

Approved symptomatic therapies for Alzheimer's disease (AD) provide modest relief. In the future, it is likely that symptomatic treatments will be utilized with AD modifying therapies, the development of which are currently a primary focus of research. The nicotinic a-7 receptor agonist may be an attractive drug candidate to potentially improve cognition in Alzheimer's disease patients either as a stand-alone therapy or in combination with other symptomatic treatments. EVP-6124 is a novel, potent, and selective alpha7 nicotinic receptor agonist. EVP-6124 has an excellent brain to plasma ratio and has shown excellent efficacy and potency in a number of animal models of cognition. Four clinical studies in healthy normal human subjects have been completed with EVP 6124. EVP-6124 exhibited linear kinetics over the range of 1 to 180mg and demonstrated a half-life suitable for once daily dosing. EVP 6124 appears to be safe and well-tolerated for up to 21 days as measured by adverse events, vital signs, continuous cardiac monitoring, physical examination, and clinical laboratory evaluations. In addition, in normal volunteers, EVP-6124 demonstrated pro-cognitive effects (CogState testing) in various cognitive domains including executive function. The safety and efficacy of EVP-6124 was assessed in a Phase 1b study of 48 mild to moderate AD patients 60-80 years of age, on stable donepezil or rivastigmine therapy. Patients were dosed with placebo or two different doses of EVP-6124 (0.3 or 1.0mg/d) for 28 days. Cognitive effects were measured by CogState computerized cognitive testing and a subset of NTB scales (category fluency, Trails A and B). EVP-6124 appeared to be safe and well tolerated with no significant adverse events reported more frequently in treated versus placebo patients; there were no SAEs reported. Subjects exposed to EVP-6124 in addition to donepezil or rivastigmine showed an increase in cognitive function, primarily in the domains of non-verbal learning, memory, and executive function. These data suggest that EVP-6124 administered to AD subjects on cholinesterase inhibitor therapies, may have a potential benefit. Larger phase II studies are currently being initiated in both Alzheimer's disease and schizophrenia.

Nicotinic Acetylcholine Receptors are Possible Therapeutic Targets for Schizophrenia

The rate of smoking in patients with schizophrenia is higher than that in the general population. Nicotinic acetylcholine receptors (nAChR) are involved in the sensorimotor gating deficits in schizophrenia. We have revealed that nicotine ameliorates the disruption of the PPI, a model of sensorimotor gating, which is induced by apomorphine, a dopamine receptor agonist, but is not effective for the disruption of the PPI induced by phencyclidine, a glutamine NMDA receptor antagonist, in rats. Furthermore, the ameliorating effect of nicotine is antagonized by methyllycaconitine, a selective alpha7 nAChR antagonist. The effect of nocitine was also investigated in the stereotyped behavior induced by apomorphine, however, nicotine was found to have no significant effect. Considering these results, the ameliorating effect of the disruption of the PPI via alpha7 nAChR is therefore thought to be involved in dopaminergic systems. The dopaminergic systems involved in alpha7 nAChR may be different from the systems involved in stereotypy. In addition, this review describes the effects of the alpha7 nicotinic receptor agonists.

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of alpha7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective alpha7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.) -treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L-NoArg (10 mg/kg, s.c.) on postnatal days 4-5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg) -treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L-NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with alpha7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in no-drug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms.

P2-462: SEN12333 (WAY-317538), a novel alpha7 nicotinic receptor agonist with neuroprotective efficacy: Implication for neurodegenerative diseases therapy

P2-462: SEN12333 (WAY-317538), a novel alpha7 nicotinic receptor agonist with neuroprotective efficacy: Implication for neurodegenerative diseases therapy