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Active maternal smoking has adverse effects on neurobehavioral development of the offspring, with nicotine (Nic) providing much of the underlying causative mechanism. To determine whether the lower exposures caused by second-hand smoke are deleterious, we administered tobacco smoke extract (TSE) to pregnant rats starting preconception and continued through the second postnatal week, corresponding to all 3 trimesters of fetal brain development. Dosing was adjusted to produce maternal plasma Nic concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers. We then compared TSE effects to those of an equivalent dose of Nic alone, and to a 10-fold higher Nic dose. Gestational exposure to TSE and Nic significantly disrupted cognitive and behavioral function in behavioral tests given during adolescence and adulthood (postnatal weeks 4-40), producing hyperactivity, working memory deficits, and impairments in emotional processing, even at the low exposure levels corresponding to second-hand smoke. Although TSE effects were highly correlated with those of Nic, the effects of TSE were much larger than could be attributed to just the Nic in the mixture. Indeed, TSE effects more closely resembled those of the 10-fold higher Nic levels, but still exceeded their magnitude. In combination with our earlier findings, this study thus completes the chain of causation to prove that second-hand smoke exposure causes neurodevelopmental deficits, originating in disruption of neurodifferentiation, leading to miswiring of neuronal circuits, and as shown here, culminating in behavioral dysfunction. As low level exposure to Nic alone produced neurobehavioral teratology, 'harm reduction' Nic products do not abolish the potential for neurodevelopmental damage., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Cognitive dysfunction has been found in epidemiological studies to be among the most sensitive impairments associated with developmental exposure to a variety of environmental contaminants from heavy metals to polyhalogenated hydrocarbons and pesticides. These chemicals have been also shown to impair cognitive function after developmental exposure in experimental animal models. The radial-arm maze (RAM) has proven to be a sensitive and reliable way to assess both learning and memory in a variety of species, most often in rats and mice. The RAM is a very adaptable test method that takes advantage of rodents' instinct to explore new places in the environment to forage. That is, rodents do not need to be trained to run through the maze; they will normally do this from the initial session of testing. Training with differential reinforcement for arm choices provides a more rigorous test of learning and memory. The RAM is quite adaptable for assessing various aspects of cognition. Although the RAM has been mostly used to assess spatial learning and memory, it can be configured to assess non-spatial memory as well. Both working and reference memory can be easily distinguished. The RAM can be run with both appetitive (food reinforced) and aversive (water escape) motivators. The RAM has been found to be sensitive to a wide variety of developmental toxicants including heavy metals such as mercury and pesticides such as chlorpyrifos. There is an extremely rich literature especially with rats showing the effects of many types of brain lesions and drug effects so that the participation of a wide variety of neural systems in RAM performance is known. These systems, notably the hippocampus and frontal cortex, and acetylcholine and glutamate neurotransmitter systems, are the same neural systems that have been shown in humans to be critical for learning and memory. This considerably aids the interpretation of neurobehavioral toxicity studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes nicotinic receptors, thus acting both as an agonist and a net antagonist. The relative roles of these two actions for nicotine-induced cognitive improvement have not yet been fully determined. We and others have found that acute nicotinic antagonist treatment can improve learning and attention. Nicotine acts on a variety of nicotinic receptor subtypes. The relative role and interactions of neuronal nicotinic receptor subtypes for cognition also needs to be better characterized. Nicotine acts on nicotinic receptors in a wide variety of brain areas. The role of some of these areas such as the hippocampus has been relatively well studied but other areas like the thalamus, which has the densest nicotinic receptor concentration are still only partially characterized. In a series of studies we characterized nicotinic receptor actions, anatomic localization and circuit interactions, which are critical to nicotine effects on the cognitive functions of learning, memory and attention. The relative role of increases and decreases in nicotinic receptor activation by nicotine were determined in regionally specific studies of the hippocampus, the amygdala, the frontal cortex and the mediodorsal thalamic nucleus with local infusions of antagonists of nicotinic receptor subtypes (α7 and α4β2). The understanding of the functional neural bases of cognitive function is fundamental to the more effective development of nicotinic drugs for treating cognitive dysfunction., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Zebrafish offer many advantages that complement classic mammalian models for the study of normal development as well as for the teratogenic effects of exposure to hazardous compounds. The clear chorion and embryo of the zebrafish allow for continuous visualization of the anatomical changes associated with development, which, along with short maturation times and the capability of complex behavior, makes this model particularly useful for measuring changes to the developing nervous system. Moreover, the rich array of developmental, behavioral, and molecular benefits offered by the zebrafish have contributed to an increasing demand for the use of zebrafish in behavioral teratology. Essential for this endeavor has been the development of a battery of tests to evaluate a spectrum of behavior in zebrafish. Measures of sensorimotor plasticity, emotional function, cognition and social interaction have been used to characterize the persisting adverse effects of developmental exposure to a variety of chemicals including therapeutic drugs, drugs of abuse and environmental toxicants. In this review, we present and discuss such tests and data from a range of developmental neurobehavioral toxicology studies using zebrafish as a model. Zebrafish provide a key intermediate model between high throughput in vitro screens and the classic mammalian models as they have the accessibility of in vitro models and the complex functional capabilities of mammalian models., (Copyright © 2013 Wiley Periodicals, Inc.)

Nicotinic α7 receptors have been shown in a variety of studies with animal models to play important roles in diverse components of cognitive function, including learning, memory and attention. Mice with α7 receptor knockouts show impairments in memory. Selective α7 agonists significantly improve learning, memory and attention. α7 receptors in limbic structures such as the hippocampus and amygdala have been demonstrated to play critical roles in memory. Blockade of α7 receptors in these areas cause memory impairments. In the brains of people with schizophrenia α7 receptors are impaired. This may be related to pronounced cognitive impairments seen with schizophrenia. There has been a major effort to develop α7 nicotinic agonists for helping to reverse cognitive impairment. These receptors are a promising target for development of therapeutic treatments for a variety of diseases of cognitive impairment including Alzheimer's disease, attention deficit hyperactivity disorder (ADHD) and schizophrenia.

Nicotine has been found in many studies to improve cognitive function. However, some studies have not found this effect and others have seen nicotine-induced impairments. Systemic administration bathes the brain with drugs. However, the brain is quite intricately organized with various regions playing very different roles in the bases of cognitive function. We have examined the role of nicotinic receptors in a variety of brain areas for memory. In the hippocampus and amygdala, local infusions of both alpha7 and alpha4beta2 antagonists methyllyaconitine (MLA) and dihydro-beta-erythroidine (DHbetaE) significantly impair memory. In the current studies we locally infused acute and chronic doses of MLA and DHbetaE into the mediodorsal thalamic nucleus and tested memory function on a 16-arm radial maze. The rats also received systemic nicotine to determine the impact of more generalized nicotine effects. Since nicotinic treatments are being developed for cognitive impairment of schizophrenia, interactions were studied with the antipsychotic drug clozapine. In the acute study, the 6.75 microg/side of DHbetaE improved working memory. Co-administration of MLA reversed the DHbetaE-induced improvement. Chronic DHbetaE infusions into the mediodorsal thalamic nucleus also improved working memory. Systemic nicotine reversed this effect. Clozapine had no significant interaction. Nicotinic alpha4beta2 receptors in the mediodorsal thalamic nucleus appear to play an opposite role with regard to working memory than those in the hippocampus and amygdala. Heterogeneity in response to nicotinic drugs given systemically may be due to anatomically distinct nicotinic systems in the brain and their unique roles in the neural bases of cognitive function.

Metallothionein (MT) is an enigmatic protein, and its physiological role remains a matter of intense study and debate 50 years after its discovery. This is particularly true of its function in the central nervous system (CNS), where the challenge remains to link its known biochemical properties of metal binding and free radical scavenging to the intricate workings of brain. In this compilation of four reports, first delivered at the 11th International Neurotoxicology Association (INA-11) Meeting, June 2007, the authors present the work of their laboratories, each of which gives an important insight into the actions of MT in the brain. What emerges is that MT has the potential to contribute to a variety of processes, including neuroprotection, regeneration, and even cognitive functions. In this article, the properties and CNS expression of MT are briefly reviewed before Dr Hidalgo describes his pioneering work using transgenic models of MT expression to demonstrate how this protein plays a major role in the defence of the CNS against neurodegenerative disorders and other CNS injuries. His group's work leads to two further questions, what are the mechanisms at the cellular level by which MT acts, and does this protein influence higher order issues of architecture and cognition? These topics are addressed in the second and third sections of this review by Dr West, and Dr Levin and Dr Eddins, respectively. Finally, Dr Aschner examines the ability of MT to protect against a specific toxicant, methylmercury, in the CNS.

People with schizophrenia often have substantial cognitive impairments, which may be related to nicotinic receptor deficits, (alpha7 and alpha4beta2), documented in the brains of people with schizophrenia. The large majority of people with schizophrenia smoke cigarettes. Thus, nicotinic interactions with antipsychotic drugs are widespread. Complementary co-therapies of novel nicotinic ligands are being developed to add to antipsychotic therapy to treat the cognitive impairment of schizophrenia. Thus, it is critical to understand the interaction between nicotinic treatments and antipsychotic drugs. Nicotinic interactions with antipsychotic drugs, are complex since both nicotine and antipsychotics have complex actions. Nicotine stimulates and desensitizes nicotinic receptors of various subtypes and potentiates the release of different neurotransmitters. Antipsychotics also act on a verity of receptor systems. For example, clozapine acts as an antagonist at a variety of neurotransmitter receptors such as those for dopamine, serotonin, norepinepherine and histamine. In a series of studies, we have found that in normally functioning rats, moderate doses of clozapine impair working memory and that clozapine blocks nicotine-induced memory and attentional improvement. Clozapine and nicotine can attenuate each other's beneficial effects in reversing the memory impairment caused by the psychototmimetic drug dizocilpine. A key to the clozapine-induced attenuation of nicotine-induced cognitive improvement appears to be its 5HT(2) antagonist properties. The selective 5HT(2) antagonist ketanserin has a similar action of blocking nicotine-induced memory and attentional improvements. It is important to consider the interactions between nicotinic and antipsychotic drugs to develop the most efficacious treatment for cognitive improvement in people with schizophrenia.

Transition metals have been associated with impaired neurological development, and neurobehavioral activity. Metallothioneins are central components in the metabolism and detoxification of a variety of metals, however, little is known concerning their role in cognitive function. To determine the role of metallothionein in learning and memory, mice with deletions of two metallothionein genes (MT-1 and MT-2) were trained on a win-shift task in an 8-arm radial maze. The parental strain of mice learned the maze at a normal rate over an 18-session acquisition period. In contrast, the MT-1/MT-2-null mice, which had a similar choice accuracy level at the beginning of training, showed a poorer rate of learning during the training period. In addition, the MT-1/MT-2-null mice showed significantly less choice accuracy than the parental strain. The MT-1/MT-2-null mice also showed a significant hypoactivity during the early and middle parts of acquisition training, but they were not different from the wildtype controls during the final phase of training. Nicotine treatment, which can improve working memory, eliminated the impairment associated with the deletion of the MT-1 and MT-2 genes in a dose-related fashion after acquisition training in the aging adult mice. These results suggest that metallothioneins, through there roles in metal physiology or cellular protection, are involved in spatial learning and memory function.

Rationale: Nicotine has been shown in a variety of studies in humans and experimental animals to improve cognitive function. Nicotinic treatments are being developed as therapeutic treatments for cognitive dysfunction., Objectives: Critical for the development of nicotinic therapeutics is an understanding of the neurobehavioral bases for nicotinic involvement in cognitive function., Methods: Specific and diverse cognitive functions affected by nicotinic treatments are reviewed, including attention, learning, and memory. The neural substrates for these behavioral actions involve the identification of the critical pharmacologic receptor targets, in particular brain locations, and how those incipient targets integrate with broader neural systems involved with cognitive function., Results: Nicotine and nicotinic agonists can improve working memory function, learning, and attention. Both alpha4beta2 and alpha7 nicotinic receptors appear to be critical for memory function. The hippocampus and the amygdala in particular have been found to be important for memory, with decreased nicotinic activity in these areas impairing memory. Nicotine and nicotinic analogs have shown promise for inducing cognitive improvement. Positive therapeutic effects have been seen in initial studies with a variety of cognitive dysfunctions, including Alzheimer's disease, age-associated memory impairment, schizophrenia, and attention deficit hyperactivity disorder., Conclusions: Discovery of the behavioral, pharmacological, and anatomic specificity of nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novel nicotinic treatments for cognitive dysfunction. Nicotinic treatments directed at specific receptor subtypes and nicotinic cotreatments with drugs affecting interacting transmitter systems may provide cognitive benefits most relevant to different syndromes of cognitive impairment such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder. Further research is necessary in order to determine the efficacy and safety of nicotinic treatments of these cognitive disorders.

In summary, neuronal nicotinic systems are important for a variety of aspects of cognitive function impacted by antipsychotic drugs. It has been demonstrated that antipsychotic drugs have memory and attentional impairing effects when given to unimpaired subjects. Nicotine can reduce some of these impairments, but antipsychotic drug administration can also attenuate nicotine effects. We have found that nicotinic agonists selective for alpha7 and alpha4beta2 receptor subtypes significantly improve learning and memory. Serotonergic actions of antipsychotic drugs may decrease efficacy of nicotinic co-treatments. When the antipsychotic drug clozapine and nicotine are administered to subjects with cognitive impairments caused by NMDA glutamate receptor blockade or hippocampal dysfunction they can significantly attenuate the attentional and memory impairments. Nicotine has been shown in our studies to reverse the memory impairment caused by acute clozapine-induced memory improvement. Acute risperidone and haloperidol has been shown to attenuate nicotine-induced memory improvement. We have determined the role of hippocampal alpha7 and alpha4beta2 nicotinic receptors in the neural basis of nicotinic antipsychotic interactions. Local acute and chronic hippocampal infusion of either nicotinic alpha7 or alpha4beta2 antagonists cause significant spatial working memory impairment. Chronic hippocampal nicotinic antagonist infusions have served as a model of persistent decreases in nicotinic receptor level seen in schizophrenia and Alzheimer's disease. Clozapine attenuated the memory deficit caused by chronic suppression of hippocampal alpha4beta2 receptors while the amnestic effects of clozapine were potentiated by chronic suppression of hippocampal alpha7 receptors. Nicotinic co-treatment may be a useful adjunct in the treatment of schizophrenia, to attenuate cognitive impairment of schizophrenia. Nicotine as well as selective nicotinic alpha7 and alpha4beta2 receptor agonists significantly improve working memory and attentional function. Nicotine treatment was found to be effective in attenuating the attentional and memory impairments caused by the psychototmimetic NMDA antagonist dizocilpine (MK-801), a model of the cognitive impairment of schizophrenia. Studies of the interactions of antipsychotic drugs with nicotinic agents provided quite useful information concerning possible co-treatment of people with schizophrenia with nicotinic therapy. Nicotine was found to significantly attenuate the memory impairments caused by the antipsychotic drugs clozapine and olanzapine. Interestingly, nicotine-induced cognitive improvement was significantly attenuated by the antipsychotic drug clozapine. One of the principal effects of clozapine is to block 5HT2 receptors. Ketanserin a 5HT2 antagonist significantly attenuated nicotine-induced improvements in attention and memory. Thus it appears that antipsychotic drugs with actions blocking 5HT2 receptors may limit the efficacy of nicotinic co-treatments for cognitive enhancement.

Objectives: Chronic transdermal nicotine has been found to improve attentional performance in patients with Alzheimer's disease (AD), but little is known about chronic nicotine effects in age-associated memory impairment (AAMI), a milder form of cognitive dysfunction. The current study was performed to determine the clinical and neuropsychological effects of chronic transdermal nicotine in AAMI subjects over a 4-week period., Design: The double-blind, placebo-controlled, cross-over study consisted of two 4-week periods separated by a 2-week washout period., Setting: An outpatient setting was used., Participants: The subjects ( n=11) met criteria for AAMI., Interventions: The subjects were given nicotine patches (Nicotrol) to wear for 16 h a day at the following doses: 5 mg/day during week 1, 10 mg/day during week 2 and week 3 and 5 mg/day during week 4., Measurements: The effects of nicotine treatment were determined with the clinical global impressions questionnaire, Conners' Continuous Performance test, and the automated neuropsychologic assessment metrics (ANAM) computerized neuropsychology battery., Results: Nicotine significantly improved the clinical global impression score as assessed by participants, as well as objective tests of attentional function on the Connors' Continuous Performance Test and decision reaction time on the neuropsychology test battery. Nicotine did not improve performance on other tests measuring motor and memory function., Conclusion: Chronic transdermal nicotine treatment in AAMI subjects caused a sustained improvement in clinical symptoms and objective computerized tests of attention. These results support the further investigation of nicotinic treatment as a promising therapy for AAMI.

Nicotinic receptor systems are involved in a wide variety of behavioral functions including cognitive function. Nicotinic medications may provide beneficial treatment for cognitive dysfunction such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Nicotine has been shown to improve attentional performance in all of these disorders. Better efficacy with fewer side effects might be achieved with novel nicotinic ligands selective for particular nicotinic subtypes. To develop these novel selective nicotinic ligands it is important to use animal models to determine the critical neurobehavioral bases for nicotinic involvement in cognitive function. Nicotine-induced cognitive improvement in rats is most consistently seen in working memory tasks. We have found that both acute and chronic nicotine administration significantly improves working memory performance of rats in the radial-arm maze. The pharmacologic and anatomic mechanisms for this effect have been examined in our laboratory in a series of local drug infusion studies. Both alpha 4 beta 2 and alpha 7 nicotinic receptors in the ventral hippocampus and basolateral amygdala are involved in working memory function. Working memory impairments were caused by local infusion of either alpha 4 beta 2 or alpha 7 antagonists. Ventral hippocampal alpha 4 beta 2 blockade-induced working memory deficits are reversed by chronic systemic nicotine treatment, while ventral hippocampal alpha 7 blockade-induced working memory deficits were not found to be reversed by the same nicotine regimen. Interestingly, alpha 4 beta 2 and alpha 7 induced deficits were not found to be additive in either the ventral hippocampus or the basolateral amygdala. In fact, in the amygdala, alpha 7 antagonist cotreatment actually reversed the working memory impairment caused by alpha 4 beta 2 antagonist administration. These studies of the neural nicotinic mechanisms underlying cognitive function are key for opening avenues for development of safe and effective nicotinic treatments for cognitive dysfunction., (Copyright 2002 Wiley Periodicals, Inc.)

Nicotine and ethanol are the most widely abused drugs in the world. They are very often used and abused together. However, little is known about the functional interaction of nicotine and ethanol. The current project studied the interactive effects of nicotine and ethanol on working memory in the eight-arm radial maze. Adult female rats were trained on a radial arm maze for 18 sessions to reach asymptotic levels of choice accuracy. During the maintenance phase of radial arm maze testing, which indexed working memory function, the rats were injected with nicotine (0, 0.15, 0.3, 0.6, and 1.2 mg/kg sc, 20 min before testing) with and without ethanol pretreatment (0 or 1.5 g/kg, 16% v/v ip, 30 min before testing). All animals received the treatments in a counterbalanced order with at least 1 week between treatments. Higher doses of nicotine had a significant interaction with ethanol in terms of radial arm maze choice accuracy. Nicotine plus ethanol coadministration precipitated a significant choice accuracy impairment at doses that when given alone had no effect on performance. At the lower dose range of nicotine, ethanol coadministration eliminated the nicotine-induced memory improvement. No significant effects were seen with either nicotine or ethanol treatment or their interaction on response latency in the radial arm maze. The nicotine-ethanol interactive effects on memory were compared with the interaction of their well-characterized hypothermic effects. Nicotine and alcohol, when injected separately or in combination, induced hypothermia with no significant interactive effect. This study found that ethanol blocked low-dose nicotine-induced memory improvement and precipitated memory impairment with high-dose nicotine treatment. This interaction may be an important consideration for nicotine and ethanol coabuse and the possible therapeutic use of nicotinic drugs for memory dysfunction.

Introduction: Menthol has been shown to target similar brain regions and neural receptors as nicotine, yet the association between menthol cigarette use and cognitive performance remains unknown.Aims and Methods: This study examined differences in cognitive task performance between menthol (MS) and nonmenthol (NMS) cigarette smokers after acute cigarette consumption. Sixty white and black and/or African American, nonabstinent, MS (n = 30) and NMS (n = 30) were assessed presmoking and postsmoking their preferred cigarette on four computerized tasks: Continuous Performance Task (CPT; alerting attention), N-Back Task (working memory), Finger Tapping Task (motor control), and Apple Picker Task (reinforcement enhancement). Self-reported nicotine dependence and objective smoking topography measures were also compared between groups.Results: Initial unadjusted analyses showed a significant effect of cigarette type × time on CPT speed (p = .042), where MS improved while NMS group worsened in CPT speed after smoking. After controlling for baseline cigarette craving and cigarette nicotine levels, the effect of cigarette type × time for all cognitive outcomes was statistically nonsignificant (ps > .05). However, there remained a significant effect of cigarette type, where MS versus NMS had poorer CPT (p = .046) and N-Back Task accuracy (p = .006) but faster N-Back speed (p = .039). There were no statistically significant differences between groups on reinforcement enhancement, nicotine dependence, or smoking behavior outcomes (ps > .05).Conclusions: Contrary to our hypotheses, results did not find a significant effect of cigarette type on the change in cognitive performance after acute smoking in nonabstinent smokers. Further studies are needed to clarify the specific pharmacological effects of nicotine and menthol on cognitive functioning.Implications: The current study is the first to compare the potential enhancement of cognitive task performance after acute cigarette smoking between satiated menthol and nonmenthol cigarette smokers. Study results suggest that acute menthol cigarette use may not enhance cognitive function above and beyond nonmenthol cigarettes to increase dependence among menthol smokers. However, the contribution of other psychological factors (eg, craving, mood) and cigarette characteristics (eg, nicotine content) may be involved in cognitive function enhancement to perpetuate dependence and smoking persistence for menthol smokers. [ABSTRACT FROM AUTHOR]

Abstract: Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention, how attention is impaired, and how therapeutic treatments can ameliorate attentional deficits. This review focuses on the ways in which animal models are used to better understand the neuronal mechanism of attention and how to develop new therapeutic treatments for attentional impairment. Several behavioral test methods have been developed for experimental animal studies of attention, including a 5-choice serial reaction time task (5-CSRTT), a signal detection task (SDT), and a novel object recognition (NOR) test. These tasks can be used together with genetic, lesion, pharmacological and behavioral models of attentional impairment to test the efficacy of novel therapeutic treatments. The most prominent genetic model is the spontaneously hypertensive rat (SHR). Well-characterized lesion models include frontal cortical or hippocampal lesions. Pharmacological models include challenge with the NMDA glutamate antagonist dizocilpine (MK-801), the nicotinic cholinergic antagonist mecamylamine and the muscarinic cholinergic antagonist scopolamine. Behavioral models include distracting stimuli and attenuated target stimuli. Important validation of these behavioral tests and models of attentional impairments for developing effective treatments for attentional dysfunction is the fact that stimulant treatments effective for attention deficit hyperactivity disorder (ADHD), such as methylphenidate (Ritalin®), are effective in the experimental animal models. Newer lines of treatment including nicotinic agonists, α4β2 nicotinic receptor desensitizers, and histamine H3 antagonists, have also been found to be effective in improving attention in these animal models. Good carryover has also been seen for the attentional improvement caused by nicotine in experimental animal models and in human populations. Animal models of attention can be effectively used for the development of new treatments of attentional impairment in ADHD and other syndromes in which have attentional impairments occur, such as Alzheimer''s disease and schizophrenia. [Copyright &y& Elsevier]

Abstract: Developmental exposure of rats to the organophosphate (OP) pesticides leads to altered neurobehavioral function in juvenile and young adult stages. The current study was conducted to determine whether effects of neonatal parathion exposure on cognitive performance persist in older adult and aged rats, and the relationship of behavioral changes to underlying cholinergic and serotonergic mechanisms. We administered parathion to rat pups on postnatal days 1–4, at doses spanning the threshold for the initial signs of systemic toxicity and for barely detectable cholinesterase inhibition (0.1 or 0.2mg/kg/day). Beginning at 14 months of age and continuing until 19 months, the rats were trained in the 16-arm radial maze. Controls showed the normal sex difference in this spatial learning and memory task, with the males committing significantly fewer working memory errors than females. Neonatal parathion exposure eliminated the sex difference primarily by causing impairment in males. In association with the effects on cognitive performance, neonatal parathion exposure elicited widespread abnormalities in indices of serotonergic (5HT) and cholinergic synaptic function, characterized by upregulation of 5HT2 receptors and the 5HT transporter, deficits in choline acetyltransferase activity and nicotinic cholinergic receptors, and increases in hemicholinium-3 binding to the presynaptic choline transporter. Within-animal correlations between behavior and neurochemistry indicated a specific correlation between working memory performance and hippocampal hemicholinium-3 binding; parathion exposure eliminated this relationship. Like the behavioral effects, males showed greater effects of parathion on neurochemical parameters. This study demonstrates the sex-selective, long-term behavioral alterations caused by otherwise nontoxic neonatal exposure to parathion, with effects increasingly expressed with aging. [Copyright &y& Elsevier]

Abstract: The nicotinic antagonist mecamylamine has been widely shown to cause cognitive impairment. However, these effects are mainly seen with high doses. There have been scattered findings that low doses of mecamylamine can have the opposite effect. This may be due to opposite effects of low doses of mecamylamine. In the current study, an extensive dose–effect function of mecamylamine was characterized in the low-dose range. Adult female Sprague–Dawley rats were trained on a repeated acquisition procedure on an automated 8-arm radial maze. Three of the eight arms were designated as correct for any particular session. Five trials per session were run. The number of errors per trial to find the three correct arms was determined. The rats were trained on the repeated acquisition procedure for at least 18 sessions at which time they showed reliable learning each session. Then, the effect of low doses of mecamylamine between 0 and 1mg/kg were assessed in a repeated measures counterbalanced design. This dose range of mecamylamine did not affect performance on the first trial when the rats were naïve to the array to be learned. On trials 2–5 a significant (p <.025) quadratic dose–effect function was seen over this dose range. The most substantial effect was seen with 0.125mg/kg of mecamylamine, which caused a significant (p <.05) improvement relative to the saline control condition. The effect diminished with increasing mecamylamine doses and with the 1mg/kg dose choice accuracy was back to control levels. This study showed that low doses of mecamylamine can effectively improve learning. A U-shaped dose–effect curve was documented. This suggests possible low-dose nicotinic antagonist lines of treatment for cognitive impairment. [Copyright &y& Elsevier]

Schizophrenia is marked by pronounced cognitive impairments in addition to the hallmark psychotic symptoms like hallucinations. Antipsychotic drugs can effectively reduce these hallucinations; however, the drugs have not resolved the cognitive impairment. Interestingly, nicotine, a drug commonly self-administered by people with schizophrenia, has been shown to significantly improve cognitive function of people with schizophrenia. The current study was conducted to determine the effect of typical (haloperidol) and atypical (clozapine and risperidone) antipsychotic drug treatment on sustained attention in rats performing a visual signal detection task. In addition, the interaction of haloperidol with chronic nicotine administration was assessed. Female Sprague–Dawley rats were injected subcutaneously with clozapine (0, 0.6, 1.25 and 2.5 mg/kg), risperidone (0, 0.025, 0.05 and 0.1 mg/kg) or haloperidol (0, 0.01, 0.02 and 0.04 mg/kg). In the second part of the study, the interaction of acute haloperidol (0, 0.005, 0.01 and 0.02 mg/kg) and chronic nicotine (5 mg/kg/day, for 4 weeks via osmotic minipump) was characterized. Clozapine, risperidone and haloperidol all caused dose-related impairments in percent hit performance. There was a significant linear dose-related impairment in percent hit caused by risperidone. All the doses of clozapine caused a significant impairment in percent hit at the higher luminance intensities in the visual signal detection task. The 0.01 and 0.02 mg/kg haloperidol doses caused significant decreases in percent hit. The 0.04 mg/kg haloperidol dose impaired performance of the task to the point that reliable choice accuracy measurements could not be made. Chronic nicotine infusion significantly diminished the impairing effects of haloperidol on performance during weeks 1–2. In summary, both typical and atypical antipsychotic drugs significantly impaired sustained attention in rats. Haloperidol was more detrimental than clozapine and risperidone. Chronic nicotine diminished the adverse effects of haloperidol on performance. This study establishes a paradigm to reliably determine the attentional impairment caused by antipsychotic drugs. [Copyright &y& Elsevier]

Nicotine and alcohol are very often co-used and co-abused. Thus, it is important to understand their interactions. In many ways, nicotine and alcohol have opposing effects. This can be clearly seen in terms of their effects on cognitive function. Nicotine effectively improves attention while alcohol impairs it. The current study was conducted to determine in a rat model the interaction of nicotine and alcohol on attention using an operant visual signal detection task. It is hypothesized that nicotine would reverse the alcohol-induced impairment in accuracy of performance in this task. Female Sprague–Dawley rats (N=35) were trained on a visual operant signal detection task for food reinforcement with 300 trials/session in three equal time blocks. The rats were divided into poor and good performers according to their predrug baseline performance accuracy. The first experiment examined the dose–effect function of alcohol (0, 0.375, and 0.75 g/kg ip) on this task. The lower alcohol dose significantly impaired percent correct rejection in the high-performing rats but not the low-performing rats. The higher alcohol dose significantly impaired percent hit performance during the first two thirds of the session in both high- and low-performing groups. The second experiment examined alcohol (0.75 g/kg ip) interactions with nicotine (0, 12.5, 25, and 50 μg/kg sc) on attentional performance. The 25 and 50 μg/kg nicotine doses caused a significant (P<.05) improvement in hit accuracy. Alcohol blocked this nicotine-induced improvement, even though at this later time it no longer had an effect of its own. In the high baseline group, the 25 μg/kg nicotine dose also caused a significant (P<.025) improvement in hit accuracy. As in Experiment 1, the high baseline group was not significantly impaired by 0.75 g/kg of alcohol. However, this alcohol dose did eliminate the nicotine-induced improvement. These results suggest that alcohol, when given alone, impairs sustained attention and blocks nicotine-induced attentional improvements even when it does not cause impairments on its own. [Copyright &y& Elsevier]

Pfiesteria piscicida, an estuarine dinoflagellate, which has been shown to kill fish, has also been associated with neurocognitive deficits in humans. With a rat model, we have demonstrated the cause-and-effect relationship between Pfiesteria exposure and learning impairment. In several studies, we have replicated the finding in Sprague–Dawley rats that exposure to fixed acute doses of Pfiesteria cells or filtrates caused radial-arm maze learning impairment. Recently, this finding of Pfiesteria-induced learning impairment in rats has been independently replicated in another laboratory as well. We have demonstrated significant Pfiesteria-induced learning impairment in both the win-shift and repeated-acquisition tasks in the radial-arm maze and in reversal learning in a visual operant signal detection task. These learning impairments have been seen as long as 10 weeks after a single acute exposure to Pfiesteria. In the current study, we used a hydrophilic toxin isolated from clonal P. piscicida cultures (PfTx) and tested its effect when applied locally to the ventral hippocampus on repeated acquisition of rats in the radial-arm maze. Toxin exposure impaired choice accuracy in the radial-arm maze repeated acquisition procedure. The PfTx-induced impairment was seen at the beginning of the session and the early learning deficit was persistent across 6 weeks of testing after a single administration of the toxin. Eventually, with enough practice, in each session, the PfTx-exposed rats did learn that session''s problem as did control rats. This model has demonstrated the cause-and-effect relationship between exposure to a hydrophilic toxin produced by P. piscicida and learning impairment, and specifically that the ventral hippocampus was critically involved. [Copyright &y& Elsevier]

Nicotinic systems have been shown to be critically involved in cognitive function including attention. Nicotine has been shown to improve performance on attentional tasks in humans with Alzheimer''s disease, schizophrenia and attention deficit hyperactivity disorder. Nicotine has mixed effects on attentional accuracy in unimpaired rats with findings of increased, reduced or unaltered accuracy under different conditions. Nicotine effects on attentional function in rats might be more clearly seen in reversing impaired performance. The current study determined nicotine effects on attentional accuracy reduced by the NMDA receptor antagonist dizocilpine (MK-801). Sprague–Dawley rats (N=35) were trained on a food-motivated two-lever operant task with one lever correct after a brief visual signal (0.027–1.22 lx) for hits and the other lever correct after the absence of a signal for correct rejections. First, a dose response study of dizocilpine was conducted to determine the threshold for impairment. The rats were administered acute doses of dizocilpine (0, 12.5, 25 and 50 μg/kg, sc). The 50 μg/kg dose caused significant (p<0.0005) reduction in percent hit at the four highest signal intensities. Percent correct rejection was also significantly lowered by this dose (p<0.005). No effect was seen with 12.5 μg/kg and only minimal effect seen with 25 μg/kg. Then, nicotine–dizocilpine interactions were investigated. The rats were administered acute doses of dizocilpine (0, 37.5 and 50 μg/kg, sc) and nicotine (0, 25 and 50 μg/kg, sc), alone or in combination. Percent hit was affected by nicotine and dizocilpine in a complex fashion with only the nicotine×dizocilpine×signal intensity interaction being significant (p<0.05). Percent correct rejection showed a more straightforward effect. Percent correct rejection was significantly reduced by 50 μg/kg dizocilpine (p<0.025). The addition of 25 μg/kg of nicotine significantly (p<0.025) reversed the dizocilpine-induced reduction of correct rejection. This study shows that dizocilpine reduces signal detection accuracy in a dose-dependent fashion. Nicotine can partially counteract an aspect of this reduction by reversing the dizocilpine-induced reduction of correct rejection. [Copyright &y& Elsevier]

Abstract: Although antipsychotic drugs are therapeutically effective in attenuating the hallmark symptoms of schizophrenia, these improvements do not return most patients to normative standards of cognitive function. Thus, complementary drug treatment may be needed to treat the attentional deficits of schizophrenia as well as to counteract the potential attentional impairments caused by some antipsychotic drugs. Nicotine, a drug commonly self-administered by a great majority of individuals with schizophrenia, has been shown to significantly improve cognitive function in some studies. The current study was conducted to determine the interactive effects of the atypical antipsychotic drugs clozapine and risperidone with chronic nicotine administration on attentional performance. Adult female Sprague-Dawley rats (N =35) were trained to perform an attentional task using an operant visual signal detection task. After training, rats were infused with a dose of 5 mg/kg/day (s.c.) nicotine base (n =18) or saline (n =17) for 28 consecutive days via osmotic pump. In Exp. 1, while being administered chronic nicotine or saline, rats were given acute doses of clozapine (0, 0.625, 1.25 and 2.5 mg/kg, s.c.) and were tested for attentional function. In Exp. 2, while on chronic nicotine or saline, other rats were challenged with acute doses of risperidone (0, 0.025, 0.05 and 0.1 mg/kg, s.c.) and were tested for attentional function. Results showed that acute administration of clozapine caused a significant dose-dependent impairment in choice accuracy (percent hit) in animals treated with chronic saline. Chronic nicotine treatment itself lowered accuracy, but attenuated further declines with acute clozapine treatment. Acute administration of risperidone at high dose significantly reduced performance (percent correct rejection) in chronically saline-treated rats, but in a similar fashion as in Exp. 1, chronic nicotine lowered accuracy but attenuated further impairment with acute risperidone. In summary, atypical antipsychotic drugs clozapine and risperidone significantly impaired choice accuracy in the visual signal detection task. Clozapine was more detrimental than risperidone but the adverse effects of both clozapine and risperidone on attentional performance were masked in rats chronically treated with nicotine. [Copyright &y& Elsevier]

Background Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities. Methods During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0 to 5 dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2 nM) or valproic acid (0, 0.5, 5.0 or 50 μM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance). Results There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation. Conclusions Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed. [ABSTRACT FROM AUTHOR]

Abstract: It is well established that nicotinic systems in the brain are critically involved in attentional processes in both animals and humans. The current study assessed the effects of a novel nicotinic α7 receptor partial agonist and 5-HT3 antagonist, R3487/MEM3454 (also referred to as R3487 or MEM 3454) on sustained attention in rats performing an operant visual signal detection task. The effects of R3487/MEM3454 were compared to those of the acetylcholinesterase inhibitor/nicotinic α7 allosteric positive modulator galanthamine. Adult female Sprague–Dawley rats were injected subcutaneously with R3487/MEM3454 (0.03, 0.1, 0.15, 0.3 and 0.6 mg/kg), galanthamine (0.25, 0.5, 1, 2 mg/kg) or vehicle 30 min before the attentional test. In the second study, the time-dependent effects of R3487/MEM3454 were assessed by injecting the compound (0.6 mg/kg, s.c.) at different pretreatment intervals (30, 60 or 90 min) before the start of the attentional task. Our results show a significant dose-effect for R3487/MEM3454 on percent hit accuracy performance without any significant alteration on percent correct rejection performance. In the time-dependent test, R3487/MEM3454 significantly increased the percent hit accuracy performance when animals were injected 60 min before the start of the attentional task. Administration of galanthamine failed to significantly increase percent hit accuracy performance and increasing the dose of galanthamine produced a decrease in percent correct rejection performance. The present findings with R3487/MEM3454 suggest that nicotinic α7 receptors and/or 5-HT3 receptors may play an important role in modulating sustained attention and that R3487/MEM3454 may have therapeutic potential in improving sustained attention in humans. [Copyright &y& Elsevier]

Abstract: Methylphenidate is widely used as a treatment option for attention deficit hyperactivity disorder. In animal models of attentional impairment, it is an important validation to determine whether this clinically effective treatment attenuates deficits. The purpose of the current study was to determine whether methylphenidate can diminish attentional impairment induced by three pharmacological agents with different mechanisms of action: scopolamine, mecamylamine, and dizocilpine. Female rats were trained on an operant visual signal detection task. Ten min before the test, the rats were injected subcutaneously with methylphenidate (0, 0.1, 0.3 mg/kg), scopolamine (0, 0.005, 0.01 mg/kg), mecamylamine (0, 2, 4 mg/kg), dizocilpine (0, 0.025, 0.05 mg/kg) or combinations of methylphenidate with these drugs. In each of the experiments, all rats received every treatment in a repeated measures counterbalanced order. Correction rejection accuracy was impaired by all three of the antagonists and these effects were attenuated by methylphenidate. Both scopolamine at 0.01 and dizocilpine at 0.05 mg/kg significantly impaired percent correct rejection choice accuracy, an effect that was ameliorated by methylphenidate. Mecamylamine (4 mg/kg) impaired attentional performance by reducing percent hit and percent correct rejection. Co-administration of methylphenidate failed to significantly affect the mecamylamine-induced attentional impairment. Methylphenidate alone at 0.3 mg/kg significantly improved percent hit choice accuracy only in low-performing rats in one experiment, an effect which was reversed by scopolamine. These data show that methylphenidate effectively reverses the attentional impairment caused by scopolamine and dizocilpine. These findings further validate the operant visual signal detection task for assessing attentional impairments and their reversal. [Copyright &y& Elsevier]