Edward D. Levin

Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization

RationaleNicotine 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.ObjectivesCritical for the development of nicotinic therapeutics is an understanding of the neurobehavioral bases for nicotinic involvement in cognitive function.MethodsSpecific 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.ResultsNicotine and nicotinic agonists can improve working memory function, learning, and attention. Both α4β2 and α7 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 Alzheimers disease, age-associated memory impairment, schizophrenia, and attention deficit hyperactivity disorder.ConclusionsDiscovery 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 Alzheimers 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.

Nicotinic acetylcholine involvement in cognitive function in animals

Abstract Nicotinic cholinergic systems are involved with several important aspects of cognitive function including attention, learning and memory. Nicotinic cholinergic receptors are located in many regions of the brain, including areas important for cognitive function such as the hippocampus and frontal cortex. Nicotinic agonists have been found in rodent and non-human primate studies to improve performance on a variety of memory tasks. In a complementary fashion, nicotinic antagonists such as mecamylamine impair working memory function. In humans, similar effects have been seen. Nicotinic agonist treatment can improve attention, learning and memory and nicotinic antagonist treatment can cause deficits. To define the neural substrates of nicotinic involvement in cognitive function, three areas of investigation are underway. 1) Critical neuroanatomic loci for nicotinic effects are beginning to be determined. The hippocampus, frontal cortex and midbrain dopaminergic nuclei have been found to be important sites of action for nicotinic involvement in memory function. 2) Nicotinic receptor subtype involvement in cognitive function is being studied. There has been considerable recent work identifying nicotinic receptor subunit conformation including alpha and beta subunits. Nicotinic receptor subtypes appear to be associated with different functional systems; however, much remains to be done to determine the precise role each subtype plays in terms of cognitive function. 3) Nicotinic interactions with other transmitter systems are being assessed. Nicotine receptors interact in important ways with other systems to affect cognitive functioning, including muscarinic ACh, dopamine, norepinepherine, serotonin, glutamate, and other systems. Nicotinic function in clinical populations and potential for therapeutics has been investigated for Alzheimer’s disease, Parkinson’s disease, schizophrenia and attention deficit/hyperactivity disorder. Areas which need to receive greater attention are the exact anatomical location and the specific receptor subtypes critically involved in nicotine’s effects. In addition, more work needs to be done to develop and determine the efficacy and safety of novel nicotinic ligands for use in the long-term treatment of human cognitive disorders.

Guidelines on nicotine dose selection for in vivo research

RationaleThis review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.ObjectivesThis review capitalizes on the authors’ collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models.ResultsSeven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses.ConclusionsThe selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose–response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

Nicotinic systems and cognitive function

Nicotinic acetylcholine receptors have been found to be important for maintaining optimal performance on a variety of cognitive tasks. In humans, nicotine-induced improvement of rapid information processing is particularly well documented. In experimental animals nicotine has been found to improve learning and memory on a variety of tasks, while the nicotinic antagonist mecamylamine has been found to impair memory performance. Nicotine has been found to be effective in attenuating memory deficits resulting from lesions of the septohippocampal pathway or aging in experimental animals. Nicotinic receptors are decreased in the cortex of patients with Alzheimers disease. Preliminary studies have found that some aspects of the cognitive deficit in Alzheimers disease can be attenuated by nicotine. Nicotine may prove to be useful therapeutic treatment for this and other types of dementia.

Cognitive effects of nicotine

Nicotine and other nicotinic agonists have been found to improve performance on attention and memory tasks. Clinical studies using nicotine skin patches have demonstrated the efficacy of nicotine in treating cognitive impairments associated with Alzheimers disease, schizophrenia, and attention-deficit/hyperactivity disorder. Experimental animal studies have demonstrated the persistence of nicotine-induced working memory improvement with chronic exposure, in addition to the efficacy of a variety of nicotinic agonists. Mechanistic studies have found that alpha7 and alpha4beta2 nicotinic receptors in the hippocampus are critical for nicotinic involvement in cognitive function. Clinical and experimental animal studies provide mutually supporting information for the development of novel nicotinic therapies for cognitive dysfunction.

The toxicology of climate change: environmental contaminants in a warming world.

Climate change induced by anthropogenic warming of the earths atmosphere is a daunting problem. This review examines one of the consequences of climate change that has only recently attracted attention: namely, the effects of climate change on the environmental distribution and toxicity of chemical pollutants. A review was undertaken of the scientific literature (original research articles, reviews, government and intergovernmental reports) focusing on the interactions of toxicants with the environmental parameters, temperature, precipitation, and salinity, as altered by climate change. Three broad classes of chemical toxicants of global significance were the focus: air pollutants, persistent organic pollutants (POPs), including some organochlorine pesticides, and other classes of pesticides. Generally, increases in temperature will enhance the toxicity of contaminants and increase concentrations of tropospheric ozone regionally, but will also likely increase rates of chemical degradation. While further research is needed, climate change coupled with air pollutant exposures may have potentially serious adverse consequences for human health in urban and polluted regions. Climate change producing alterations in: food webs, lipid dynamics, ice and snow melt, and organic carbon cycling could result in increased POP levels in water, soil, and biota. There is also compelling evidence that increasing temperatures could be deleterious to pollutant-exposed wildlife. For example, elevated water temperatures may alter the biotransformation of contaminants to more bioactive metabolites and impair homeostasis. The complex interactions between climate change and pollutants may be particularly problematic for species living at the edge of their physiological tolerance range where acclimation capacity may be limited. In addition to temperature increases, regional precipitation patterns are projected to be altered with climate change. Regions subject to decreases in precipitation may experience enhanced volatilization of POPs and pesticides to the atmosphere. Reduced precipitation will also increase air pollution in urbanized regions resulting in negative health effects, which may be exacerbated by temperature increases. Regions subject to increased precipitation will have lower levels of air pollution, but will likely experience enhanced surface deposition of airborne POPs and increased run-off of pesticides. Moreover, increases in the intensity and frequency of storm events linked to climate change could lead to more severe episodes of chemical contamination of water bodies and surrounding watersheds. Changes in salinity may affect aquatic organisms as an independent stressor as well as by altering the bioavailability and in some instances increasing the toxicity of chemicals. A paramount issue will be to identify species and populations especially vulnerable to climate-pollutant interactions, in the context of the many other physical, chemical, and biological stressors that will be altered with climate change. Moreover, it will be important to predict tipping points that might trigger or accelerate synergistic interactions between climate change and contaminant exposures.

Nicotine-haloperidol interactions and cognitive performance in schizophrenics

Nearly 90% of schizophrenics smoke cigarettes, considerably higher than the general populations rate of 25%. There is some indication that schizophrenics may smoke as a form of self-medication. Nicotine has a variety of pharmacologic effects that may both counteract some of the cognitive deficits of schizophrenia and counteract some of the adverse side effects of antipsychotic drugs. In the current study, we assessed the interactions of haloperidol and nicotine on cognitive performance of a group of schizophrenics. These patients were in a double-blind study, randomly assigning them to low, moderate, and high dose levels of haloperidol. The subjects, all smokers, came to the laboratory on four different mornings after overnight deprivation from cigarettes. In a double-blind fashion, they were administered placebo, low (7 mg/day), medium (14 mg/day), or high (21 mg/day) dose nicotine skin patches. Three hours after administration of the skin patch, the subjects were given a computerized cognitive test battery including: simple reaction time, complex reaction time (spatial rotation), delayed matching to sample, the Sternberg memory test, and the Conners continuous performance test (CPT). With the placebo nicotine patch, there was a haloperidol dose-related impairment in delayed matching to sample choice accuracy and an increase in response time on the complex reaction time task. Nicotine caused a dose-related reversal of the haloperidol-induced impairments in memory performance and complex reaction time. In the CPT, nicotine reduced the variability in response that is associated with attentional deficit. These results demonstrate the effects of nicotine in reversing some of the adverse side effects of haloperidol and improving cognitive performance in schizophrenia.

Anxiolytic effects of nicotine in zebrafish

Anxiolytic effects of nicotine have been documented in studies with rodents and humans. Understanding the neural basis of nicotine-induced anxiolysis can help both with developing better aids for smoking cessation as well as with the potential development of novel nicotinic ligands for treating anxiety. Complementary non-mammalian models may be useful for determining the molecular bases of nicotine effects on neurobehavioral function. The current project examined whether a zebrafish model of anxiety would be sensitive to nicotine. When zebrafish are placed in a novel environment, they dive to the bottom of the tank. In the wild, diving could help to escape predation. We tested the anxiolytic effect of nicotine on the novelty-elicited diving response and subsequent habituation. Zebrafish placed in a novel tank spent the majority of time at the bottom third of the tank during the first minute of a 5-min session and then show a gradual decrease in time spent at the tank bottom. Nicotine treatment at 100 mg/l for 3 min by immersion before testing caused a significant decrease in diving throughout the session, while 50 mg/l was effective during the first minute when the greatest bottom dwelling was seen in controls. Nicotine effects were reversed by the nicotinic antagonist mecamylamine given together with nicotine, but not when administered shortly before the test session after prior nicotine dosing. This implies that the effect of nicotine on diving was due to net stimulation at nicotinic receptors, an effect that is blocked by mecamylamine; and that once invoked, this effect is no longer dependent on continuing activation of nicotinic receptors. The effect of nicotine on diving did not seem to be the result of a general disorientation of the fish. The 100 mg/ml nicotine dose was shown in our earlier study to significantly improve spatial-discrimination learning in zebrafish. Nicotine-induced anxiolytic effects can be modeled in the zebrafish. This preparation will help in the investigation of the molecular bases of this effect.

Transdermal nicotine effects on attention

Abstract Nicotine has been shown to improve attentiveness in smokers and attenuate attentional deficits in Alzheimer’s disease patients, schizophrenics and adults with attention-deficit/hyperactivity disorder (ADHD). The current study was conducted to determine whether nicotine administered via transdermal patches would improve attentiveness in non-smoking adults without attentional deficits. The subjects underwent the nicotine and placebo exposure in a counterbalanced double-blind manner. Measures of treatment effect included the Profile of Mood States (POMS), Conners’ computerized Continuous Performance Test (CPT) of attentiveness and a computerized interval-timing task. The subjects were administered a 7 mg/day nicotine transdermal patch for 4.5 h during a morning session. Nicotine significantly increased self-perceived vigor as measured by the POMS test. On the CPT, nicotine significantly decreased the number of errors of omission without causing increases in either errors of commission or correct hit reaction time. Nicotine also significantly decreased the variance of hit reaction time and the composite measure of attentiveness. This study shows that, in addition to reducing attentional impairment, nicotine administered via transdermal patches can improve attentiveness in normal adult nonsmokers.

Nicotinic system involvement in Alzheimer's and Parkinson's diseases : Implications for therapeutics

SummaryAdvances in our understanding of the structure, function and distribution of nicotinic acetylcholine receptors in the CNS have provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realisation that such receptors must be involved in the maintenance of cigarette smoking, and from clues provided by studies of degenerative neurological diseases such as Alzheimer’s disease and Parkinson’s disease, in which the loss of nicotinic receptors has been described.Ongoing investigations of the molecular substructure of central nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioural, motor and sensory functioning. Clues from careful studies of human cognition are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents.Despite the promising results of acute studies, few long term studies with nicotine or nicotinic drugs have been performed in dementing disorders. Thus, there is uncertainty as to whether long term nicotinic treatment will provide sustained cognitive benefit. It is even more uncertain whether such cognitive benefit will have a significant clinical impact on patients and their families. To maximise the potential benefit of long term treatment with nicotinic agonists (or other cholinergic drugs), we suggest that drug treatment should be combined with cognitive rehabilitation strategies. This will enable patients and/or their families to focus on the particular cognitive domains that may be improved.