Alexandra S. Potter

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.

Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease.

Abstract To explore further the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer’s disease (AD), six otherwise healthy subjects with moderate AD received placebo and three doses (6, 12, and 23 mg) of the novel selective cholinergic channel activator (ChCA) (nicotinic agonist) ABT-418 over 6 h in a double-blind, within-subjects, repeated-measures design. Subjects showed significant improvements in total recall and a decline in recall failure on a verbal learning task. Qualitatively similar improvements were seen in non-verbal learning tasks such as spatial learning and memory, and repeated acquisition. No significant behavioral, vital sign, or physical side effects were seen. These results confirm that stimulating central nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective ChCAs have a potential therapeutic role in dementing disorders, and that further studies with this or similar agents in AD and/or Parkinson’s disease are warranted.

Effects of acute nicotine administration on behavioral inhibition in adolescents with attention-deficit/hyperactivity disorder

RationaleAdolescents with attention-deficit/hyperactivity disorder (ADHD) become cigarette smokers at twice the rate of non-ADHD adolescents, and this finding continues into adulthood. Abnormal cognitive/behavioral inhibition is one core cognitive symptom of ADHD, leading to impulsive behavior in people with this disorder. Nicotine, contained in tobacco smoke, is known to improve attention, vigilance, and short-term memory. However, little is known about how nicotine might effect cognitive/behavioral inhibition.ObjectiveThis study tested the hypothesis that acute nicotine administration would improve cognitive/behavioral inhibition in non-smoking adolescents with ADHD.MethodsThis single-dose, acute, repeated-measures, double blind study in adolescents (13–17 years) with DSM-IV confirmed ADHD assessed the effects of transdermal nicotine, oral methylphenidate, and placebo on inhibition in non-smoking adolescents with ADHD. Dependent measures included tests of cognitive/behavioral inhibition (the stop signal task), cognitive interference control (the Stroop task), and a measure of verbal learning and recognition (the hi–low imagery task).ResultsResults from five subjects indicated that stop signal reaction time (SSRT), an estimate of the speed of inhibiting a response, was significantly (P<0.01) improved following both nicotine and methylphenidate treatment as compared to placebo treatment. Neither “go” reaction time nor accuracy showed any effect of drug. In the Stroop task, another task of cognitive inhibition, nicotine but not methylphenidate significantly (P<0.05) decreased the Stroop effect compared to placebo.ConclusionsThese results indicate that nicotine administration has measurable positive effects on cognitive/behavioral inhibition in adolescents with ADHD. The size of the effect is at least comparable to methylphenidate. Positive effects of nicotine on inhibitional performance may contribute to higher rates of cigarette use in adolescents with ADHD.

Acute nicotinic blockade produces cognitive impairment in normal humans

Single oral doses of the central and peripheral nicotinic antagonist mecamylamine were administered to healthy young normal males in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. The 20 mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition task, producing a slower acquisition curve. The lower doses produced less errors, but more than in the placebo condition. There was no effect of drug on the performance component (retrieval of previously learned information). On the recognition memory task, dose-related increases in false-alarms during the delay period were seen, with little effect on misses or hits. Reaction time measures suggested a dose-related slowing of RT on several tasks. Behavioral effects were minimal and physiologic measures were consistent with dose-related ganglionic blockade. We interpret these results to indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment, even in non-smoking normals.

Nicotinic treatment of Alzheimer’s disease

Approximately 20 years after the formulation of the cholinergic hypothesis to explain the cognitive symptoms of Alzheimers disease, cholinesterase therapy remains the mainstay of treatment for this disorder, Although partially effective, currently available agents have limited effects on cognitive function and long-term efficacy appears modest. Direct or indirect stimulation of nicotinic cholinergic receptors may offer an additional therapeutic strategy. Ongoing investigations of the molecular substructure of central nervous system nicotinic receptors, their accompanying pharmacology, and the effects of nicotinic agents on cognitive function have suggested the possibility that nicotinic stimulation may have beneficial effects in Alzheimers disease and other neuropsychiatric disorders. Studies from our laboratory and others have explored the role of central nervous system nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in Alzheimers disease. Results from acute therapeutic trials with nicotine arid novel nicotinic agents suggest that nicotinic stimulation in Alzheimers disease patients can improve the acquisition and retention of verbal and visual information and decrease errors in cognitive tasks, as well as improve accuracy and response time, Whether such results will translate into improved clinical functioning remains to be fully tested. Development of subtype-selective nicotinic agonists with an improved safety profile will enable long-term testing of the efficacy of nicotinic stimulation on cognitive performance as well as potential cytoprotective effects. Direct or indirect (allosteric) modulation of nicotinic receptor function offers a new opportunity for Alzheimers disease therapeutics.

Age-Related Effects of the Nicotinic Antagonist Mecamylamine on Cognition and Behavior

Studies of the neurochemical pathology of Alzheimers disease and Parkinsons disease reveal a severe and specific loss of central nicotinic cholinergic receptors. We have investigated the functional significance of this finding for cognitive functioning by studying the effects of the centrally active nicotinic antagonist mecamylamine. Single oral doses of mecamylamine were administered to 12 healthy young males and 15 healthy elderly subjects in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. In both groups, the 20-mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition Task, producing a slower acquisition curve. There was no effect of drug on the performance component (retrieval of previously learned information). However, elderly subjects showed enhanced sensitivity to mecamylamine, with lO-mg dose producing significant impairment of learning not seen in the young normals. On a recognition memory task, there was an age-associated shift in response bias, with the elderly subjects becoming more liberal with increasing dose. Reaction-time measures suggested a dose-related slowing of reaction time on several tasks. Behavioral effects were minimal and physiologic effects were consistent with dose-related ganglionic blockade. These results indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment similar to some deficits seen in dementing illnesses, and that there is an age-related increase in sensitivity to nicotinic blockade.

Central nicotinic cholinergic systems: A role in the cognitive dysfunction in Attention-Deficit/Hyperactivity Disorder?

Theories of the neurobiological basis of Attention-Deficit/Hyperactivity Disorder (ADHD) have largely focused on dysregulation of central dopaminergic function. However, other neurotransmitter systems may be implicated in specific cognitive deficits in ADHD. Interest in the potential involvement of nicotinic cholinergic systems in ADHD has arisen in part from the observation that adolescents and adults with ADHD smoke cigarettes at significantly higher rates than people without this disorder. In addition, several studies report that nicotine alleviates ADHD symptoms, and recent neuro-genetics studies indicate that cholinergic systems may be altered in persons with ADHD. In this review, we describe the evidence for a role of central nicotinic cholinergic systems in cognitive deficits in ADHD. We also propose mechanisms by which alterations in cholinergic function may contribute directly and/or indirectly to these deficits. Finally, we identify specific paradigms and models to guide future investigations into the specific involvement of nicotinic cholinergic systems in ADHD, possibly leading to the development of more effective pharmacotherapies for ADHD.

Functional Brain Imaging of Nicotinic Effects on Higher Cognitive Processes

Significant advances in human functional brain imaging offer new opportunities for direct observation of the effects of nicotine, novel nicotinic agonists and nicotinic antagonists on human cognitive and behavioral performance. Careful research over the last decade has enabled investigators to explore the role of nicotinic systems on the functional neuroanatomy and neural circuitry of cognitive tasks in domains such as selective attention, working memory, episodic memory, cognitive control, and emotional processing. In addition, recent progress in understanding functional connectivity between brain regions utilized during cognitive and emotional processes offers new opportunities for examining drug effects on network-related activity. This review will critically summarize available nicotinic functional brain imaging studies focusing on the specific cognitive domains of attention, memory, behavioral control, and emotional processing. Generally speaking, nicotine appears to increase task-related activity in non-smokers and deprived smokers, but not active smokers. By contrast, nicotine or nicotinic stimulation decreases the activity of structures associated with the default mode network. These particular patterns of activation and/or deactivation may be useful for early drug development and may be an efficient and cost-effective method of screening potential nicotinic agents. Further studies will have to be done to clarify whether such activity changes correlate with cognitive or affective outcomes that are clinically relevant. The use of functional brain imaging will be a key tool for probing pathologic changes related to brain illness and for nicotinic drug development.

Effects of nicotinic cholinergic agents on cognitive functioning in Alzheimer's and Parkinson's disease

The loss of central nicotinic receptors is a neurochemical hallmark of several degenerative brain disorders, notably Alzheimers (AD) and Parkinsons Disease (PD). Investigation of the effects of nicotinic agents in both normal and diseased individuals has produced strong evidence of the importance of the integrity of these systems for normal cognitive functioning. Studies in our laboratory utilizing the nicotinic antagonist mecamylamine show that blockade of nicotinic receptors produces measurable and significant cognitive impairment similar in nature to deficits seen in dementing illnesses. This work suggests that symptoms of impaired acquisition of information and short‐term storage, impaired memory consolidation, attention, visual perception, and speed may reflect nicotinic lesions. These studies and others have suggested that nicotinic systems may be involved in the modulation, partitioning, and maintenance of attention, especially for tasks involving working memory, e.g. nicotinic systems may help constrain the focus of attention. Recent studies with nicotine in AD patients reviewed here suggest that nicotinic stimulation can improve the acquisition and retention of verbal information and decrease errors. Finally a review of attentional deficits in AD and PD is presented as a suggested target for nicotinic intervention. Further work will attempt to examine whether nicotinic augmentation effects attentional systems, mnemonic systems, or both as well as whether chronic stimulation with nicotine or novel agonists will produce clinical benefit. Drug Dev. Res. 38:278–289

Effects of acute ultra-low dose mecamylamine on cognition in adult attention-deficit/hyperactivity disorder (ADHD)

Nicotinic cholinergic stimulation has known beneficial effects in attention‐deficit/hyperactivity disorder (ADHD). Mecamylamine is a non‐competitive nicotinic antagonist which is reported in several animal studies to have paradoxical positive effects on cognition at ultra‐low doses. Comparable studies in humans have not been conducted. The aim of this study was to determine the effects of acute ultra‐low doses of mecamylamine on cognition in adult ADHD.