α7-Nicotinic receptors and cognition

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.     

Nicotinic acetylcholine involvement in cognitive function in animals

 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. Received: 18 November 1997 / Final version: 28 November 1997     

Nicotinic treatment for cognitive dysfunction

Nicotinic medications may provide beneficial therapeutic treatment for cognitive dysfunction such as Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder (ADHD). For development of nicotinic treatments we are fortunate to have a well characterized lead compound, nicotine. Transdermal nicotine patches offer a way to deliver measured doses of nicotine in a considerably safer fashion than the more traditional means of administration, tobacco smoking. We have found that transdermal nicotine significantly improves attentional function in people with Alzheimer's disease, schizophrenia or ADHD as well as normal nonsmoking adults. To follow-up on this proof of principal that nicotinic treatment of cognitive dysfunction holds promise, it is important to use animal models to determine the critical neurobehavioral bases for nicotinic involvement in cognitive function so that more selective nicotinic analogues that improve cognitive function with fewer side effects can be developed. We have found with local infusion in rat studies that the hippocampus and amygdala are important substrates for nicotinic effects on working memory function. Both alpha7 and alpha4beta2 nicotinic receptors are involved in working memory. Nicotinic interactions with dopaminergic and glutaminergic systems are also important in the basis of cognitive function. 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.     

Development of nicotinic drug therapy for cognitive disorders

Nicotine, as well as other nicotinic drugs, may provide useful therapeutic treatment for a variety of cognitive impairments including those found in Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder (ADHD). We have found that nicotine skin patches significantly improve attentional performance in people with these disease states as well as normal nonsmoking adults. Animal models are critical for determining the neurobehavioral bases for nicotinic effects on cognitive function. We have found in lesion and local infusion studies with rats that the hippocampus is an important substrate for nicotinic effects on working memory function. Both alpha7 and alpha4beta2 nicotinic receptors in the hippocampus are involved. Further work has investigated the relationship of nicotinic systems with dopaminergic and glutaminergic systems in the basis of cognitive function. Nicotine has proven to be a useful prototypic compound for the family of nicotinic compounds. It produces cognitive improvements in both animal models and clinical populations. Recent work with more selective nicotinic receptor agonists and antagonists in animal models is providing important information concerning the neural mechanisms for nicotinic involvement in cognitive function and opening avenues for development of safe and effective nicotinic treatments for clinical use.     

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 Alzheimer's disease. Preliminary studies have found that some aspects of the cognitive deficit in Alzheimer's disease can be attenuated by nicotine. Nicotine may prove to be useful therapeutic treatment for this and other types of dementia.     

Ventral hippocampal α7 and α4β2 nicotinic receptor blockade and clozapine effects on memory in female rats

Rationale Nicotinic systems in the hippocampus play important roles in memory function. Decreased hippocampal nicotinic receptor concentration is associated with cognitive impairment in schizophrenia and Alzheimer’s disease.Methods We modeled in rats the cognitive effects of chronic decrease in hippocampal α7 or α4β2 receptors with 4-week continuous bilateral local infusions of the α7 nicotinic antagonist methyllycaconitine (MLA) or the α4β2 antagonist dihydro-β-erythroidine (DHβE). The working memory effects of these infusions were assessed by performance on the radial-arm maze. To test the effect of antipsychotic medication, we gave acute injections of clozapine and to determine the impact of nicotine, which is widely used by people with schizophrenia approximately half of the rats received chronic systemic infusions of nicotine.Results Chronic ventral hippocampal DHβE infusion caused a significant (p<0.001) working memory impairment. Acute systemic clozapine (2.5 mg/kg) caused a significant (p<0.005) working memory impairment in rats given control aCSF hippocampal infusions. Clozapine significantly (p<0.025) attenuated the memory deficit caused by chronic hippocampal DHβE infusions. Chronic ventral hippocampal infusions with MLA did not significantly affect the working memory performance in the radial-arm maze, but it did significantly (p<0.05) potentiate the memory impairment caused by 1.25 mg/kg of clozapine. Chronic systemic nicotine did not significantly interact with these effects.Conclusions The state of nicotinic receptor activation in the ventral hippocampus significantly affected the impact of clozapine on working memory with blockade of α7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of α4β2 receptors reversing the clozapine effect from impairing to improving memory.     

Selective nicotinic acetylcholine receptor agonists: potential therapies for neuropsychiatric disorders with cognitive dysfunction

Cognitive impairment is one of the most functionally debilitating aspects of neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease, despite treatment with available pharmacotherapies. There is emerging evidence that nicotine improves cognitive function in humans and nonhuman species and this has sparked interest in the development of novel nicotinic treatments for cognitive dysfunction. The examination of selective alpha7 and alpha4beta2 nicotinic acetylcholine receptor (nAChR) agonists suggests that both receptor subtypes mediate improvement in attention, learning and working memory. When compared with available pharmacotherapies, specific nAChR agonists may represent unique targets for the treatment of neuropsychiatric and neurodegenerative disorders that feature cognitive impairment as a key symptom.     

Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function

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.     

Interaction of nicotinic and histamine H(3) systems in the radial-arm maze repeated acquisition task

Nicotinic systems have been found in a variety of studies to play important roles in cognitive function. Nicotinic involvement in different aspects of cognitive function such as learning vs. memory may differ. We have found in rats that the spatial repeated acquisition task in the radial-arm maze is significantly improved by low doses of the nicotinic receptor antagonist mecamylamine, the atypical nicotinic receptor ligand lobeline, as well as the alpha7 nicotinic receptor agonist ARR-17779. Interestingly, nicotine in the same dose range that improves working memory in the win-shift radial maze task was not effective in improving repeated acquisition performance. Nicotinic systems interact with a variety of other neural systems. Differential involvement of these extended effects with learning vs. memory may help explain differential effects of nicotinic drugs with these cognitive functions. Histamine H(3) receptor antagonists have been shown by some studies to improve cognitive function, but others have not found this effect and some have found impairment. Nicotine stimulates the release of histamine. This effect may counter other cascading effects of nicotine in the performance of learning and memory tasks. A specific test of this hypothesis involves our study of nicotine (0.1-0.4 mg/kg) interactions with the histamine H(3) receptor antagonist thioperamide (2.5-10 mg/kg) on learning memory in the repeated acquisition test in the radial-arm maze. The highest dose of thioperamide tested caused a significant choice accuracy impairment, which was most evident during the later portions of the learning curve. The highest dose of nicotine did not change overall errors but did cause a significant impairment in learning over trials. The choice accuracy impairment induced by thioperamide was significantly attenuated by nicotine (0.4 mg/kg). The learning impairment caused by the highest dose of nicotine was significantly attenuated by thioperamide. Thioperamide also caused a slowing of response, an effect, which was attenuated by nicotine co-administration. The repeated acquisition test can help differentiate acute drug effects on learning. Nicotine and thioperamide effectively reversed each other's choice accuracy impairment even though each by itself impaired accuracy.     

Timing of nicotine effects on learning in zebrafish

Rationale Nicotine has been shown in many, but not all, studies to improve cognitive function in a number of species including rats, mice, monkeys, and humans. Recently, we have found that nicotine also improves memory in zebrafish. Nicotinic agonists are being developed as novel treatments for Alzheimer's disease and other cognitive impairments. Objectives In screening the therapeutic potential of novel nicotinic agonists, it is important to have a rapid assay of cognitive improvement. Zebrafish can help with this effort. Methods We have developed a method of rapidly assessing spatial position discrimination learning in zebrafish in one session of seven trials. We used this method to determine the cognitive effects of nicotine. Results Nicotine (100 mg/l administered during 3 min of immersion) caused a significant improvement in percent correct performance. This dose was within the effective range we found to improve the choice accuracy performance of zebrafish using the more time-intensive delayed spatial alternation procedure. Interestingly, the positive effect of nicotine was seen at 20–40 min postadministration, but not earlier, and declined at 80 and 160 min posttreatment. At the 40-min postdosing interval, 200 mg/l nicotine was also found to significantly improve choice accuracy. Nicotine-induced accuracy improvement was reversed by the nicotinic antagonist mecamylamine given shortly before testing but not when given concurrently with nicotine. Conclusions This position discrimination procedure in zebrafish effectively demonstrated the cognitive-enhancing effects of nicotine. This model may be useful in the early screening of novel nicotinic compounds for treatment of cognitive dysfunction.