Amir H. Rezvani

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.

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.

Chronic mild stress-induced anhedonia : greater effect in a genetic rat model of depression

The effects of acute and chronic stressors on saccharin intake and preference in the hypercholinergic Flinders Sensitive Line (FSL) rat, a putative genetic animal model of depression, were studied and compared to the control Flinders Resistant Line (FRL) rats. Overall, the FRL rats drank significantly less saccharin and water than the FSL rats when compared over a wide range of saccharin concentrations (0.01-5%) under baseline conditions. A 0.02% saccharin concentration was used in subsequent experiments. We observed a significant suppression of saccharin intake/preference at 1 h following a single 5-min exposure to cold swim stress only in FSL rats. There was a tendency to increase saccharin intake in both lines at 1 h following a scrambled foot shock stress. These effects of acute stressors disappeared upon retesting for saccharin consumption/preference 23 h after the stress. Chronic 4-week exposure to unpredictable mild stressors significantly (p < 0.01) decreased saccharin consumption in the FSL rats, but not in the FRL rats. The FSL rats also exhibited a significantly greater decrease in saccharin preference (-24% vs. prestress baseline, as compared to -7% in FRL controls, p < 0.05). In conclusion, FSL rats appear more prone than the FRL rats to chronic, as well as immediate acute, stress-induced anhedonic effects. This outcome further supports the notion that the FSL rat is a useful model of a genetic predisposition to depressive-like reactions.

Antidepressant effects of nicotine in an animal model of depression

Abstract Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg SC) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the α4β2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the α7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders.

Nicotinic treatment for cognitive dysfunction.

Nicotinic medications may provide beneficial therapeutic treatment for cognitive dysfunction such as Alzheimers 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 Alzheimers 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.

MK-801 potently inhibits alcohol withdrawal seizures in rats

The ability of MK-801, an N-methyl-D-aspartate (NMDA)-channel antagonist, to suppress alcohol withdrawal seizures generated audio-genically was studied in adult male rats using a cross-over experimental design. MK-801 treatment reduced overall seizure score and proportion of rats seizing. In comparison to other seizure models, alcohol withdrawal seizures seem to be particularly sensitive to MK-801, suggesting that mechanisms which result in seizure susceptibility after withdrawal of chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes.

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 Alzheimers 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.

Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression

Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these “therapeutic” effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond “therapeutically” to antidepressants and not psychomotor stimulants.

Effects of Chronic Mild Stress on Serum Complement Activity, Saccharin Preference, and Corticosterone Levels in Flinders Lines of Rats

Complement proteins and fragments participate in the induction and modulation of specific and nonspecific immune reactions. We have examined the effect of 4 weeks of chronic mild stress (CMS) on complement sheep red blood cell hemolytic activity measured in CH50 units in two selectively bred lines of rats, the Flinders resistant line (FRL) and the Flinders sensitive line (FSL), that differ in cholinergic sensitivity and behavioral characteristics. Additionally, CMS-induced hedonic deficit (decreased preference for 0.02% saccharin over water) and serum corticosterone levels were compared in FRL and FSL rats. CMS caused a significantly (p < 0.01) greater decline in CH50 responses in FSL (-15%) than in FRL (-7%) rats. This was accompanied by a significant (p < 0.01) suppression of saccharin preference over a 24 h period in both FRL and FSL rats. Both lines showed a similar, more than 2-fold (p < 0.01) increase in corticosterone levels following CMS. These results further confirm that CMS induces a depressive-like state in rats as well as the validity of the FSL rat as a genetic model of depression. They also indicate that the effect of stress on the immune system can be monitored by measuring the complement CH50 response.

Genetic Animal Models of Depression and Ethanol Preference Provide Support for Cholinergic and Serotonergic Involvement in Depression and Alcoholism

The present article summarizes some comparative studies of the Fawn-Hooded (FH) rat, a potential animal model of ethanol preference, and the Flinders Sensitive Line (FSL) rat, a potential animal model of depression. Both FH and FSL rats exhibit high degrees of immobility in the forced swim test and have difficulty learning a two-way active avoidance task. However, there were no differences between the FH and FSL rats in the elevated plus maze. Studies of ethanol preference indicated high rates of ethanol intake (greater than 4 g/kg) and preference (greater than 50%) in the FH rats, but low rates of ethanol intake (less than 1.1 g/kg) and preference (less than 20%) in FSL rats. It is concluded that the FSL rats exhibit behaviors consistent with their being an animal model of depression, whereas the FH rats exhibit features consistent with their being an animal model of both depression and alcoholism. Psychopharmacological challenges indicated that both FSL and FH rats were more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist. However, FSL rats were also more sensitive to serotonergic agonists, and some of the present results and other investigators have reported serotonergic subsensitivity in the FH rats. Thus, FSL rats exhibit both cholinergic and serotonergic supersensitivity, whereas FH rats exhibit cholinergic supersensitivity but normal or reduced serotonergic sensitivity. Progeny from a genetic cross between FH and FSL rats exhibit cholinergic supersensitivity and have high ethanol preference scores. These data are consistent with genetic models suggesting that ethanol preference may be influenced by dominant genes, whereas cholinergic sensitivity may be influenced by recessive genes.