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Biomedical subjects

Edward D Levin

Publications and source records attributed to Edward D Levin.

At least 19 recordsLinked to original sources
PubMed2007

Effects of atypical anxiolytic N-phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) on alcohol intake in alcohol-preferring P rats.

BACKGROUND: N-Phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) is a structurally novel atypical anxiolytic with an overall in vivo profile in animals suggestive of the potential to show anxiolytic efficacy in humans at doses that will not cause CNS-related side effects. Furthermore, unlike the benzodiazepines, JNJ-5234801 does not have an adverse interaction with ethanol even at doses 20 to 40 times the minimal effective dose in the rat elevated plus maze (MED=1.0 mg/kg, p.o.). METHODS: In the present study, JNJ-5234801 was evaluated for potential efficacy in reducing alcohol intake in alcohol-preferring rats. Alcohol-preferring P rats were allowed to drink water or alcohol (10%, v/v) in a 2-bottle choice procedure. Once stable baselines were established, the acute effects of JNJ-5234801 [(10-40 mg/kg, intraperitoneally (i.p.)] were assessed. In a separate study, chronic treatment with JNJ-5234801 (40 mg/kg once daily, i.p.) for 12 consecutive days was compared with naltrexone (20 mg/kg, twice daily, i.p.). RESULTS: There was a selective dose-dependent reduction in alcohol intake in the alcohol-preferring (P) rats after acute administration of JNJ-5234801 (10-40 mg/kg, i.p.). There were no significant effects on food or water intake. When administered subchronically, both JNJ-5234801 (40 mg/kg once daily, i.p.) and naltrexone (20 mg/kg, twice daily, i.p.) considerably reduced alcohol intake, but tolerance to the alcohol-suppressing effects appeared to occur sooner in the naltrexone-treated group. While both compounds slightly but significantly reduced food intake at the beginning, only JNJ-5234801 increased water intake and decreased alcohol preference. CONCLUSIONS: The novel atypical anxiolytic JNJ-5234801 has a favorable profile effects on alcohol intake and related measures compared with naltrexone, which is recommended for the treatment of alcoholism.

Acute Disease↗
PubMed2006

Increased nicotine self-administration following prenatal exposure in female rats.

There is a significant association between maternal cigarette smoking during pregnancy and greater subsequent risk of smoking in female offspring. In animal models, prenatal nicotine exposure causes persistent alterations in cholinergic and monoaminergic systems, both of which are important for nicotine actions underlying tobacco addiction. Accordingly, the current study was conducted to determine if there is a cause-and-effect relationship between prenatal nicotine exposure and nicotine self-administration starting in adolescence. Pregnant rats were administered nicotine (6 mg/kg/day) by osmotic minipump infusion throughout gestation and then, beginning in adolescence and continuing into adulthood, female offspring were given access to nicotine via a standard operant IV self-administration procedure (0.03 mg/kg/infusion). Gestational nicotine exposure did not alter the initial rate of nicotine self-administration. However, when animals underwent one week of forced abstinence and then had a second opportunity to self-administer nicotine, the prenatally-exposed animals showed a significantly greater rate of self-administration than did the controls. Prenatal nicotine exposure causes increased nicotine self-administration, which is revealed only when the animals are allowed to experience a period of nicotine abstinence. This supports a cause-and-effect relationship between the higher rates of smoking in the daughters of women who smoke cigarettes during pregnancy and implicates a role for nicotine in this effect. Our results further characterize the long-term liabilities of maternal smoking but also point to the potential liabilities of nicotine-based treatments for smoking cessation during pregnancy.

Animals↗
PubMed2006

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.

Animals↗
PubMed2006

Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial.

RATIONALE: Despite established links between nicotine dependence and depression, little research has examined the effects of nicotine on depression symptoms. OBJECTIVE: This study evaluated the acute and chronic effects of transdermal nicotine in nonsmokers with baseline depression symptoms during a 4-week, double-blind, placebo-controlled trial. METHODS: Nonsmokers with scores >or=10 on the Center for Epidemiological Studies Depression scale (CES-D) were recruited from the community. Mood and cognitive performance were measured at baseline (day 0) and at 1, 8, 21, and 28 days. Participants were randomly assigned to wear a placebo or nicotine patch for 4 weeks (3.5 mg/day during weeks 1 and 4; 7 mg/day during weeks 2 and 3). The final sample consisted of 11 nonsmokers with a mean baseline CES-D score of 27.36 (SD=10.53). RESULTS: Salivary nicotine levels indicated the majority of participants were compliant with treatment. Acute nicotine did not alter mood. After adjusting for baseline values, chronic nicotine resulted in a significant decline in CES-D scores at day 8 (3.5 mg/day), but returned to placebo levels by the last visit. This return to baseline levels was coincident with a decrease in nicotine administration from 7 to 3.5 mg/day. A similar trend for improved response inhibition as measured by the Conners Continuous Performance Task was also observed. Reported side effects were infrequent and minimal. CONCLUSION: These findings suggest a role for nicotinic receptor systems in the pathophysiology of depression and that nicotinic compounds should be evaluated for treating depression symptoms.

Administration, Cutaneous↗
PubMed2006

Persistent neurobehavioral effects of early postnatal domoic acid exposure in rats.

Domoic acid (DA) is a marine biotoxin, produced by the diatom Pseudo-nitzchia spp., which has been shown to cause cognitive impairment in adults who are exposed via contaminated seafood. The neurobehavioral consequences of developmental exposure are much less well understood. In a previous study, we showed that a single prenatal exposure to DA in rats at mid-gestation caused neurobehavioral changes that persist into adulthood including increased susceptibility to the benchmark amnestic drug scopolamine. In the current study, we examined the lasting neurobehavioral consequences of DA exposure on the first day of postnatal life, a time in rats marking the completion of the major phase of neuroproliferation and corresponding to week 24 of human gestation. The effects of DA exposure at doses from 0.025-0.1 mg/kg (s.c.) twice per day on each of postnatal days 1 and 2 were compared with vehicle-treated controls and rats treated by the same protocol with 1 mg/kg of kainic acid. Following kainic acid exposure, a sex-selective effect was seen with females but not males showing a significant slowing of response latency in the radial-arm maze. The high DA dose of 0.1 mg/kg was quite toxic causing lethality in all of the offspring exposed and this group was excluded from further analysis. When the offspring in the 0.05 mg/kg DA dose group were tested, significant hypoactivity in the Figure-8 maze was observed during adolescence. No significant DA effects were seen in response latency or choice accuracy on the radial-arm maze during either acquisition or with challenge of the amnestic drug scopolamine. Early postnatal DA exposure in the rat can be lethal and sublethal exposure can cause neurobehavioral effects manifest in modest hypoactivity during the adolescent period. However, the sublethal persistent neurobehavioral toxicity appears to be less pervasive than reported effects following DA administered mid-gestation.

Animals↗
PubMed2006

Guidelines on nicotine dose selection for in vivo research.

RATIONALE: This 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. OBJECTIVES: This 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. RESULTS: Seven 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. CONCLUSIONS: The 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.

Animals↗
PubMed2006

Ventral hippocampal alpha7 and alpha4beta2 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 alpha7 or alpha4beta2 receptors with 4-week continuous bilateral local infusions of the alpha7 nicotinic antagonist methyllycaconitine (MLA) or the alpha4beta2 antagonist dihydro-beta-erythroidine (DHbetaE). 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 DHbetaE 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 DHbetaE 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 alpha7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of alpha4beta2 receptors reversing the clozapine effect from impairing to improving memory.

Aconitine↗
PubMed2006

Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure.

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 1 mg/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 0.125 mg/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 1 mg/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.

Animals↗
PubMed2006

Dorsal hippocampal alpha7 and alpha4beta2 nicotinic receptors and memory.

Nicotinic receptor systems have been shown to be important for working memory. In general, nicotinic agonists have been shown to improve memory, and nicotinic antagonists impair it. All of the neuronal substrates for nicotinic involvement in memory still remain to be discovered. The amygdala and ventral hippocampus have both been found to be important for nicotinic involvement in memory function. Local infusion of the nicotinic antagonist methyllycaconitine (MLA) to block alpha7 nicotinic receptors and dihydro-beta-erythrodine (DHbetaE) to block alpha4beta2 nicotinic receptors into the basolateral amygdala and the ventral hippocampus have been found to impair working memory function, with no additive effects being observed. The current project assessed the roles of alpha7 and alpha4beta2 nicotinic receptors in the dorsal hippocampus for memory function. Adult female Sprague-Dawley rats were trained on the 16-arm radial maze. The rats (n = 10) had bilateral cannulae implanted into the dorsal hippocampus. The rats were given acute infusions of DHbetaE (0, 1.69, 3.38, and 6.75 microg/side) and MLA (6.75 microg/side) alone and in combination in a repeated measures counter-balanced design. DHbetaE and MLA infusion into the dorsal hippocampus significantly increased working memory errors. However, when the two drugs were given in combination, an attenuated effect was seen. No significant effects of MLA or DHbetaE were seen with reference memory errors or response latency. These results confirm the importance of alpha4beta2 and alpha7 nicotinic acetylcholine receptors in the dorsal hippocampus for appetitively-motivated spatial cognitive function.

Aconitine↗
PubMed2006

Metallothionein expression and neurocognitive function in mice.

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.

Animals↗
PubMed2006

Nicotinic-antipsychotic drug interactions and cognitive function.

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.

Animals↗
PubMed2006

Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity.

A comparative approach to the differences between systemic toxicity and developmental neurotoxicity of organophosphates is critical to determine the degree to which multiple mechanisms of toxicity carry across different members of this class of insecticides. We contrasted neuritic outgrowth and cholinergic synaptic development in neonatal rats given different organophosphates (chlorpyrifos, diazinon, parathion) at doses spanning the threshold for impaired growth and viability. Animals were treated daily on postnatal days 1-4 by subcutaneous injection so as to bypass differences in first-pass activation to the oxon or catabolism to inactive products. Evaluations occurred on day 5. Parathion (maximum tolerated dose, 0.1 mg/kg) was far more systemically toxic than was chlorpyrifos or diazinon (maximum tolerated dose, 1-5 mg/kg). Below the maximum tolerated dose, diazinon impaired neuritic outgrowth in the forebrain and brainstem, evidenced by a deficit in the ratio of membrane protein to total protein. Diazinon also decreased choline acetyltransferase activity, a cholinergic neuronal marker, whereas it did not affect hemicholinium-3 binding to the presynaptic choline transporter, an index of cholinergic neuronal activity. There was no m(subscript)2(/subscript)-muscarinic acetylcholine receptor down-regulation, as would have occurred with chronic cholinergic hyperstimulation. The same pattern was found previously for chlorpyrifos. In contrast, parathion did not elicit any of these changes at its maximum tolerated dose. These results indicate a complete dichotomy between the systemic toxicity of organophosphates and their propensity to elicit developmental neurotoxicity. For parathion, the threshold for lethality lies below that necessary for adverse effects on brain development, whereas the opposite is true for chlorpyrifos and diazinon.

Animals↗
PubMed2006

Organophosphate insecticides target the serotonergic system in developing rat brain regions: disparate effects of diazinon and parathion at doses spanning the threshold for cholinesterase inhibition.

BACKGROUND: In the developing brain, serotonin (5HT) systems are among the most sensitive to disruption by organophosphates. OBJECTIVES: We exposed neonatal rats to daily doses of diazinon or parathion on postnatal days (PND)1-4 and evaluated 5HT receptors and the 5HT transporter in brainstem and forebrain on PND5, focusing on doses of each agent below the maximum tolerated dose and spanning the threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg for diazinon, and 0.02, 0.05, and 0.1 mg/kg for parathion. RESULTS: Diazinon evoked up-regulation of 5HT1A and 5HT2 receptor expression even at doses devoid of effects on cholinesterase activity, a pattern similar to that seen earlier for another organophosphate, chlorpyrifos. In contrast, parathion decreased 5HT1A receptors, again at doses below those required for effects on cholinesterase. The two agents also differed in their effects on the 5HT transporter. Diazinon evoked a decrease in the brainstem and an increase in the forebrain, again similar to that seen for chlorpyrifos; this pattern is typical of damage of nerve terminals and reactive sprouting. Parathion had smaller, nonsignificant effects. CONCLUSIONS: Our results buttress the idea that, in the developing brain, the various organophosphates target specific neurotransmitter systems differently from each other and without the requirement for cholinesterase inhibition, their supposed common mechanism of action.

Animals↗
PubMed2005

Effects of clozapine on memory function in the rat neonatal hippocampal lesion model of schizophrenia.

Clozapine is an effective atypical antipsychotic drug used to treat schizophrenia. It has the advantage of producing fewer extrapyramidal motor side effects than typical antipsychotic drugs such as haloperidol. Schizophrenia involves more than the hallmark symptom of psychosis. Substantial cognitive impairment is also seen. Effective drug treatments against the cognitive impairment of schizophrenia need to be developed. The current study was conducted to determine the effects of clozapine on working memory in the rat neonatal hippocampal lesion model of schizophrenia, which includes symptoms of cognitive impairment. Infant Sprague-Dawley rats were given ibotenic acid lesions of the hippocampus on day 7 of age (using the day of birth as day 0). Controls were given vehicle infusions. In adulthood, the rats were trained on the 8-arm radial maze using the win-shift procedure. After 6 sessions of training, the lesioned rats and their controls were administered repeated injections of saline or clozapine (2.5 mg/kg) for the next 12 sessions of training. The females had significant radial-arm maze choice accuracy impairments caused by either clozapine or the hippocampal lesion, but the combination of the two treatments had no additive effect. The males showed a different pattern of effects. Intact males did not show a significant clozapine-induced impairment, whereas males with hippocampal lesions did show significant clozapine-induced impairment although hippocampal lesions by themselves did not significantly impair male choice accuracy. These data show that clozapine can cause memory impairment and it potentiates rather than reverses hippocampal lesion-induced deficits. There are critical sex-related differences in these effects.

Analysis of Variance↗
PubMed2005

Chronic nicotine interactions with clozapine and risperidone and attentional function in rats.

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.

Animals↗
PubMed2005

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

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.

Alzheimer Disease↗
PubMed2005

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.

Animals↗