Chronic inhibition of α4β2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response

Arthur, David; Levin, Edward D.

doi:10.1007/s00213-001-0961-6

Cited by 51 publications

(38 citation statements)

References 18 publications

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“…Nicotinic α4β2 blockade in the ventral hippocampus by chronic DHβE infusion caused a significant working memory impairment in the radial-arm maze, replicating our previous work (Arthur and Levin 2002). In the current study, the memory impairment caused by chronic hippocampal DHβE infusion was significantly attenuated by acute systemic administration of the antipsychotic drug clozapine.…”

Section: Discussionsupporting

confidence: 89%

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

2006

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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.

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Section: Discussionsupporting

confidence: 89%

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

2006

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“…In other animal studies, nicotine administration resulted in significant improvements in response speed and in spatial memory accuracy in rats performing the eight-arm radial maze under the influence of a a4b2 nicotinic receptor antagonist (Arthur and Levin, 2002). Other studies showed that chronic nicotine administration improved the working memory (WM) performance of young normal adult rats, and acute nicotine administration improved the WM performance of aged rats in the radial-arm maze (Levin et al, 1997;Levin and Torry, 1996).…”

Section: Cholinergic Agonistsmentioning

confidence: 97%

Psychoactive Drugs and Pilot Performance: A Comparison of Nicotine, Donepezil, and Alcohol Effects

Mumenthaler

Yesavage

Taylor

et al. 2003

Neuropsychopharmacol

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The cholinergic system plays a major role in cognitive abilities that are essential to piloting an aircraft: attention, learning, and memory. In previous studies, drugs that enhance the cholinergic system through different pharmacologic mechanisms have shown beneficial effects on cognition; but dissimilar cognitive measures were used and samples were not comparable. A comparison within the same cognitive tasks, within comparable samples appears desirable. Toward this aim, we compared effect sizes (ES) of performance-enhancing doses of nicotine (a nicotinic receptor agonist) and donepezil (an acetylcholinesterase inhibitor) as found in our prior work on pilot performance. We also compared cholinergic ES to those of performance-impairing doses of alcohol. In three randomized, placebo-controlled trials, we assessed the flight performance of aircraft pilots in a Frasca 141 simulator, testing I: the acute effects of nicotine gum 2 mg; II: the effects of administration of 5 mg donepezil/day for 30 days; and III: the acute and 8 h-carryover effects of alcohol after a target peak BAC of 0.10%. We calculated the ES of nicotine, donepezil, and alcohol on a flight summary score and on four flight component scores. Compared to placebo, nicotine and donepezil significantly improved, while alcohol significantly impaired overall flight performance: ES (nicotine) ¼ 0.80; ES (donepezil) ¼ 1.02; ES (alcohol acute) ¼ À3.66; ES (alcohol 8 h) ¼ À0.82. Both cholinergic drugs showed the largest effects on flight tasks requiring sustained visual attention. Although the two tested cholinergic drugs have different pharmacologic mechanisms, their effects on flight performance were similar in kind and size. The beneficial effects of the cholinergic drugs on overall flight performance were large and the absolute (ie nondirectional) sizes were about one-fourth of the absolute ES of acute alcohol intoxication and roughly the same as the absolute 8 h-carryover ES of alcohol.

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“…These nicotinic receptors are located in a variety of brain regions including the prefrontal cortex and the hippocampus, both of which are important for memory function (Goldman-Rakic, 1996;Jarrard, 1993;Laroche et al, 2000). We have shown that nicotinic receptors in the hippocampus are important for memory performance as local hippocampal infusion of nicotinic receptor antagonists significantly impairs memory function (Arthur and Levin, 2002;Bancroft and Levin, 2000;Bettany and Levin, 2001;Felix and Levin, 1997;Kim and Levin, 1996;Levin et al, 2002).…”

Section: Introductionmentioning

confidence: 95%

Reversal of Clozapine Effects on Working Memory in Rats with Fimbria–Fornix Lesions

Addy

Pocivavsek

Levin

2005

Neuropsychopharmacol

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Clozapine is an effective antipsychotic drug, but its effects on cognitive function are unclear. Previously, we found that clozapine caused a working memory deficit, which was reversed by nicotine. Hippocampal systems are important in determining clozapine effect on memory. In the current study, the memory effects of clozapine and nicotine administration were determined in rats with lesions of the fimbria-fornix, a fiber bundle which carries cholinergic and other projections between the septum and the hippocampus. Female Sprague-Dawley rats were trained on a win-shift procedure in the radial-arm maze, in which each arm entry was rewarded once per session. Then, 13 rats received bilateral knife-cut lesions of the fimbria-fornix, while 14 rats underwent sham surgery. The rats were tested after subcutaneous injections with combinations of clozapine (0 and 1.25 mg/kg) and nicotine (0, 0.2, and 0.4 mg/kg). In shamoperated rats, clozapine caused a significant (Po0.005) working memory impairment. Fimbria-fornix lesions also caused a significant (Po0.05) memory impairment. Interestingly, clozapine had the opposite effect on working memory in the lesioned vs sham-operated rats. In contrast to its effects in controls, clozapine (1.25 mg/kg) significantly (Po0.05) attenuated the working memory deficit caused by fimbria-fornix lesions. Nicotine (0.2 mg/kg) did not quite significantly improve memory in lesioned rats. The effects of clozapine and nicotine were not additive in the lesioned rats. This study demonstrates the efficacy of clozapine in improving working memory in fimbria-fornix-lesioned rats, whereas it causes impairments in intact rats. Therapeutic treatment with clozapine in people with malfunctions of the hippocampus such as seen in schizophrenia may improve cognitive performance, whereas the same doses of clozapine may impair memory in individuals without hippocampal malfunction.

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Chronic inhibition of α4β2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response

Cited by 51 publications

References 18 publications

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

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

Psychoactive Drugs and Pilot Performance: A Comparison of Nicotine, Donepezil, and Alcohol Effects

Reversal of Clozapine Effects on Working Memory in Rats with Fimbria–Fornix Lesions

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