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

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Abstract

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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Acknowledgement

The authors thank Nii Addy for his help with this study. This research was supported by NIH grant MH64494.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, 27710, USA

    Ana Pocivavsek, Laura Icenogle & Edward D. Levin

  2. Department of Psychiatry, Neurobehavioral Research Laboratory, Duke University Medical Center, P.O. Box #3412, Durham, NC, 27710, USA

    Edward D. Levin

Authors
  1. Ana Pocivavsek
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  2. Laura Icenogle
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  3. Edward D. Levin
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Correspondence to Edward D. Levin.

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Pocivavsek, A., Icenogle, L. & Levin, E.D. Ventral hippocampal α7 and α4β2 nicotinic receptor blockade and clozapine effects on memory in female rats. Psychopharmacology 188, 597–604 (2006). https://doi.org/10.1007/s00213-006-0416-1

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  • DOI: https://doi.org/10.1007/s00213-006-0416-1

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