Ventral hippocampal alpha7 and alpha4beta2 nicotinic receptor blockade and clozapine effects on memory in female rats.

Full 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 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.

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Author information

Author/s: Pocivavsek, Ana (A); Icenogle, Laura (L); Levin, Edward D (ED);

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

Grants: MH64494 (Agency:NIMH NIH HHS) ; R01 MH064494-05 (Agency:NIMH NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Psychopharmacology (Psychopharmacology (Berl)), published in Germany. (Language: eng)

Reference: 2006-Nov; vol 188 (issue 4) : pp 597-604

Dates: Created 2006/10/23; Completed 2007/03/13; Revised 2008/11/20;

PMID: 16715255, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Aconitine - analogs & derivatives; pharmacology
Animals
Antipsychotic Agents - pharmacology
Clozapine - pharmacology
Dihydro-beta-Erythroidine - pharmacology
Female
Hippocampus - physiology
Maze Learning - drug effects; physiology

Maze Learning - drug effects; physiology
Memory - drug effects; physiology
Nicotine - pharmacology
Nicotinic Agonists - pharmacology
Nicotinic Antagonists - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Nicotinic - physiology

Associated Chemicals: Antipsychotic Agents (0) ; Nicotinic Agonists (0) ; Nicotinic Antagonists (0) ; Receptors, Nicotinic (0) ; alpha-bungarotoxin receptor (0) ; nicotinic receptor alpha4beta2 (0) ; methyllycaconitine (21019-30-7) ; Dihydro-beta-Erythroidine (23255-54-1) ; Aconitine (302-27-2) ; Nicotine (54-11-5) ; Clozapine (5786-21-0)

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