NDLI: Chronic underactivity of medial frontal cortical beta2-containing nicotinic receptors increases clozapine-induced working memory impairment in female rats.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Levin, Edward D. Perkins, Abigail Brotherton, Terrell Qazi, Melissa Berez, Chantal Montalvo-Ortiz, Janitza Davis, Kasey Williams, Paul Christopher, N. Channelle
Description	Country affiliation: United States Author Affiliation: Levin ED ( Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. edlevin@duke.edu)
Abstract	Nicotinic receptor decreases in the frontal cortex and hippocampus are important mediators of cognitive impairment in both schizophrenia and Alzheimer's disease. Drug treatments for these diseases should take into account the impacts of compromised brain function on drug response. This study investigated the impact of compromised nicotinic receptor activity in the frontal cortex in rats on memory function. Since both Alzheimer's disease and schizophrenia can involve psychosis, antipsychotic drugs are often given. The impacts of antipsychotic drugs on cognitive function have been found to be quite variable. It is the hypothesis of this and previous studies that the cognitive effects of antispychotic drugs on cognitive function depend on the integrity of brain systems involved in cognition. Previously in studies of the hippocampus, we found that chronic inhibition of beta2-containing nicotinic receptors with dihydro-beta-erythrodine (DHbetaE) impaired working memory and that this effect was attenuated by the antipsychotic drug clozapine. In contrast, chronic hippocampal alpha7 nicotinic receptor blockade with methyllycaconitine (MLA) potentiated the clozapine-induced memory impairment which is seen in rats without compromised nicotinic receptor activity. The current study determined medial frontal cortical alpha7 and beta2-containing nicotinic receptor involvement in memory and the interactions with antipsychotic drug therapy with clozapine. Chronic DHbetaE and MLA infusion effects and interactions with systemic clozapine were assessed in female rats tested for memory on the radial-arm maze. Antipsychotic drug interactions with chronic systemic nicotine were investigated because nicotinic procognitive treatment has been proposed. The same local infusion DHbetaE dose that impaired memory with hippocampal infusion did not impair memory when infused in the medial frontal cortex. Frontal DHbetaE infusion potentiated clozapine-induced memory impairment, whereas previously the memory impairment caused by hippocampal DHbetaE infusion was attenuated by clozapine. Frontal cortical MLA infusions at a dose that previously was found to potentiate the clozapine-induced memory impairment with hippocampal infusion had no significant effect when infused into the medial frontal cortex. The location and subtype of nicotinic receptor underactivity are critical determinates for clozapine effects on memory. Patients with hippocampal beta2-containing nicotinic receptor loss may be well treated with clozapine therapy, while those with frontal cortical beta2-containing receptor loss may have a potentiated memory impairment caused by clozapine.
File Format	HTM / HTML
ISSN	02785846
e-ISSN	18784216
DOI	10.1016/j.pnpbp.2008.12.003
Journal	Progress in Neuro-Psychopharmacology and Biological Psychiatry
Issue Number	2
Volume Number	33
Language	English
Publisher	Elsevier
Publisher Date	2009-03-17
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Discipline Psychiatry Antipsychotic Agents Pharmacology Cerebral Cortex Drug Effects Metabolism Clozapine Memory Disorders Chemically Induced Psychology Memory, Short-term Prefrontal Cortex Physiology Receptors, Nicotinic Aconitine Analogs & Derivatives Animals Administration & Dosage Chronic Disease Dihydro-beta-erythroidine Maze Learning Microinjections Nicotinic Antagonists Rats, Sprague-dawley Alpha7 Nicotinic Acetylcholine Receptor Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Biological Psychiatry Pharmacology

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Chronic Underactivity of Medial Frontal Cortical β2-Containing Nicotinic Receptors Increases Clozapine-Induced Working Memory Impairment in Female Rats

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