Chronic nicotine infusion in rats has been found in our studies with the radial-arm maze to improve working memory function. This type of chronic nicotine infusion models that achieved by the nicotine skin patch, an increasingly common way to administer nicotine which has been found in our studies to effectively improve cognitive function in schizophrenics, Alzheimer's disease patients and adults with attention deficit disorder. The proposed studies will help determine the critical neural systems underlying chronic nicotine infusion-induced memory improvement. The primary hypothesis is that nicotinic receptors in the hippocampus are critical for the nicotine infusion effect on memory. We have found that ibotenic acid lesions of neurons in the ventral hippocampus eliminates the effectiveness of chronic nicotine for improving memory. Also we have found that local ventral hippocampal infusion of the nicotinic antagonists mecamylamine, DH-beta-E and MLA cause significant deficits in working memory. MLA effectively blocks alpha-7 receptors, DH-beta-E effectively blocks alpha-3 beta-4 receptors and mecamylamine effectively blocks alpha-3 beta-4 receptors all of which are found in the hippocampus. These three nicotinic antagonists will be infused either during the development of the chronic nicotine effect or during its expression to determine the involvement of these nicotinic receptors in different phases of the chronic nicotine effect on memory. In the later phases of the project similar studies will be carried out in other brain areas including the dorsal hippocampus, medial and lateral frontal cortex, nucleus accumbens and the midbrain dopaminergic nuclei. This will further complete our analysis of the neural bases for chronic nicotine effects on memory. These studies will further our understanding of the neural systems underlying cognitive function and dysfunction. This will be of critical importance for the development of nicotinic-based therapeutics for cognitive dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011943-03
Application #
6175741
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Aigner, Thomas G
Project Start
1998-08-20
Project End
2002-06-30
Budget Start
2000-07-15
Budget End
2002-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$174,468
Indirect Cost
Name
Duke University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Rezvani, Amir H; Levin, Edward D (2004) Adolescent and adult rats respond differently to nicotine and alcohol: motor activity and body temperature. Int J Dev Neurosci 22:349-54
Levin, Edward D; Rezvani, Amir H; Montoya, Daniel et al. (2003) Adolescent-onset nicotine self-administration modeled in female rats. Psychopharmacology (Berl) 169:141-9
Rezvani, Amir H; Levin, Edward D (2003) Nicotine-alcohol interactions and attentional performance on an operant visual signal detection task in female rats. Pharmacol Biochem Behav 76:75-83
Levin, E D; Bradley, A; Addy, N et al. (2002) Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory. Neuroscience 109:757-65
Rezvani, Amir H; Levin, Edward D (2002) Nicotine-alcohol interactions and cognitive function in rats. Pharmacol Biochem Behav 72:865-72
Levin, E D; Rezvani, A H (2002) Nicotinic treatment for cognitive dysfunction. Curr Drug Targets CNS Neurol Disord 1:423-31
Addy, Nii; Levin, Edward D (2002) Nicotine interactions with haloperidol, clozapine and risperidone and working memory function in rats. Neuropsychopharmacology 27:534-41
Levin, Edward D (2002) Nicotinic receptor subtypes and cognitive function. J Neurobiol 53:633-40
Arthur, David; Levin, Edward D (2002) Chronic inhibition of alpha4beta2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response. Psychopharmacology (Berl) 160:140-5
Rezvani, Amir H; Bushnell, Philip J; Levin, Edward D (2002) Effects of nicotine and mecamylamine on choice accuracy in an operant visual signal detection task in female rats. Psychopharmacology (Berl) 164:369-75

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