Although current research into the causes of smoking focuses largely on nicotine, there is accumulating evidence that other tobacco constituents, such as monoamine oxidase (MAO) inhibitors, may increase the addictive liability of tobacco use. The goal of the proposed research is to elucidate the contribution of MAO inhibition to the psychoactive effects of tobacco. We will use the rat as a model to test the hypothesis that MAO inhibition enhances the effects of nicotine on smoking initiation and dependence. We base this hypothesis on prior findings that i) MAO is an important modulator of monoamines in brain reward systems, ii) smoking reduces brain MAO activity thereby increasing brain monoamines, and iii) MAO inhibition enhances nicotine-induced locomotor sensitization and reward. We propose to explore the effects of MAO inhibition on nicotine-induced actions at the behavioral, biochemical and anatomical levels.
The specific aims are: 1. To determine the selectivity requirements for MAO inhibitor enhancement of nicotine's reinforcing actions. We will use adult male and female rats to evaluate how the selectivity of MAO inhibitors affects the acquisition of nicotine self-administration; 2. To determine how MAO inhibition alters nicotine- induced changes in regional brain activity. We will use neuroanatomical and neurochemical approaches to evaluate the neural circuitry underlying the enhancement of nicotine reward by the MAO inhibitor, tranylcypromine; 3. To determine whether tranylcypromine selectively enhances nicotine reward as compared to other psychostimulants. We will compare the effect of tranylcypromine pretreatment on the acquisition of nicotine, cocaine and amphetamine self-administration. If selectivity for nicotine is observed, we will test whether MAO inhibition alters nicotine's relative reward strength in a 2-lever choice paradigm; 4. To determine if MAO inhibition increases nicotine withdrawal as a measure of dependence. Animals which are chronically infused with nicotine will be treated with saline or tranylcypromine and compared for mecamylamine- and naloxone-precipitated withdrawal symptoms and conditioned place aversion. The results of these studies should advance our understanding of the interaction of nicotine with other tobacco constituents, and lead to improved animal models of smoking that will strengthen our search for tobacco addiction's causes and cures. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA021267-02
Application #
7198110
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Rapaka, Rao
Project Start
2006-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$254,143
Indirect Cost
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Arnold, Monica M; Loughlin, Sandra E; Belluzzi, James D et al. (2014) Reinforcing and neural activating effects of norharmane, a non-nicotine tobacco constituent, alone and in combination with nicotine. Neuropharmacology 85:293-304
Villégier, Anne-Sophie; Belluzzi, James D; Leslie, Frances M (2011) Serotonergic mechanism underlying tranylcypromine enhancement of nicotine self-administration. Synapse 65:479-89
Lotfipour, Shahrdad; Arnold, Monica M; Hogenkamp, Derk J et al. (2011) The monoamine oxidase (MAO) inhibitor tranylcypromine enhances nicotine self-administration in rats through a mechanism independent of MAO inhibition. Neuropharmacology 61:95-104
Villegier, Anne-Sophie; Gallager, Brittney; Heston, Jon et al. (2010) Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats. Psychopharmacology (Berl) 208:593-601
Cao, Junran; Belluzzi, James D; Loughlin, Sandra E et al. (2007) Acetaldehyde, a major constituent of tobacco smoke, enhances behavioral, endocrine, and neuronal responses to nicotine in adolescent and adult rats. Neuropsychopharmacology 32:2025-35
Gehricke, Jean-G; Loughlin, Sandra E; Whalen, Carol K et al. (2007) Smoking to self-medicate attentional and emotional dysfunctions. Nicotine Tob Res 9 Suppl 4:S523-36
Villegier, Anne-Sophie; Lotfipour, Shahrdad; Belluzzi, James D et al. (2007) Involvement of alpha1-adrenergic receptors in tranylcypromine enhancement of nicotine self-administration in rat. Psychopharmacology (Berl) 193:457-65