A new medication for drug abuse and drug craving is proposed. Positive results have been obtained with the combination of properties in two appetite suppressants, the serotonergic drug fenfluramine (Fen) and the dopamineric drug phentermine (Phen). The Fen-Phen combination decreased oral intake of nicotine in mice, decreased i.v. self-administration of cocaine+heroin in rats, and decreased binge eating and food craving in humans. The proposal for animal research is to investigate where, how, and when Fen-Phen works, and for humans, to determine whether it is an effective medication to reduce nicotine and cocaine craving. Fen-Phen probably suppresses appetite via the hypothalamus. Most drugs of abuse act on the mesolimbic dopamine (DA) system that generates conditioned incentives and behavior reinforcement. Therefore, the logic behind Fen-Phen therapy for drug abuse is to activate hypothalamic systems for appetite suppression in a manner that imposes limits on the DA incentive/reinforcement system. This will inhibit conditioned or unconditioned stimuli for drug abuse. [The application is designed to address the following questions:] 1. Where does Fen-Phen work? At the behavioral level, the proposed plan is to compare d- and d,l-fenfluramine and phentermine, separately and together for efficacy in inhibiting drug self-administration in rats and for locomotor side effects, abuse liability, and sites of action in the hypothalamus and a DA terminal region. 2. How does Fen-Phen work? At the neural systems level, our studies suggest that Fen-Phen acts in the hypothalamus to inhibit drug abuse by releasing acetylcholine in nucleus accumbens (NAc), where acetylcholine can limit dopamine's effects. Drugs and neurotransmitters in the brain will be measured by microdialysis. 3. When does Fen-Phen work? Food deprivation and weight loss are known to augment drug abuse. It was discovered that food-restricted rats with low body weight have low DA release in the NAc. Therefore, food restricted animals may be prone to drug abuse as a means to restore DA. Fen-Phen may have special potential in drug abuse prevention or treatment in situations that benefit from appetite suppression. The above three studies will clarify the mechanism and potential of Fen-Phen therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010608-03
Application #
2749160
Study Section
Special Emphasis Panel (SRCD)
Program Officer
Aigner, Thomas G
Project Start
1996-09-15
Project End
2001-07-31
Budget Start
1998-09-30
Budget End
2001-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Princeton University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Avena, Nicole M; Bocarsly, Miriam E; Hoebel, Bartley G (2012) Animal models of sugar and fat bingeing: relationship to food addiction and increased body weight. Methods Mol Biol 829:351-65
Chau, David T; Rada, Pedro V; Kim, Kay et al. (2011) Fluoxetine alleviates behavioral depression while decreasing acetylcholine release in the nucleus accumbens shell. Neuropsychopharmacology 36:1729-37
Taylor, Kathleen M; Mark, Gregory P; Hoebel, Bartley G (2011) Conditioned taste aversion from neostigmine or methyl-naloxonium in the nucleus accumbens. Physiol Behav 104:82-6
Hoebel, Bartley G; Avena, Nicole M; Bocarsly, Miriam E et al. (2009) Natural addiction: a behavioral and circuit model based on sugar addiction in rats. J Addict Med 3:33-41
Berner, Laura A; Avena, Nicole M; Hoebel, Bartley G (2008) Bingeing, self-restriction, and increased body weight in rats with limited access to a sweet-fat diet. Obesity (Silver Spring) 16:1998-2002
Avena, Nicole M; Rada, Pedro; Hoebel, Bartley G (2008) Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev 32:20-39
Avena, N M; Rada, P; Hoebel, B G (2008) Underweight rats have enhanced dopamine release and blunted acetylcholine response in the nucleus accumbens while bingeing on sucrose. Neuroscience 156:865-71
Avena, Nicole M (2007) Examining the addictive-like properties of binge eating using an animal model of sugar dependence. Exp Clin Psychopharmacol 15:481-91
Hoebel, Bartley G; Avena, Nicole M; Rada, Pedro (2007) Accumbens dopamine-acetylcholine balance in approach and avoidance. Curr Opin Pharmacol 7:617-27
Rada, P; Colasante, C; Skirzewski, M et al. (2006) Behavioral depression in the swim test causes a biphasic, long-lasting change in accumbens acetylcholine release, with partial compensation by acetylcholinesterase and muscarinic-1 receptors. Neuroscience 141:67-76

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