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Assessing nicotine relapse in a mouse model

Institution: SRI International
Investigator(s): Taline Khroyan, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10KT-0007 Award: $183,804
Subject Area: Nicotine Dependence
Award Type: New Investigator Awards

Initial Award Abstract
Nicotine plays a critical role in maintenance of tobacco dependence. Following a period of abstinence, the likelihood of relapse to nicotine use is high and limits the effectiveness of therapeutic interventions (Simpson et al., 1999). Animal models have been developed to study the rewarding effects of drugs. One such model is the place conditioning (PC) paradigm. The PC paradigm measures the incentive motivational properties of stimuli that become associated with drug effects through classical conditioning. The drug is administered in a distinct environment. After several pairings the environment becomes associated with the effects of the drug, thereby acquiring incentive-motivational properties. Thus, the environment becomes a cue eliciting approach (i.e., conditioned place preference; CPP) or avoidance (i.e., conditioned place aversion; CPA) depending on whether rewarding or aversive properties of the drug have been conditioned respectively. In fact, drugs that have addictive properties in humans such as cocaine, morphine, alcohol, and nicotine are also deemed to be rewarding in animals using the PC paradigm. This provides validity to the PC paradigm since this model can effectively measure the rewarding properties of drugs.

Recently the PC paradigm was further developed to assess relapse to extinguished cocaine and morphine seeking in rats (i.e., Mueller and Stewart, 2000; Parker and McDonald 2000, Wang, 2000). However, with the development of a complete genetic library in mice, the mouse is becoming an increasingly valuable tool for studying the genetic contributions to drug dependence. Thus, the objective of the proposed research is to adapt the PC reinstatement paradigm to assess relapse to nicotine seeking in mice. During conditioning, nicotine injections will be paired with a distinct compartment, whereas vehicle injections will be paired with another compartment. Twenty-four hours following the last conditioning day, animals will be given access to both compartments in order to assess nicotine-induced PC. Following the test for PC, animals will undergo extinction training such that the compartment previously associated with nicotine does not elicit a CPP or a CPA. Subsequently, a range of doses of nicotine as well as vehicle will be assessed for their ability to reinstate nicotine-induced PC. Thus, in future studies, we can examine other variables important in nicotine dependence such as the effect of the environment on nicotine seeking. Indeed, the proposed experiments will lay the foundation from which we can develop animal models of gene-environment interactions in nicotine-induced reward.

Genetics and prevendion of drug abuse: Implications for transdisciplinary research and practice.
Periodical: Substance Use and Misuse Index Medicus:
Authors: Lessov CN, Swan GE, Ring HZ, Khroyan TV, Lerman C ART
Yr: 2004 Vol: Nbr: Abs: Pg:

Intergenerational transmission of tobacco use and dependence: a transdisciplinary perspective.
Periodical: Nicotine and Tobacco Research Index Medicus:
Authors: Shenassa ED, McCaffery JM, Swan GE, Khroyan TV, Shakib S, Lerman C, Lyons M, et al ART
Yr: 2003 Vol: 5 Nbr: 1 Abs: Pg: s55-69

Environmental and genetic determinants of tobacco use: Methodology for a multidisciplinary, longitudinal family-based investigation.
Periodical: Cancer Epidemiology Biomarkers and Prevention Index Medicus:
Authors: Swan GE, Hudmon KS, Jack LM, Hemberger K, Carmelli D, Khroyan TV, et al ART
Yr: 2003 Vol: 12 Nbr: 10 Abs: Pg: 994-1005

Dopamine receptor DRD2 genotype and smoking cessation outcome following bupropion SR treatment.
Periodical: Pharmacogenetics Index Medicus:
Authors: Swan GE, Valdes AM, Ring HZ, Khroyan TV, Jack LM, Ton CC, Curry SJ, McFee T ART
Yr: 2004 Vol: Nbr: Abs: Pg: