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interest is knocked out prior to birth, possibly resulting in compensatory changes in the developing central nervous system of the animal For a ner assessment of the role of various nACHR subtypes, mutant mice that undergo genespeci c mutations in certain brain regions at a precise time in their adult life are needed Eventually, this line of research will provide identi cation of molecular sites that modulate nicotine addiction facilitating medication development for the treatment of tobacco dependence in human smokers Relevance of Preclinical Studies to Understanding Tobacco Dependence Animal models, such as the SA and PC paradigms (discussed previously), provide a unique contribution toward our understanding of tobacco dependence in humans These models allow the examination of the reinforcing effects of nicotine that are highly relevant to tobacco dependence in humans, and that cannot be easily studied in human subjects mainly for ethical reasons.



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In animals, potential behavioral effects of pharmacological agents can be more fully characterized Furthermore, these animal models allow the investigation of the basic underlying neurochemical mechanisms that are relevant to nicotine addiction Animal models also can be used to study environmental factors in initiation and maintenance of nicotine addiction Smokers report that environmental factors such as stress induce smoking behavior and that smoking helps to alleviate stress (McKennell, 1970; USDHHS, 1988) Preclinical studies have shown that environmental stressors can increase corticosterone levels and in turn can alter behavioral responses to administration of drugs of abuse For example, prenatal stress (Deminiere et al, 1992), isolation (Alexander, Coambs, & Hadaway, 1978; Schenk, Lacelle, Gorman, & Amit, 1987), foot-shocks (Goeders & Guerin, 1994), and exposure to social defeat stress (Miczek & Mutschler, 1996) can activate as well as facilitate SA of psychomotor stimulants and opioids.





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tice that the distribution is actually a probability function. The area under each line corresponds with the probability of that outcome. Half of the outcomes occur to the left of the midpoint of each curve (because it represents half of the area). The taller bell curve for asset A is actually the less volatile of the two assets. Returns close to the midpoint are likely and either extremely high or extremely low returns are less likely than the asset with the atter bell curve for asset B. At the same time, both distributions share one characteristic: About 5 percent of the time, return for the year is lower than 1.65 standard deviations below the mean (the one-tailed test in statistics). In other words, 95 percent of the time, asset A with the 20 percent standard deviation will have a return of 39 percent or better (0 percent mean return less 1.65 20 percent) and 95 percent of the time, asset B with the 40 percent standard deviation will have a return of 78 percent or better (0 percent mean return less 1.65 40 percent). The 95 percent con dence level is the basis of the VaR calculation. If a hedge fund portfolio holds $2.5 million of asset A, 95 percent of the time the asset will lose less than $975,000 ($2.5 million 39 percent) over a year. If the hedge fund portfolio holds $5.25 million of asset B, 95 percent

In addition, exposure to intermittent foot-shock can reinstate heroin (Shaham & Stewart, 1995), cocaine (Ahmed & Koob, 1997; Erb, Shaham, & Stewart, 1996), alcohol (L et al, 1998), and nicotine (Buczek, L , Stewart, & Shaham, 1999) drug-seeking behavior following extinction and an extended period of abstinence However, the role of environmental stressors in eliciting nicotine reinforcement using animal models has not been characterized thoroughly These experiments will lead to the development of animal models of gene-environment interactions in nicotine addiction Future experiments will provide us with clues as to whether the interactions can be demonstrated, the magnitude of their effect, and the conditions under which the interactions vary in strength..

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3.4. Osteogenic Medium Double Concentration Dulbecco s modi ed Eagle s medium (DMEM) fetal bovine serum (FBS), 10% Penicillin, 100 U/ml, streptomycin, 100 g/ml Fungizone, 0.5 g/ml Ascorbic acid 2-phosphate, 100 g/ml Dexamethasone, 20 nM

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