Individual self-administration of nicotine by rats

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Abstract

Self-administration (SA) of nicotine (N) was studied in 20 male and 19 female N:NIH rats using the two-bottle method. The experimental protocol consisted of seven consecutive periods each lasting 6 days: Period (P)1, choice of water (W) and 0.003% N; P2, choice of W and 0.006% N; P3, choice of W and 0.012% N; P4, W only; P5, choice of W and 0.006% N; P6, 0.006% N only; and P7, choice of W and 0.006% N. Group means showed that males and female rats consumed similar amounts of N during Ps 1–3. After an N-free period (P4), a small decline was observed in the subsequent voluntary intake of N (P5). Forced N (P6) exposure did not affect a subsequent N intake (P7) in males but increased it slightly in females. A survey of individual animals, however, showed that the voluntary N consumption varied greatly among animals, but was quite consistent for a particular rat. Values ranged from 0.43 to 7.59 for males and from 0.35 to 4.69 mg/kg/day for females for Ps 1–3. The N-free (P4) and the forced-N (P6) periods each affected a subsequent voluntary N intake (P5, P7) of the rats very differently, but again consistently, in that some rats decreased, some increased and some did not change their N choice. The results indicate that group means can be misleading in their conclusions and strongly support the assumption that the response of an individual animal to N, and not N per se, is the determining force of its SA.

Introduction

The exact causes of heavy smoking or tobacco use and abuse are unknown, although nicotine has been identified as an important agent involved in the initiation and maintenance of, as well as the inability to stop, this behavior. Thus, nicotine has been labeled and is commonly referred to as an “addictive” substance, which when acting on the brain of the user causes an uncontrollable craving for this substance. To better understand the underlying causes of this craving for nicotine, the self-administration (SA) of this substance has been studied extensively in rats Brower et al., 2002, Cabeza de Vaca and Carr, 1998, Corrigall and Coen, 1989, De la Garcia and Liu, 2002, Donny et al., 1998, Donny et al., 1999, Donny et al., 2000, Glick et al., 1996, Horan et al., 1997, LeSage et al., 2002, Maehler, 1999, Maehler et al., 2000, Shoaib et al., 1997, Smith and Lang, 1980, Todte et al., 2001, Valentine et al., 1997, Wilmpouth and Spear, 2002. These studies have shown that animals readily self-administer nicotine. However, many of these studies have used only male rats of an older age, although in the human situation smoking can be found in both sexes and usually starts early during puberty DiFranza et al., 2000, Eisenberg and Balster, 2000, Griffin et al., 1999, Koplan, 2002, Satcher, 2002, Unger et al., 1987, Unger et al., 2002. In addition, these studies have focused mostly on group means of nicotine self-administered under various experimental conditions. Little attention has usually been paid to individual differences that do seem to exist in the abovementioned studies as evidenced by rather large S.D.s or S.E.M.s in the group means, by sometimes citing that not all animals could be trained to self-administer nicotine or by indicating that animals showed quite different SA patterns Brower et al., 2002, Corrigall and Coen, 1989, Donny et al., 1998, Glick et al., 1996, Kalman, 2002, Rosecrans, 1995.

However, these individualized responses to nicotine and the individual variations in avoidance and/or preference among animals are of special interest because they resemble the human situation where humans are known to vary greatly in the avoidance and use or abuse of this substance DiFranza et al., 2000, Eisenberg and Balster, 2000, Griffin et al., 1999, Koplan, 2002, Satcher, 2002, Unger et al., 1987, Unger et al., 2002 as well as in their success of stopping this addiction Fiore et al., 2000, Fagerstrom et al., 1993, Foulds et al., 1992. To fill this gap we investigated the oral SA of nicotine in a large number of both male and female rats at a young age under a variety of experimental conditions. While group means were obtained, particular attention was paid to the individual responses of each rat and the stability of this particular response to nicotine over the entire experiment.

The method used was the two-bottle free-choice method, where animals could choose freely between water and a nicotine solution. This allows the simultaneous observation of a large number of male and female animals. The strain chosen was the strain of N:NIH rats, which was derived from cross-breeding eight different rat strains. The original purpose was to obtain a “true” outbred strain, and breeding was not directed towards a specific biochemical or behavioral parameter. Such an outbred strain is expected to show marked individual differences among its members. This was the reason why this strain has been chosen. Like the human situation where most smokers begin to smoke at puberty, the experiment was started with young male and female rats during sexual maturation and then continued for 42 days.

The different experimental conditions used were, in succession, exposure of the animals to (1) water and three successively increasing concentrations of nicotine for 6 days each to see if a gradual increase in the nicotine concentration would lead to an increase in the SA of this substance, (2) a period of nicotine withdrawal and water only followed again by a voluntary water and nicotine choice to see how a nicotine-free period would affect a subsequent voluntary consumption of nicotine and (3) a period of nicotine forcing (with no choice) followed again by a choice between water and nicotine to see how a forced exposure to a high amount of nicotine would affect a subsequent free choice of this substance.

Section snippets

Chemicals

Nicotine as the nicotine (−) tartrate salt was obtained from Sigma, St. Louis, MO. The salt was dissolved in tap water to obtain the neutral different concentrations (wt/vol).

Animals

The male and female rats were obtained through the courtesy of Dr. C. Hansen from the National Institutes of Health (NIH), Bethesda, MD.

The animals were housed individually in standard cages in rooms controlled for climate (temperature about 22 °C and humidity about 55%) and a light/dark cycle (light from 0800 to 2000 h).

Voluntary nicotine consumption of different nicotine concentrations

The purpose of this part of the experiment was to investigate if increasing the nicotine concentrations offered would affect the voluntary consumption of this substance. Three different nicotine solutions were offered successively, each for 6 days, with the rats having a choice between water and a particular nicotine concentration.

The data from Table 1 show the voluntary consumption of nicotine at the three nicotine concentrations by 20 male rats. The rats weighed about 125±13 g at the start of

Conclusion

Studies on the SA of nicotine by animals are usually performed by operant methodology where the animal is trained to work for the reward of a psychoactive substance Brower et al., 2002, Cabeza de Vaca and Carr, 1998, Corrigall and Coen, 1989, Donny et al., 1998, Donny et al., 1999, Donny et al., 2000, Glick et al., 1996, Horan et al., 1997, LeSage et al., 2002, Maehler et al., 2000, Todte et al., 2001, Valentine et al., 1997. Although the advantages of this method are obvious, drawbacks are

Acknowledgments

The financial support of this study by Philip Morris Incorporated and the editorial help by Dr. J.J. Kocsis are gratefully acknowledged.

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