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Chronic Nicotine Administration in the Drinking Water Affects the Striatal Dopamine in Mice

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Abstract

PIETILÄ, K. AND L. AHTEE. Chronic nicotine administration in the drinking water affects the striatal dopamine in mice. PHARMACOL BIOCHEM BEHAV 66(1) 95–103, 2000.—Although tobacco contains a large variety of substances, its addictive properties are most probably due to the reinforcing actions of nicotine that motivates continued tobacco use. Animals and humans self-administer nicotine, a response that appears to involve the mesolimbic dopamine system and to be common to other abused drugs. The present article reviews animal models to administer nicotine chronically. We also describe a new animal model in which nicotine is given to mice in drinking water as their sole source of fluid. This treatment produced nicotine plasma concentrations comparable to or above those found in smokers. We found that mice withdrawn from nicotine were tolerant to the effects of nicotine challenge on striatal dopamine metabolism as well as on body temperature and locomotor activity. Furthermore, 3H-nicotine binding in the cortex and midbrain was significantly increased in mice withdrawn from nicotine. The last part of the article will focus on the effects of this chronic nicotine treatment on striatal dopamine. Dopamine and its metabolites and locomotor activity were increased in the forenoon in mice still drinking nicotine solutions. We also report recent data in which chronic nicotine administration in the drinking water enhanced the effect of dopamine receptor agonist, quinpirole, on striatal metabolism. The animal model described appears to be a relevant method for studying the mechanisms that are thought to be involved in nicotine dependence.

Section snippets

Chronic nicotine administration via parenteral routes to experimental animals

Nicotine self-administration studies have been conducted in monkeys, rats, baboons, dogs, and humans by giving nicotine intravenously (IV). In these experiments both simple and complex schedules of drug administration (fixed-interval and fixed-ratio schedules) have been used 1, 21, 32, 80. The conditions under which nicotine can be established as a reinforcer are much more limited than those for other dependence-producing drugs (80). Nicotine seems to maintain self-administration behavior more

Chronic oral nicotine administration to experimental animals

Nicotine has been administered orally to experimental animals via liquid diets or in drinking fluids. In addition, nicotine has been administered by forced oral administration or schedule-induced polydipsia, in which food delivery in animals with reduced body weight is associated with increased fluid intake (38). In most studies employing the oral route, nicotine has been given ad libitum by adding it in the drinking water 2, 35, 54, 56, 62, 67, 78.

It has been especially difficult to get rats

Chronic nicotine administration in the drinking water to mice

In our animal model, nicotine is administered to mice in their drinking water as the sole source of fluid with gradually increasing concentrations (50 to 500 μg/ml) during the 7-week period (56). Nicotine administered to mice orally in the drinking water does not alter the body weight gain or fluid intake of the mice until after 2 weeks of administration when the drinking fluid contains 200 μg/ml nicotine (Fig. 1). A longer treatment with a further elevation of the nicotine concentration

Tolerance to nicotine in mice treated chronically with nicotine in the drinking water

It is known already from the studies by Langley (39) that tolerance may develop to the effects elicited by nicotine. Tolerance can be defined as a state in which a challenge dose following repeated administration of a drug produces a smaller effect than before, or alternatively a state in which increased amounts of a drug are required to achieve the effect observed with the first dose. Chronic administration of nicotine has been shown to induce tolerance to its various acute effects in rats and

Nicotine's effects on dopamine release and metabolism in the striata of mice during chronic nicotine treatment

Nicotine exerts its effects in the brain by interacting with neuronal nicotinic acetylcholine receptors (nAChRs). These receptors are located on both somatodendritic and nerve terminal membranes and thus, may influence neurotransmitter secretion at synapses (3).

As cerebral dopamine (DA) systems are widely believed to be central to nicotine's role in tobacco smoking 36, 77, we have focused our studies on the effects of nicotine on DA systems by estimating the striatal concentrations of DA and

Conclusions

Administration of nicotine in the drinking water to mice as the sole source of fluid for several weeks can be used for studying the mechanisms underlying the nicotine-induced changes in the brain and behavior as it mimics the daily variation in nicotine intake in smokers. Further, our findings suggest that the mice receive enough nicotine from drinking water during the chronic experiment to induce changes which are thought to be involved in nicotine dependence. Finally, the present results

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