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Chapter 3 Addiction and Cigarettes as Nicotine Delivery Devices
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Project Hippo I

Project Hippo I was designed to explore nicotine's role in several areas the investigators thought involved hypothalamic functions, including reduction of stress, inhibition of weight gain, maintenance of water balance (hormonally controlled through the hypothalamus), and regulation of gonadotrophic (sex) hormones. The results of Project Hippo I are described in a January 1962 report from Battelle to BAT {1211.01}. The introduction to this forty-eight-page report describes the background and goals of Project Hippo I:

It is an everyday experience to each smoker that smoking a cigarette helps mastering the numerous stressful stimuli of modern life.

This effect is possibly one of the most powerful reasons which make one smoke.

How does nicotine exert this action? The normal defence mechanism against stressful agents is a nearly immediate release of those hormones synthesized by the adrenal cortex which act upon the cell metabolisms: they are called "corticosteroids" and play the cardinal role in the defence of the organism against stress. Their release from the gland is mediated through a very complicated system involving the stimulation of hypothalamus and pituitary function. ...

As a working hypothesis we assumed the idea that nicotine could help to master the stressful stimuli by way of enhancing (or facilitating) the normal defence mechanism.

If this were true, it would be easier to understand another very important effect of smoking: it is well known that stopping to smoke has an immediate


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effect on body weight. As body weight is regulated by the hypothalamo-pituitary system, our working hypothesis could be enlarged in order to assume the idea of an interference of nicotine in the hypothalamic regulation of body weight as well as in the defence against stress. {1212.01, pp. 6–7}

By conducting these experiments, Battelle was testing some of the most advanced neuroendocrine theories of the day. The adrenal corticosteroids had been introduced as wonder drugs into clinical medicine about a decade before this, and since the mid-1950s neuroendocrinologists had been gradually coming to understand the central role of the hypothalamus in the regulation of pituitary gland function (10, 11).

The report also discusses experiments that Battelle's scientists conducted on nicotine tolerance in rats. Tolerance to a drug is said to have developed when an animal requires a larger dose to achieve the same effect as that previously produced by a smaller dose. Tolerance is a common feature of addicting drugs. It need not be present for addiction to exist, but it usually is. Addiction, or dependence, is a clinical syndrome that includes loss of control over use of a psychoactive drug, withdrawal symptoms when the drug is no longer taken, and continued use despite problems caused by the drug. The report notes that tolerance could be induced in all rats, although some required several months to achieve this state.

The report describes in detail the effects of nicotine on rats in the various experiments. Of interest here is the importance the authors attached to nicotine's ability to influence the response to stress. For these scientists, this response helped explain the tranquilizing effect of nicotine and provided a direct link to the subsequent project, Hippo II.

Project Hippo I also included an elegant series of experiments on weight control in rats using nicotine. Nicotine was shown to inhibit food intake in both tolerant and nontolerant animals. Reserpine did not modify this action of nicotine. Nicotine rapidly stimulated the mobilization of lipid deposits (fat) and the degradation of free fatty acids. Each of these actions was in the direction expected for a drug that would be of benefit in controlling obesity {1211.01, p. 3}. The work Battelle conducted for BAT under Project Hippo I on weight control preceded published accounts of these phenomena by twenty years (3, 12).


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Chapter 3 Addiction and Cigarettes as Nicotine Delivery Devices
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