Nicotine tolerance development

Netting et al. 1998). Tolerance develops to lobeline s behavioral or analgesic effects by 10 days of daily treatment, and cross-tolerance develops between lobeline and nicotine (Damaj et al. 1997). Mechanisms of Action... 

Similar to tobacco, lobelia may also have analgesic effects. However, it depends on the mode of administration (Damaj et al. 1997). Intrathecal lobeline produces analgesia on the tail-flick test, but subcutaneous administration is ineffective. On the other hand, subcutaneous lobeline dose-dependently enhances nicotine analgesia. Tolerance develops to this effect of lobeline after 10 days. Lobeline can also produce hyperalgesic effects when administered into the dorsal posterior mesencephalic tegmentum (Hamann and Martin 1994). However, the relevance of this to peripheral administration of lobelia is questionable because chronic injections (IP) of lobeline in rats induced no changes in tail-flick latencies (Sopranzi et al. 1991). 

Marks Ml, Collins AC (1982) Characterization of nicotine binding in mouse brain and comparison with the binding of a-bungarotoxin and quinuclidinyl benzilate. Mol Pharmacol 22 554-564 Marks Ml, Burch JB, Collins AC (1983) Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. J Pharmacol Exp Ther 226 817-825 Marks Ml, Stitzel JA, Romm E, Wehner JM, Collins AC (1986) Nicotinic binding sites in rat and mouse brain comparison of acetylchohne, nicotine, and alpha-bungarotoxin. Mol Pharmacol 30 427 36... 

Butschky MF, Bailey D, Henningfleld JE, Pickworth WB (1995) Smoking without nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacol Biochem Behav 50 91-96 Collins AC, Romm E, Wehner JM (1988) Nicotine tolerance an analysis of the time course of its development and loss in the rat. Psychopharmacology 96 7-14 CorrigaU WA (1999) Nicotine self-administration in animals as a dependence model. Nicotine Tob Res 1 11-20... 

The actions of nicotine on the central nervous system are the result of a composite of stimulatory and depressant effects. These can include tremors, convulsions, respiratory stimulation or depression, and release of antidiuretic hormone from the pituitary. Nausea and emesis are frequently observed after the initial use of nicotine in the form of tobacco smoke. However, tolerance to these effects rapidly develops. This is in contrast to the effects of nicotine on the cardiovascular system, where tolerance develops much more slowly. 

Tolerance to nicotine s effects develops rapidly and most likely involves multiple processes, although the pattern and extent of tolerance development is not identical for all of nicotine s effects. It has been proposed that rapid tolerance or desensitization occurs to the behavioral or reinforcing effects of nicotine. These effects are of such a short duration that a smoker continually cycles between a sensitized and desensitized state. This notion is consistent with the fact that drugs with high abuse liability have a rapid onset and short duration of action. 

Marks MJ, Burch JB, CoUins AC (1983) Effects of chronic nicotine infusion on tolerance development and iticotinic receptors. J Pharmacol Exp Ther 226 817-825... 

Repeated exposure, as occurs in habitual smokers, leads to an increased rate of metabolism of nicotine and decreased sensitivity of the receptors to the nicotine. More nicotine is therefore required to satisfy the needed stimulation, and tolerance develops. This is a separate effect from addiction which seems to be due to increased levels of a substance called dopamine in the brain. This is due to the nicotine activating nerve cells which results in increased release of dopamine and causes a reduction in the amount of an enzyme that destroys dopamine. It seems that other addictive drugs may also work by increasing dopamine levels. 

Tolerance develops to some of the effects of nicotine, taken repeatedly over a few hours a first experience commonly causes nausea and vomiting, which quickly ceases with repetition of smoking. Tolerance is usually rapidly lost the first cigarette of the day has a greater effect on the cardiovascular system than do subsequent cigarettes. 

Nicotinic acid inhibits the release of free fatty acids, followed by a fall in the VLDL, and then the LDL level. Nicotinic acid may cause intense flushing and itching (vasodilation and histamine release), and tolerance develops to these effects. 

Marks MJ et al. Genotype influences the development of tolerance to nicotine in the mouse. J Pharmacol Exp Ther 1991 259(1)392-402. 

Zarrindast MR, Khoshayand MR, Shafaghi B. (1999). The development of cross-tolerance between morphine and nicotine in mice. Eur Neuropsychopharmacoi. 9(3) 227-33. 

Marks Ml, Campbell SM, Romm E, Collins AC (1991) Genotype influences the development of tolerance to nicotine in the mouse. J Pharmacol Exp Ther 259 392 02 Marks MJ, Pauly JR, Gross SD, Deneris ES, Hermans-Borgmeyer I, Heinemann SF, Collins AC (1992) Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci 12 2765-2784... 

Catania MA, Firenzuoli F, Crupi A, Mannucd C, Caputi AP, Calapai G (2003) Hypericum perforatum attenuates nicotine withdrawal signs in mice. Psychopharmacology 169 186-189 Cheeta S, Irvine EE, Kenny PJ, File SE (2001) The dorsal raphd nucleus is a crucial structure mediating nicotine s anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology 155 78-85... 

Plants that produce "specific toxins may be plagued by Insects that develop a tolerance to these toxins in much the same way as Insects develop tolerance to synthetic insecticides. Two examples from this chapter are the tobacco hornworm and the boll weevil which have developed a high tolerance to nicotine and gossypol, respectively. Some occurrence in the distant past may have placed sufficiently high selection pressure on these Insects that they developed tolerance to these compounds. Alternatively, the same effect could have occurred by a low selection pressure applied over a very long period time. Other plants protect themselves by employing general" toxins. 

Since nicotinic acid can cause unpleasant flushing and other symptoms of vasodilatation, attempts have been made to develop modified-release formulations. Modified-released nicotinic acid formulations may be better tolerated than the immediate-release formulation, because they reduce the vasodilatory effects of the drug. However, the low frequency of flushing produced by modified-release formulations may be offset by an increased risk of hepatotoxicity. Some reports have suggested a higher frequency of hepatic dysfunction with traditional modified-release nicotinic acid formulations compared with immediate-release products (2, 40). 

The use of tobacco is addictive. Most users develop tolerance for nicotine and need greater amounts to produce a desired effect. Smokers become physically and psychologically dependent and will suffer withdrawal symptoms including changes in body temperature, heart rate, digestion, muscle tone, and appetite. 

---