Abstract
Nicotine was infused via the jugular vein into DBA mice, and the effects of such treatment on brain nicotinic receptors and various behavioral and physiological responses to nicotine were determined. Nicotinic receptors were measured using [3H]nicotine or [125I]α-bungarotoxin (α-BTX) as the ligands. Infusion with nicotine resulted in tolerance to several of nicotine’s effects. This change in drug sensitivity was accompanied by an increase in Bmax, for both brain nicotinic receptors. A dose-response analysis indicated that [3Hlnicotine binding increased at lower infusion doses than did [125I]α-BTX binding. The maximal increase in nicotine binding was seen at a 4-mg/kg/hr infusion dose, while α-BTX binding continued to increase with nicotine dose up to a dose of 8 mg/kg/hr. Tolerance to nicotine’s effects correlated best with the changes in [3H]nicotine binding. Time course studies for the onset and offset of tolerance and changes in nicotinic receptors were also carried out. Alpha-BTX binding increased rapidly at the nicotine dose used and reached its new equilibrium value within 2 days. Nicotine binding reached its new equilibrium value in 4 days. Approximately 8 days were required, following termination of nicotine treatment, for nicotine binding to return to control levels, while α-BTX binding was at control levels at the earliest post-treatment test time (4 days). The rates of acquisition and loss of tolerance to nicotine paralleled the changes in brain nicotine binding. These results suggest that chronic tobacco use may lead to changes in brain nicotinic receptors. Such effects could explain not only tolerance to nicotine, but also effects of tobacco on such processes as learning and memory.
Tolerance accompanies chronic treatment with a wide variety of centrally acting drugs, including nicotine. Tolerance to nicotine’s effects on locomotor activity has been studied most frequently. The intraperitoneal injection of large (approximately 1 mg/kg) doses of nicotine induces decreased locomotor activity in the rat, and chronic treatment with nicotine results in tolerance to this effect (1,2,3). Similarly, we have demonstrated that high doses of nicotine elicit decreases in locomotor activity in the mouse, and, as is the case with the rat, that chronic treatment with nicotine results in tolerance to this effect (4,5,6,7). We have also observed tolerance to several other behavioral and physiological effects of nicotine (5,6,7). This tolerance cannot be explained by differences in the metabolism of nicotine (4,5). This finding suggests that nicotine tolerance is due to pharmacodynamic rather than pharmacokinetic changes.
Our research has focused on the possible involvement of changes in brain nicotinic receptors in the development of tolerance to nicotine. Nicotinic receptors in the central nervous system have been measured several ways. Snake neurotoxins, primarily α-bungarotoxin (α-BTX), have been widely used for these measurements (8,9), but the use of α-BTX to measure nicotinic receptors in the brain has been criticized because this compound fails to inhibit neurotransmission in several preparations (10–14). Nonetheless, the sites labeled with α-BTX display many properties expected of a nicotinic, cholinergic receptor (9,15,16), and may be related to the incidence of nicotine-induced convulsions (17).
As an alternative to α-BTX, nicotine itself has been used as a ligand for nicotinic receptors (18–21). The binding properties of the site labeled with nicotine are in many ways consistent with those anticipated for a nicotinic, cholinergic receptor. However, most classical nicotinic receptor antagonists inhibit nicotine binding poorly (18,19,21), leading to the suggestion that this binding site may not be cholinergic (18,20). Under the proper conditions, acetylcholine (ACh) has been shown to bind to sites in the brain which are apparently nicotinic, cholinergic receptors (22). These binding sites also have low affinity for most nicotinic antagonists. A recent autoradiographic analysis of radiolabeled nicotine and ACh binding has revealed a strikingly similar distribution in the binding of these two agents in rat brain (23). This, plus the observation that nicotinic cholinergic agonists inhibit the binding of both compounds while nicotinic antagonists inhibit poorly (21,22), suggests that the nicotine and ACh binding sites are very similar, if not identical. The nicotine/ACh binding site is probably different from the α-BTX site (21,23), and we (21) have suggested that the nicotine binding site is a high-affinity nicotinic receptor and that the α-BTX binding site is a lower-affinity nicotinic receptor.
Our studies, as mentioned above, have been designed to assess the relationship between brain nicotinic receptors and tolerance to nicotine. Details concerning most of the studies summarized here may be found in our earlier publications (5,6,7).
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© 1987 Plenum Press, New York
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Collins, A.C., Marks, M.J. (1987). The Effects of Chronic Nicotine Administration on Brain Nicotinic Receptor Numbers. In: Martin, W.R., Van Loon, G.R., Iwamoto, E.T., Davis, L. (eds) Tobacco Smoking and Nicotine. Advances in Behavioral Biology, vol 31. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-1911-5_28
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