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The Journal of Neuroscience, November 10, 2004, 24(45):10035-10039; doi:10.1523/JNEUROSCI.1939-04.2004
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Decreased Signs of Nicotine Withdrawal in Mice Null for the  4 Nicotinic Acetylcholine Receptor Subunit
Ramiro Salas,
Fredalina Pieri, and
Mariella De Biasi
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030
Withdrawal from chronic exposure to nicotine, the main addictive component of tobacco, produces distinctive symptoms in humans. The appearance of these symptoms is a major deterrent when people try to quit smoking. To study which type of nicotine receptor is relevant for the onset of the withdrawal syndrome, we used a mouse model of nicotine withdrawal. Wild-type mice and mice null for the  4 (4-/-) or the 2 (2-/-) nicotinic acetylcholine receptor subunits were implanted with osmotic minipumps delivering 24 mg · kg-1 · d-1 nicotine for 13 d. Subsequently, a single intraperitoneal injection of the nicotinic receptor antagonist mecamylamine induced behavioral symptoms of withdrawal measured as increased grooming, chewing, scratching, and shaking, plus the appearance of some unique behaviors such as jumping, leg tremors, and cage scratching. Mecamylamine injection triggered comparable withdrawal signs in wild-type and in 2-/- mice, whereas the 4-/- mice displayed significantly milder somatic symptoms. In addition, nicotine withdrawal produced hyperalgesia in wild-type but not 4-/- mice. Finally, chronic nicotine produced an increase in epibatidine binding in several areas of the brain in both wild-type and in 4-/- mice, but such receptor upregulation did not correlate with the severity of withdrawal signs.
Our results demonstrate a major role for 4-containing nicotinic acetylcholine receptors in the appearance of nicotine withdrawal symptoms. In contrast, the 2 subunit does not seem to greatly influence this phenomenon. We also show that the upregulation of epibatidine binding sites attributable to chronic nicotine, an effect associated with 2-containing receptors, is probably not related to the mechanisms underlying withdrawal.
Key words: nicotinic acetylcholine receptor; knock-out mice; 4 subunit; 2 subunit; nicotine; withdrawal
Received May 18, 2004;
revised September 20, 2004;
accepted September 20, 2004.
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