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 (4Ϫ/Ϫ) or the 2 (2Ϫ/Ϫ) nicotinic acetylcholine receptor subunits were implanted with osmotic minipumps delivering 24 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 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 2Ϫ/Ϫ mice, whereas the 4Ϫ/Ϫ mice displayed significantly milder somatic symptoms. In addition, nicotine withdrawal produced hyperalgesia in wild-type but not 4 Ϫ/Ϫ mice. Finally, chronic nicotine produced an increase in epibatidine binding in several areas of the brain in both wild-type and in 4Ϫ/Ϫ 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.
Nicotine, acting at nicotinic acetylcholine receptors (nAChRs), is the primary addictive component of tobacco. Smokers often report an anxiolytic effect of cigarettes. This relief of anxiety, attributed to nicotine, is an important contributor to relapse when smokers try to quit. Hence, the study of the anxiolytic effects of nicotine is important for understanding the mechanisms underlying nicotine addiction. Mammalian nAChRs are pentameric ion channels usually composed of alpha andbeta subunits. Taking advantage of beta4-homozygous-null mice (beta4-/-), we examined the role of the nAChR beta4 subunit in anxiety-related behaviors. The beta4-/- mice behaved as though they were less anxious than wild-type littermates on the elevated-plus and staircase mazes, tests that measure anxiety-related behaviors. To obtain an independent, physiological indication of the stress produced by several tests, we measured changes in heart rate using telemetry. Consistently with the behavioral phenotype, beta4-/- mice had a smaller heart rate increase in the elevated-plus maze than did wild-type littermates. In contrast, during social isolation, a separate test for anxiety,beta4-/- mice exhibited a greater increase in heart rate than did wild-type littermates. Finally, beta4-/- mice were indistinguishable from their wild-type littermates in the open field, the light/dark box, and the mirrored chamber. The overall results demonstrate that beta4-containing (beta4*) nAChRs influence behavioral responses during anxiety-related tests, and that this effect depends on the type of anxiety-provoking experience. Through their influence on anxiety-related behavior, beta4* nAChRs might influence both tobacco consumption and smoking relapse.
Corticotropin-releasing hormone (Crh) plays an important role in modulating physiological and behavioral responses to stress. Its actions are mediated through two receptors, Crhr1 and Crhr2. Urocortin (Ucn), a Crh-related neuropeptide and the postulated endogenous ligand for Crhr2, is a potential mediator of stress responses. We generated Ucn-deficient mice using embryonic stem cell technology to determine its role in stress-induced behavioral and autonomic responses. Unlike Crhr1-or Crhr2-deficient mice, Ucn-deficient mice exhibit normal anxiety-like behavior as well as autonomic regulation in response to stress. However, the mutant mice display an impaired acoustic startle response that is not due to an obvious hearing defect. Thus, our results suggest that Ucn does not play an essential role in stress-induced behavioral and autonomic responses. Ucn may modulate the acoustic startle response through the Ucn-expressing neuron projections from the region of the Edinger-Westphal nucleus.
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