Department of Psychiatry, School of Medicine, University California San Diego, 9500 Gilman Drive, M/C 0603, La Jolla, CA 92093, USA.
Department of Psychiatry, School of Medicine, University California San Diego, 9500 Gilman Drive, M/C 0603, La Jolla, CA 92093, USA.
Pharmacol Biochem Behav. 2018 Aug;171:54-65. doi: 10.1016/j.pbb.2018.06.002. Epub 2018 Jun 14.
Chronic nicotine exposure produces neuroadaptations in brain reward systems and α4β2 nicotinic acetylcholine receptors (nAChRs) in the corticolimbic brain areas. We previously demonstrated opposite effects of nicotine exposure delivered by self-administration or pumps on brain reward thresholds that can be attributed to the different temporal pattern and contingency of nicotine exposure. We investigated the effects of these two factors on reward thresholds and somatic signs during nicotine withdrawal, and on nAChRs binding in corticolimbic brain areas.
The intracranial self-stimulation procedure was used to assess reward thresholds in rats prepared with pumps delivering various doses of nicotine continuously or intermittently. Separate group of rats were randomly exposed to nicotine via pumps (non-contingent) or nicotine self-administration (contingent) to determine [I]-epibatidine binding at α4β2* nAChRs.
Withdrawal from continuous non-contingent nicotine exposure led to significant elevations in thresholds and increases in somatic signs in rats, while there was no significant effect of withdrawal from intermittent non-contingent nicotine exposure at the same doses. nAChRs were upregulated during withdrawal from continuous non-contingent nicotine exposure. α4β2* nAChRs were upregulated in the ventral tegmental area and prelimbic cortex during withdrawal from non-contingent intermittent exposure and in the nucleus accumbens during withdrawal from contingent intermittent nicotine exposure to the same dose.
During non-contingent nicotine exposure, the temporal pattern of nicotine delivery differentially affected thresholds and somatic signs of withdrawal. Upregulation of α4β2* nAChRs was brain site-specific and depended on both temporal pattern and contingency of nicotine exposure.
慢性尼古丁暴露会导致大脑奖励系统和皮质边缘脑区的α4β2 烟碱型乙酰胆碱受体（nAChRs）发生神经适应性变化。我们之前的研究表明，通过自我给药或泵输送尼古丁暴露对大脑奖励阈值有相反的影响，这归因于尼古丁暴露的不同时间模式和偶然性。我们研究了这两个因素对尼古丁戒断期间奖励阈值和躯体征象的影响，以及对皮质边缘脑区 nAChRs 结合的影响。
使用颅内自我刺激程序评估通过泵输送不同剂量尼古丁连续或间歇给药的大鼠的奖励阈值。另一组大鼠随机通过泵（非偶然）或尼古丁自我给药（偶然）暴露于尼古丁，以确定α4β2*nAChRs 上的[I]-epibatidine 结合。
连续非偶然尼古丁暴露戒断导致大鼠阈值显著升高和躯体征象增加，而相同剂量间歇非偶然尼古丁暴露戒断则没有显著影响。连续非偶然尼古丁暴露戒断期间 nAChRs 上调。非偶然间歇暴露戒断期间，腹侧被盖区和前额皮质的α4β2nAChRs 上调，而相同剂量的偶然间歇尼古丁暴露戒断期间，伏隔核的α4β2nAChRs 上调。
在非偶然尼古丁暴露期间，尼古丁输送的时间模式对戒断时的阈值和躯体征象有不同的影响。α4β2*nAChRs 的上调具有脑区特异性，取决于尼古丁暴露的时间模式和偶然性。
