Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol.
Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol.
复制标题
蓝斑神经元的活动决定了选择性繁殖的易于饮酒的老鼠的饮酒倾向。
DOI：
10.1016/j.alcohol.2015.08.008
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Weiss,JayM
中科院分区：
文献类型：
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作者：
West,CharlesHK;Boss-Williams,KatherineA;Ritchie,JamesC;Weiss,JayM
在我们实验室中选择性饲养的易受应激影响的Sprague-Dawley大鼠（易感大鼠或SUS大鼠）自愿摄入大量酒精，并且如本文所示，具有药理作用的量，而正常大鼠不会这样做。在本文中，我们探讨了大脑中的神经事件，这些事件是这种容易饮酒的倾向的基础。蓝斑神经元（LC），大脑中主要的去甲肾上腺素能细胞体浓度的活动，影响中皮质边缘系统（VTA-DA神经元）的腹侧被盖多巴胺能细胞体的放电，介导酒精的奖励方面。我们测试的假设，在SUS大鼠酒精有效地抑制LC活动，显着减少LC介导的抑制腹侧被盖区-DA神经元，这使得酒精大大增加腹侧被盖区-DA活动和奖励方面的酒精。电生理单单位记录显示，酒精使SUS大鼠LC爆发放电明显减少，VTA-DA活性明显增加，而对正常大鼠无此作用。与此一致，在使用条件性位置偏好（CPP）的奖励行为测试中，SUS大鼠显示通过腹膜内（i. p.）注射，是奖励。接下来，通过向SUS大鼠的LC区微量输注药物来操纵LC活性，结果表明：（a）雅阁上述公式，降低LC活性会增加酒精摄入量，而增加LC活性会减少酒精摄入量;（B）增加LC活性会阻断CPP试验中酒精的奖赏效应和SUS大鼠中常见的酒精诱导的VTA-DA单单位活性增加。在CPP测试中的一个重要的辅助发现是，LC活动的增加本身是奖励的，而LC活动的减少是令人厌恶的;因此，在CPP测试中，LC操作对酒精相关奖励的影响可能比测试中明显的还要大。最后，当增加的LC活性与（即，在条件化的情况下，通过腹腔注射酒精，SUS大鼠随后的酒精消耗显著减少，表明SUS大鼠消耗大量的酒精是因为需要增加VTA-DA活性的奖励性生理后果。这里报道的研究结果是一致的，认为酒精对LC活动的影响，导致VTA-DA活动的变化强烈影响酒精介导的奖励，并可能是SUS大鼠贪婪地消费酒精的倾向的基础。
Sprague–Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol.