Decreased sensitivity of NMDA receptors on dopaminergic neurons from the posterior ventral tegmental area following chronic nondependent alcohol consumption.
Decreased sensitivity of NMDA receptors on dopaminergic neurons from the posterior ventral tegmental area following chronic nondependent alcohol consumption.
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DOI：
10.1111/j.1530-0277.2012.01762.x
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Morzorati SL
中科院分区：
文献类型：
--
作者：
Fitzgerald GJ;Liu H;Morzorati SL
中皮质边缘多巴胺系统介导显著刺激的强化效应，包括滥用药物。非依赖性的慢性酒精消耗修改这个系统，导致在后腹侧被盖区（VTA）的酒精偏好（P）大鼠自发活动的多巴胺神经元的数量增加。突触后谷氨酸受体反应的增强可能有助于活跃多巴胺神经元的增加。因此，评估了假定的多巴胺神经元对局部应用的NMDA（谷氨酸受体亚型激动剂）的兴奋。将P大鼠分为酒精初治组（仅饮水）和饮酒组（连续8周饮用15%的酒精和水）。使用微离子电渗施加的NMDA在体内评估了23个来自未处理大鼠的假定多巴胺神经元和19个来自饮酒大鼠的假定多巴胺神经元的反应。使用非线性混合效应模型构建了放电频率和爆发活动的电流响应曲线。对EC 50（产生半数最大兴奋反应的有效电流）、Emax（最大兴奋效应）和CDB（发生去极化阻滞时的电流-神经元活性显著降低）进行了组间比较。饮酒的P大鼠在8周的实验中稳定地饮酒，没有表现出依赖或戒断的迹象。饮酒大鼠的假定多巴胺神经元表现出对去极化阻滞的抗性（较高的CDB值），并需要较大剂量的NMDA来引起中度兴奋性反应（较高的EC 50值），与受体亲和力降低一致。最大兴奋反应（Emax）组间无差异，与受体数量无变化一致。血液中的酒精含量在实验时无法检测到。NMDA受体敏感性降低后腹侧被盖区假定多巴胺神经元在P大鼠的非依赖性时间表的酒精消费。自发性多巴胺神经元活动增加的机制可能独立于NMDA受体功能的变化。NMDA受体敏感性降低可能先于依赖性的发展。
The mesocorticolimbic dopamine system mediates the reinforcing effects of salient stimuli, including drugs of abuse. Nondependent chronic alcohol consumption modifies this system, resulting in an increased number of spontaneously active dopamine neurons in the posterior ventral tegmental area (VTA) of alcohol-preferring (P) rats. Enhanced responses of postsynaptic glutamate receptors may contribute to the increase in active dopamine neurons. Thus, excitations of putative dopamine neurons to locally-applied NMDA (glutamate receptor subtype agonist) were evaluated. P rats were assigned to alcohol naïve (water only) or alcohol drinking (continuous access to 15% alcohol and water for 8 consecutive weeks) groups. Responses of 23 putative dopamine neurons from naïve rats and 19 putative dopamine neurons from drinking rats were assessed in vivo using microiontophoretically-applied NMDA. Current-response curves for firing frequency and burst activity were constructed using nonlinear mixed effects models. Between-group comparisons were made for EC50 (effective current producing a half maximal excitatory response), Emax (maximal excitatory effect) and the CDB (the current at which depolarization block - marked decrease in neuronal activity - occurred). Drinking P rats steadily consumed alcohol over the eight-week protocol and did not exhibit signs of dependence or withdrawal. Putative dopamine neurons from drinking rats exhibited resistance to depolarization block (higher CDB values) and required larger doses of NMDA to elicit moderate excitatory responses (higher EC50 values), consistent with decreased receptor affinity. Maximal excitatory responses (Emax) did not differ between the groups, consistent with no change in receptor number. Blood alcohol was at undetectable levels at the time of experimentation. NMDA receptor sensitivity is decreased on posterior VTA putative dopamine neurons in P rats on a nondependent schedule of alcohol consumption. Mechanisms underlying increased spontaneous dopamine neuron activity may be independent of changes in NMDA receptor function. Decreased NMDA receptor sensitivity may precede the development of dependence.
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DOI：
10.1097/00000374-199911000-00019
发表时间：
1999-11-01
影响因子：
3.2
作者：
Brodie, MS;Pesold, C;Appel, SB
通讯作者：
Appel, SB
DOI：
10.1111/j.1530-0277.2009.00985.x
发表时间：
2009-09-01
影响因子：
3.2
作者：
Ding, Zheng-Ming;Rodd, Zachary A.;McBride, William J.
通讯作者：
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影响因子：
1.6
作者：
Hubscher, CH;Brooks, DL;Johnson, JR
通讯作者：
Johnson, JR
影响因子：
4.7
作者：
DILDYMAYFIELD, JE;LESLIE, SW
通讯作者：
LESLIE, SW
DOI：
10.1523/jneurosci.2961-09.2009
发表时间：
2009-12-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Blythe SN;Wokosin D;Atherton JF;Bevan MD
通讯作者：
Bevan MD