LEWIS AND FISCHER RAT STRAINS DISPLAY DIFFERENCES IN BIOCHEMICAL, ELECTROPHYSIOLOGICAL AND BEHAVIORAL PARAMETERS - STUDIES IN THE NUCLEUS-ACCUMBENS AND LOCUS-CERULEUS OF DRUG NAIVE AND MORPHINE-TREATED ANIMALS
LEWIS AND FISCHER RAT STRAINS DISPLAY DIFFERENCES IN BIOCHEMICAL, ELECTROPHYSIOLOGICAL AND BEHAVIORAL PARAMETERS - STUDIES IN THE NUCLEUS-ACCUMBENS AND LOCUS-CERULEUS OF DRUG NAIVE AND MORPHINE-TREATED ANIMALS
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DOI：
10.1016/0006-8993(93)91770-s
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发表时间：
1993-05-14
期刊：
影响因子：
2.9
通讯作者：
NESTLER, EJ
中科院分区：
文献类型：
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作者：
GUITART, X;KOGAN, JH;NESTLER, EJ
在之前的研究中，我们证明了斯普拉格-道利大鼠腹侧被盖区的酪氨酸羟化酶和神经丝蛋白受到长期吗啡和长期可卡因治疗的调节，近交系Lewis和Fischer 344大鼠品系在未接受药物的条件下，特别在该大脑区域显示出不同水平的这些蛋白质。在当前的研究中，我们比较了 Lewis 和 Fischer 大鼠伏隔核 (NAc) 和蓝斑 (LC) 中的腺苷酸环化酶、环 AMP 依赖性蛋白激酶和 G 蛋白的水平，Sprague-Dawley 大鼠的大脑区域中这些蛋白质受长期暴露于吗啡或可卡因的调节。我们发现，与 Fischer 大鼠相比，Lewis 大鼠的 NAc 和 LC 中腺苷酸环化酶和环 AMP 依赖性蛋白激酶活性水平较高，而 G(ialpha) 和 G(β) 水平较低。在分析的其他几个大脑区域中没有发现这些应变差异，并且在其他 G 蛋白亚基的水平中没有检测到应变差异。 Lewis 和 Fischer 大鼠在慢性吗啡调节 NAc 和 LC 中腺苷酸环化酶和环 AMP 依赖性蛋白激酶的能力方面也存在差异。在 NAc 中，慢性吗啡仅增加了 Fischer 品系中两种酶的水平，而在 LC 中，慢性吗啡增加了两种品系中两种酶的水平，并且在 Lewis 大鼠中观察到更强烈的效果。为了了解环 AMP 通路中这些菌株差异可能产生的生理后果，我们研究了基础和慢性吗啡治疗条件下的 LC 神经元活动。 Lewis 大鼠的 LC 神经元在体外脑切片中表现出比 Fischer 大鼠更高的自发放电率，并且吗啡诱导的对浴施加的 8-溴环 AMP 的反应性也表现出更大的增加。这些电生理学结果通常与生化观察结果一致。此外，Lewis 和 Fischer 大鼠表现出非常不同的阿片戒断综合征，在阿片受体拮抗剂纳曲酮沉淀阿片戒断时引发不同类型的行为。讨论了这些行为发现与生化和电生理学数据之间可能的关系。这些研究进一步证明了刘易斯和费舍尔大鼠品系提供了一个有用的模型系统的可能性，在该系统中可以研究一些导致药物相关行为的遗传因素。
In previous studies, we demonstrated that tyrosine hydroxylase and neurofilament proteins are regulated by chronic morphine and chronic cocaine treatments in the ventral tegmental area in Sprague-Dawley rats and that the inbred Lewis and Fischer 344 rat strains, under drug-naive conditions, show different levels of these proteins specifically in this brain region. In the current study, we compared Lewis and Fischer rats with respect to levels of adenylate cyclase, cyclic AMP-dependent protein kinase and G-proteins in the nucleus accumbens (NAc) and locus coeruleus (LC), brain regions in Sprague-Dawley rats where these proteins are regulated by chronic exposure to morphine or to cocaine. We found that levels of adenylate cyclase and cyclic AMP-dependent protein kinase activity are higher in the NAc and LC of Lewis rats compared to Fischer rats, whereas levels of G(ialpha) and G(beta) were lower. These strain differences were not seen in several other brain regions analyzed and no strain differences were detected in levels of other G-protein subunits. Lewis and Fischer rats also differed in the ability of chronic morphine to regulate adenylate cyclase and cyclic AMP-dependent protein kinase in the NAc and LC. In the NAc, chronic morphine increased levels of the two enzymes in the Fischer strain only, whereas in the LC chronic morphine increased levels of the enzymes in both strains, with more robust effects seen in the Lewis rat. To understand possible physiological consequences of these strain differences in the cyclic AMP pathway, we studied LC neuronal activity under basal and chronic morphine-treated conditions. LC neurons of Lewis rats showed higher spontaneous firing rates in brain slices in vitro than those of Fischer rats and also showed greater morphine-induced increases in responsiveness to bath-applied 8-bromo-cyclic AMP. These electrophysiological findings are generally consistent with the biochemical observations. Moreover, Lewis and Fischer rats displayed very different opiate withdrawal syndromes, with different types of behaviors elicited upon precipitation of opiate withdrawal with the opiate receptor antagonist, naltrexone. The possible relationship between these behavioral findings and the biochemical and electrophysiological data is discussed. These studies provide further support for the possibility that Lewis and Fischer rat strains provide a useful model system in which some of the genetic factors that contribute to drug-related behaviors can be investigated.