Wazlawik Elisabeth, Morato Gina Struffaldi
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Rua Ferreira Lima 82, 88015-420 Florianopolis, Santa Catarina, Brazil.
Psychopharmacology (Berl). 2003 Dec;170(4):343-50. doi: 10.1007/s00213-003-1555-2. Epub 2003 Sep 4.
Our previous studies have shown that the inhibition of nitric oxide (NO) synthesis with drugs administered either by systemic or ICV routes blocks the development of tolerance to some of the effects of ethanol.
The aim of this study was to further investigate the role of NO-dependent pathways in tolerance to the incoordinating effect of ethanol through ICV administration of drugs that activate or interfere with NO-dependent pathways.
Male Wistar rats were pretreated with IP ethanol (2.7 g/ kg) or saline before receiving ICV injections of the soluble guanylyl cyclase (sGC) inhibitors methylene blue (30 nmol), 6(phenylamino)-5,8-quinolinedione (LY83583, 10 nmol), 1H-(1,2,4)-oxodiazolo (4,3-a)quinoxalin-1-one (ODQ, 1 nmol), and 4H-8-bromo-1,2,4-oxadiazolo (3,4-d)benz(b)(1,4)oxazin-1-one (NS2028, 10 nmol), or the respective control solutions. The animals were tested on the tilt plane apparatus. Tolerance was assessed 24 h after the first ethanol injection, by administering ethanol to all animals and re-testing them on the tilt plane. The effects of the cyclic guanylate 3',5'-monophosphate (cGMP) analogue, 8-bromo-cGMP (40 nmol or 80 nmol) and of the NO donors S-nitroso-N-acetylpenicillamine (SNAP, 40 or 80 nmol) and sodium nitroprusside (SNP, 40 or 80 nmol) were also studied.
All sGC inhibitors significantly blocked rapid tolerance, whereas SNP (40 nmol) and 8-bromo-cGMP (80 nmol) increased the magnitude of ethanol tolerance (ANOVA+Tukey's test).
The present results suggest that activation or inhibition of NO-dependent pathways increases or blocks rapid tolerance, respectively. These results give additional support to the hypothesis that brain NO plays a role in the development of tolerance to ethanol, but it remains to be confirmed if the same basic cellular mechanisms are also applicable to tolerance to other behavioural and/or physiological effects of this drug.
我们之前的研究表明，通过全身给药或脑室内给药的方式使用药物抑制一氧化氮（NO）合成，可阻断对乙醇某些作用的耐受性的发展。
本研究的目的是通过脑室内注射激活或干扰NO依赖性途径的药物，进一步研究NO依赖性途径在乙醇不协调作用耐受性中的作用。
雄性Wistar大鼠在接受脑室内注射可溶性鸟苷酸环化酶（sGC）抑制剂亚甲蓝（30 nmol）、6-（苯氨基）-5,8-喹啉二酮（LY83583，10 nmol）、1H-（1,2,4）-恶二唑并（4,3-a）喹喔啉-1-酮（ODQ，1 nmol）和4H-8-溴-1,2,4-恶二唑并（3,4-d）苯并（b）（1,4）恶嗪-1-酮（NS2028，10 nmol）或各自的对照溶液之前，先腹腔注射乙醇（2.7 g/kg）或生理盐水进行预处理。动物在倾斜平面装置上进行测试。在首次注射乙醇24小时后，通过给所有动物注射乙醇并在倾斜平面上重新测试来评估耐受性。还研究了环磷酸鸟苷（cGMP）类似物8-溴-cGMP（40 nmol或80 nmol）以及NO供体N-亚硝基-N-乙酰青霉胺（SNAP，40或80 nmol）和硝普钠（SNP，40或80 nmol）的作用。
所有sGC抑制剂均显著阻断快速耐受性，而SNP（40 nmol）和8-溴-cGMP（80 nmol）增加了乙醇耐受性的程度（方差分析+Tukey检验）。
目前的结果表明，激活或抑制NO依赖性途径分别增加或阻断快速耐受性。这些结果进一步支持了脑内NO在乙醇耐受性发展中起作用的假说，但该药物对其他行为和/或生理作用的耐受性是否也适用相同的基本细胞机制仍有待证实。
