Meyer P J, Palmer A A, McKinnon C S, Phillips T J
Portland Alcohol Research Center, Portland, OR, USA.
Neuroscience. 2005;131(2):263-73. doi: 10.1016/j.neuroscience.2004.11.005.
The ability of ethanol to facilitate GABA(A) receptor-mediated transmission may result in GABA(A) receptor alterations during repeated ethanol administration, and lead to dynamic behavioral changes, including sensitization to the locomotor stimulant effect of ethanol. Since alterations in GABA(A) receptors are likely to alter sensitivity to GABAergic drugs such as 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) and pentobarbital, we determined whether enhanced sensitivity to ethanol was associated with enhanced sensitivity (cross-sensitization) to these drugs. Two procedures that produced differences in the magnitude of expression of ethanol-induced locomotor sensitization were used.
After habituation to testing procedures for 2 days, female DBA/2J mice were injected with ethanol or saline for 12 days. On the following day, locomotion was recorded after a challenge injection of ethanol (2 g/kg), allopregnanolone (10 or 17 mg/kg), or pentobarbital (10 or 20 mg/kg). Due to evidence that exposure to the test chambers influenced sensitization, in some experiments, mice were exposed to the test apparatus on the day prior to challenge.
Exposure to the test apparatus prior to drug challenge attenuated the expression of ethanol sensitization, compared with mice without this pre-exposure. Cross-sensitization was not observed to either allopregnanolone or pentobarbital under any condition; however, some groups of repeated ethanol-treated mice displayed tolerance to the initial stimulant effects of allopregnanolone and pentobarbital.
These studies indicate that behavioral sensitization to ethanol is not associated with cross-sensitization to pentobarbital or allopregnanolone, and that the expression of ethanol sensitization is influenced by the relative novelty of the test chamber. In addition, these results do not support a mechanism in which alterations in the neurosteroid or barbiturate modulatory sites of the GABA(A) receptor are responsible for the expression of sensitization to the locomotor stimulant effects of ethanol.
乙醇促进γ-氨基丁酸A（GABA(A)）受体介导的神经传递的能力，可能在反复给予乙醇期间导致GABA(A)受体改变，并引发动态行为变化，包括对乙醇运动刺激作用的敏化。由于GABA(A)受体的改变可能会改变对诸如3α-羟基-5α-孕烷-20-酮（别孕烯醇酮）和戊巴比妥等GABA能药物的敏感性，我们确定了对乙醇的敏感性增强是否与对这些药物的敏感性增强（交叉敏化）相关。我们采用了两种方法，这两种方法在乙醇诱导的运动敏化表达程度上产生了差异。
在适应测试程序2天后，给雌性DBA/2J小鼠注射乙醇或生理盐水，持续12天。在接下来的一天，在给予乙醇（2克/千克）、别孕烯醇酮（10或17毫克/千克）或戊巴比妥（10或20毫克/千克）激发注射后记录运动情况。由于有证据表明暴露于测试箱会影响敏化，在一些实验中，小鼠在激发前一天暴露于测试装置。
与未进行这种预暴露的小鼠相比，在药物激发前暴露于测试装置减弱了乙醇敏化的表达。在任何条件下均未观察到对别孕烯醇酮或戊巴比妥的交叉敏化；然而，一些反复用乙醇处理的小鼠组对别孕烯醇酮和戊巴比妥的初始刺激作用表现出耐受性。
这些研究表明，对乙醇的行为敏化与对戊巴比妥或别孕烯醇酮的交叉敏化无关，并且乙醇敏化的表达受测试箱相对新奇性的影响。此外，这些结果不支持一种机制，即GABA(A)受体的神经甾体或巴比妥酸盐调节位点的改变是对乙醇运动刺激作用敏化表达的原因。
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