Kreuter J D, Mattson B J, Wang B, You Z-B, Hope B T
Behavioral Neuroscience Branch, Intramural Research Program, The National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Neuroscience. 2004;127(1):233-42. doi: 10.1016/j.neuroscience.2004.04.047.
Anesthetics used in electrophysiological studies alter the effects of cocaine and amphetamine on neural activity in the striatum. However, the mechanism underlying this alteration has not been established. In the present study, we examined the effects of anesthetics on cocaine-induced neural activity in the striatum. We first assayed the ability of 20 mg/kg cocaine to induce Fos expression in the striatum following pretreatment with 400 mg/kg chloral hydrate or 1.3 g/kg urethane, two of the most commonly used anesthetics for in vivo electrophysiology. Chloral hydrate blocked, while urethane strongly attenuated cocaine-induced Fos expression without affecting basal levels of expression. We then examined dopaminergic and glutamatergic mechanisms for anesthetic effects on cocaine-induced Fos expression. Chloral hydrate and urethane did not attenuate basal or cocaine-induced increases of dopamine levels as assessed by microdialysis in dorsal striatum. In contrast, chloral hydrate attenuated glutamatergic neurotransmission as assessed by microdialysis in the presence of the glutamate transport blocker L-trans-pyrrolidone-2,4-dicarboxylic acid. Chloral hydrate attenuated basal levels of glutamate by 70%, while cocaine had no effect on glutamate levels. Since glutamate levels were tetrodotoxin-sensitive, the majority of glutamate measured in our assay was by synaptic release. To assess a causal role for a reduction of glutamatergic neurotransmission in anesthetic effects on cocaine-induced Fos expression, we injected the glutamate receptor agonists AMPA and NMDA into the dorsal striatum of chloral hydrate-anesthetized rats. The glutamate receptor agonists partially reinstated cocaine-induced Fos expression in anesthetized rats. We conclude anesthetics attenuate cocaine-induced neuronal activity by reducing glutamatergic neurotransmission.
用于电生理研究的麻醉剂会改变可卡因和苯丙胺对纹状体神经活动的影响。然而，这种改变背后的机制尚未明确。在本研究中，我们检测了麻醉剂对可卡因诱导的纹状体神经活动的影响。我们首先测定了在分别用400mg/kg水合氯醛或1.3g/kg氨基甲酸乙酯（两种体内电生理最常用的麻醉剂）预处理后，20mg/kg可卡因诱导纹状体Fos表达的能力。水合氯醛阻断了可卡因诱导的Fos表达，而氨基甲酸乙酯则强烈减弱了该表达，同时不影响基础表达水平。然后，我们研究了麻醉剂对可卡因诱导的Fos表达产生影响的多巴胺能和谷氨酸能机制。通过对背侧纹状体进行微透析评估，水合氯醛和氨基甲酸乙酯并未减弱基础或可卡因诱导的多巴胺水平升高。相反，在存在谷氨酸转运体阻滞剂L-反式-吡咯烷-2,4-二羧酸的情况下，通过微透析评估发现水合氯醛减弱了谷氨酸能神经传递。水合氯醛使谷氨酸基础水平降低了70%，而可卡因对谷氨酸水平无影响。由于谷氨酸水平对河豚毒素敏感，我们检测中测得的大部分谷氨酸是通过突触释放的。为了评估谷氨酸能神经传递减少在麻醉剂对可卡因诱导的Fos表达影响中的因果作用，我们将谷氨酸受体激动剂AMPA和NMDA注射到水合氯醛麻醉大鼠的背侧纹状体中。谷氨酸受体激动剂部分恢复了麻醉大鼠中可卡因诱导的Fos表达。我们得出结论，麻醉剂通过减少谷氨酸能神经传递来减弱可卡因诱导的神经元活动。
