Melis Miriam, Camarini Rosana, Ungless Mark A, Bonci Antonello
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, California 94110, USA.
J Neurosci. 2002 Mar 15;22(6):2074-82. doi: 10.1523/JNEUROSCI.22-06-02074.2002.
The mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) is involved in many drug-related behaviors, including ethanol self-administration. In particular, VTA activity regulating ethanol consummatory behavior appears to be modulated through GABA(A) receptors. Previous exposure to ethanol enhances ethanol self-administration, but the mechanisms underlying this phenomenon are not well understood. In this study, we examined changes occurring at GABA synapses onto VTA DA neurons after a single in vivo exposure to ethanol. We observed that evoked GABA(A) IPSCs in DA neurons of ethanol-treated animals exhibited paired-pulse depression (PPD) compared with saline-treated animals, which exhibited paired-pulse facilitation (PPF). Furthermore, PPD was still present 1 week after the single exposure to ethanol. An increase in frequency of spontaneous miniature GABA(A) IPSCs (mIPSCs) was also observed in the ethanol-treated animals. Additionally, the GABA(B) receptor antagonist (3-aminopropyl)(diethoxymethyl) phosphinic acid shifted PPD to PPF, indicating that presynaptic GABA(B) receptor activation, likely attributable to GABA spillover, might play a role in mediating PPD in the ethanol-treated mice. The activation of adenylyl cyclase by forskolin increased the amplitude of GABA(A) IPSCs and the frequency of mIPSCs in the saline- but not in the ethanol-treated animals. Conversely, the protein kinase A (PKA) inhibitor N-[z-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide significantly decreased both the frequency of spontaneous mIPSCs and the amplitude of GABA(A) IPSCs in the ethanol-treated mice but not in the saline controls. The present results indicate that potentiation of GABAergic synapses, via a PKA-dependent mechanism, occurs in the VTA after a single in vivo exposure to ethanol, and such potentiation might be a key synaptic modification underlying increased ethanol intake.
起源于腹侧被盖区（VTA）的中脑边缘多巴胺（DA）系统参与许多与药物相关的行为，包括乙醇自我给药。特别是，调节乙醇消费行为的VTA活动似乎是通过GABA(A)受体进行调节的。先前接触乙醇会增强乙醇自我给药，但这种现象背后的机制尚不清楚。在本研究中，我们研究了在体内单次接触乙醇后，VTA DA神经元上GABA突触发生的变化。我们观察到，与生理盐水处理的动物相比，乙醇处理动物的DA神经元中诱发的GABA(A)抑制性突触后电流（IPSCs）表现出双脉冲抑制（PPD），而生理盐水处理的动物表现出双脉冲易化（PPF）。此外，在单次接触乙醇1周后，PPD仍然存在。在乙醇处理的动物中还观察到自发性微小GABA(A) IPSCs（mIPSCs）频率增加。此外，GABA(B)受体拮抗剂（3-氨丙基）（二乙氧基甲基）次膦酸将PPD转变为PPF，表明突触前GABA(B)受体激活，可能归因于GABA溢出，可能在介导乙醇处理小鼠的PPD中起作用。福司可林激活腺苷酸环化酶增加了生理盐水处理动物而非乙醇处理动物的GABA(A) IPSCs幅度和mIPSCs频率。相反，蛋白激酶A（PKA）抑制剂N-[z-（对溴肉桂酰胺基）乙基]-5-异喹啉磺酰胺显著降低了乙醇处理小鼠而非生理盐水对照组的自发性mIPSCs频率和GABA(A) IPSCs幅度。目前的结果表明，在体内单次接触乙醇后，VTA中通过PKA依赖性机制发生了GABA能突触增强，这种增强可能是乙醇摄入量增加背后的关键突触修饰。
