Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria Monserrato, Monserrato, CA, Italy.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
Transl Psychiatry. 2024 Sep 28;14(1):391. doi: 10.1038/s41398-024-03112-6.
The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A adenosine receptors (AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the AR antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.
酒精和咖啡因的消费影响着全球数十亿人的生活。尽管最近的证据表明咖啡因会损害酒精的强化特性，但人们对其对酒精刺激的中脑边缘多巴胺（DA）功能的影响仍缺乏描述。作为撒醇啉的前体药物，酒精会兴奋后腹侧被盖区（pVTA）中的 DA 神经元，并增加伏隔核壳（AcbSh）中的 DA 释放。在这里，我们通过 AcbShDA 的脑微透析和 pVTA DA 神经元放电的电生理记录，在体内和体外显示，咖啡因通过对 A 腺苷受体（AR）的拮抗活性，阻止了酒精对中脑边缘 DA 功能的依赖性激活。因此，虽然 AR 拮抗剂 DPCPX 不能阻止酒精对 DA 功能的影响，但咖啡因和 AR 拮抗剂 SCH 58261 都能阻止酒精依赖性的 pVTA 产生撒醇啉和增加 AcbShDA 的体内释放，以及酒精依赖性的 pVTA DA 神经元的兴奋在体外。然而，咖啡因也能阻止撒醇啉和吗啡直接刺激的 DA 功能，这表明它可以通过独立于影响酒精诱导的撒醇啉形成或生物利用度来发挥这些抑制作用。最后，pVTA 的非靶向代谢组学显示，咖啡因拮抗了酒精对涉及脂质信号和能量代谢的分子（如磷脂、脂肪酸酰胺、肉碱）的影响，这可能是咖啡因在损害酒精介导的中脑边缘 DA 传递中的另一种撒醇啉非依赖性机制。总之，这项研究的结果加强了咖啡因以及 AR 拮抗剂在未来开发预防/治疗酒精使用障碍的策略中的潜力。
