Carlezon W A, Thome J, Olson V G, Lane-Ladd S B, Brodkin E S, Hiroi N, Duman R S, Neve R L, Nestler E J
Division of Molecular Psychiatry, Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, CT 06508, USA.
Science. 1998 Dec 18;282(5397):2272-5. doi: 10.1126/science.282.5397.2272.
Cocaine regulates the transcription factor CREB (adenosine 3', 5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade-culminating in gene expression-through which exposure to cocaine modifies subsequent responsiveness to the drug.
可卡因可调节大鼠伏隔核中的转录因子CREB（3',5'-单磷酸腺苷反应元件结合蛋白），伏隔核是大脑中对成瘾至关重要的区域。该区域中CREB的过表达会降低可卡因的奖赏效应，并使低剂量药物产生厌恶感。相反，显性负性突变体CREB的过表达会增强可卡因的奖赏效应。强啡肽转录的改变可能导致了这些效应：CREB过表达会使其表达增加，而突变体CREB过表达则会使其表达减少。此外，κ阿片受体（强啡肽作用的靶点）的阻断可拮抗CREB对可卡因奖赏的负面影响。这些结果确定了一个以基因表达为终点的细胞内级联反应，通过该反应，接触可卡因会改变随后对该药物的反应性。
