Dinieri Jennifer A, Nemeth Christina L, Parsegian Aram, Carle Tiffany, Gurevich Vsevolod V, Gurevich Eugenia, Neve Rachael L, Nestler Eric J, Carlezon William A
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA.
J Neurosci. 2009 Feb 11;29(6):1855-9. doi: 10.1523/JNEUROSCI.5104-08.2009.
The transcription factor cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) plays an important role in regulating mood. In rodents, increased CREB activity within the NAc produces depression-like signs including anhedonia, whereas disruption of CREB activity by expression of a dominant-negative CREB (mCREB, which acts as a CREB antagonist) has antidepressant-like effects. We examined how disruption of CREB activity affects brain reward processes using intracranial self-stimulation (ICSS) and inducible bitransgenic mice with enriched expression of mCREB in forebrain regions including the NAc. Mutant mice or littermate controls were prepared with lateral hypothalamic stimulating electrodes, and trained in the ICSS procedure to determine the frequency at which the stimulation becomes rewarding (threshold). Inducible expression of mCREB did not affect baseline sensitivity to brain stimulation itself. However, mCREB-expressing mice were more sensitive to the rewarding (threshold-lowering) effects of cocaine. Interestingly, mCREB mice were insensitive to the depressive-like (threshold-elevating) effects of the kappa-opioid receptor agonist U50,488. These behavioral differences were accompanied by decreased mRNA expression of G-protein receptor kinase-3 (GRK3), a protein involved in opioid receptor desensitization, within the NAc of mCREB mice. Disruption of CREB or GRK3 activity within the NAc specifically by viral-mediated gene transfer enhanced the rewarding impact of brain stimulation in rats, establishing the contribution of functional changes within this region. Together with previous findings, these studies raise the possibility that disruption of CREB in the NAc influences motivation by simultaneously facilitating reward and reducing depressive-like states such as anhedonia and dysphoria.
伏隔核（NAc）内的转录因子环磷腺苷反应元件结合蛋白（CREB）在调节情绪方面发挥着重要作用。在啮齿动物中，NAc内CREB活性增加会产生包括快感缺失在内的抑郁样症状，而通过表达显性负性CREB（mCREB，其作为CREB拮抗剂）破坏CREB活性则具有抗抑郁样作用。我们使用颅内自我刺激（ICSS）以及在前脑区域（包括NAc）中富集表达mCREB的诱导型双转基因小鼠，研究了CREB活性破坏如何影响大脑奖赏过程。用下丘脑外侧刺激电极制备突变小鼠或同窝对照小鼠，并在ICSS程序中进行训练，以确定刺激变得具有奖赏性的频率（阈值）。mCREB的诱导型表达并不影响对大脑刺激本身的基线敏感性。然而，表达mCREB的小鼠对可卡因的奖赏（降低阈值）作用更为敏感。有趣的是，mCREB小鼠对κ-阿片受体激动剂U50,488的抑郁样（升高阈值）作用不敏感。这些行为差异伴随着mCREB小鼠NAc内G蛋白受体激酶-3（GRK3，一种参与阿片受体脱敏的蛋白质）的mRNA表达降低。通过病毒介导的基因转移特异性破坏NAc内的CREB或GRK3活性可增强大鼠大脑刺激的奖赏作用，证实了该区域内功能变化的作用。与先前的研究结果一起，这些研究提出了一种可能性，即NAc中CREB的破坏通过同时促进奖赏和减少诸如快感缺失和烦躁不安等抑郁样状态来影响动机。
