Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
J Neurosci. 2010 Jan 20;30(3):1096-109. doi: 10.1523/JNEUROSCI.2309-09.2010.
Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. alpha(2)-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of alpha(2)-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that alpha(2)-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine beta-hydroxylase knock-out (Dbh(-/-)) mice lacking norepinephrine, supporting a role for alpha(2)-heteroceptors on progenitor cells, rather than alpha(2)-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the alpha(2)-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of alpha(2)-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the alpha(2)-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that alpha(2)-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants.
慢性适应变化源于持续的抗抑郁治疗，如增强成年海马神经发生和增加营养因子表达，在抗抑郁药的行为效应中发挥关键作用。α2-肾上腺素能受体参与调节情绪，是开发更快作用抗抑郁药的潜在靶点。我们研究了α2-肾上腺素能受体对成年海马神经发生的影响。我们的结果表明，α2-肾上腺素能受体激动剂可乐定和胍那苄通过对祖细胞的增殖（而非存活或分化）的选择性作用，减少成年海马神经发生。这些效应在缺乏去甲肾上腺素的多巴胺-β-羟化酶敲除（Dbh（-/-））小鼠中持续存在，支持α2-异受体在祖细胞上的作用，而不是去甲肾上腺素能神经元上的α2-自身受体抑制去甲肾上腺素释放。体外成年海马祖细胞表达所有α2-肾上腺素能受体亚型，神经球频率和 BrdU 掺入减少表明α2-肾上腺素能受体刺激对祖细胞的直接作用。此外，α2-肾上腺素能受体拮抗剂育亨宾与抗抑郁药丙咪嗪共同给药可显著加速对海马祖细胞增殖、新生神经元形态成熟以及脑源性神经营养因子和血管内皮生长因子表达的影响，这些因子与抗抑郁药的神经发生和行为效应有关。最后，短时间（7 天）育亨宾和丙咪嗪治疗可导致新奇抑制喂养试验中的强烈行为反应，而经典抗抑郁药通常需要 3 周的治疗才能产生这种反应。我们的结果表明，表达于祖细胞上的α2-肾上腺素能受体减少成年海马神经发生，而其阻断可加速抗抑郁作用，突出了它们作为更快作用抗抑郁药靶点的重要性。
