Amat Jose, Dolzani Samuel D, Tilden Scott, Christianson John P, Kubala Kenneth H, Bartholomay Kristi, Sperr Katherine, Ciancio Nicholas, Watkins Linda R, Maier Steven F
Department of Psychology and Neuroscience and the Center for Neuroscience and
Department of Psychology and Neuroscience and the Center for Neuroscience and Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado 80305, and.
J Neurosci. 2016 Jan 6;36(1):153-61. doi: 10.1523/JNEUROSCI.3114-15.2016.
Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection.
The reported data show that systemic ketamine, given up to 2 weeks before a stressor, blunts behavioral and neurochemical effects of the stressor. The study also advances understanding of the mechanisms involved and suggests that ketamine acts at the prelimbic cortex to sensitize neurons that project to and inhibit the DRN.
近期，人们对N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮亚麻醉剂量的抗抑郁和抗应激作用产生了兴趣，已经确定了氯胺酮逆转应激作用的机制，但对于氯胺酮对未来应激源可能具有的预防作用知之甚少。在此，我们研究了氯胺酮对斯普拉格-道利大鼠不可逃避、无法控制的尾部电击（IS）后神经化学和行为变化的预防作用。IS会导致焦虑增加，这依赖于投射到基底外侧杏仁核（BLA）的血清素能（5-羟色胺，5-HT）背侧中缝核（DRN）神经元的激活。在IS前2小时、1周或2周给予氯胺酮（10毫克/千克，腹腔注射）可预防IS通常引起的BLA中细胞外5-HT水平升高。此外，在这些时间点给予氯胺酮可阻断IS导致的幼年社交探索减少。将氯胺酮微量注射到内侧前额叶皮质的前边缘（PL）区域可重现全身氯胺酮的作用，相反，通过对PL进行药理抑制可预防全身氯胺酮的作用。尽管IS不会激活来自PL的DRN投射神经元，但在给予氯胺酮后IS会激活，这表明氯胺酮的预防作用是该投射功能改变的结果。
所报告的数据表明，在应激源出现前长达2周给予全身氯胺酮可减轻应激源的行为和神经化学影响。该研究还推进了对所涉及机制的理解，并表明氯胺酮作用于前边缘皮质，使投射到DRN并抑制DRN的神经元敏感化。
