Todtenkopf Mark S, Marcus Jacqueline F, Portoghese Philip S, Carlezon William A
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, MRC 217, Belmont, MA 02478, USA.
Psychopharmacology (Berl). 2004 Apr;172(4):463-70. doi: 10.1007/s00213-003-1680-y. Epub 2004 Jan 16.
Elevations in cAMP response element binding protein (CREB) function within the mesolimbic system of rats reduce cocaine reward in place conditioning studies and increase immobility in the forced swim test. Each of these behavioral adaptations can be interpreted as a depressive-like effect (i.e., anhedonia, despair) that may reflect reduced activity of brain reward systems. Furthermore, each effect appears due to increases in CREB-mediated expression of dynorphin, since each is attenuated by intracranial injections of the kappa-opioid receptor antagonist norBNI.
Intracranial self-stimulation (ICSS) studies were conducted in rats to determine whether administration of a kappa-agonist would have depressive-like effects on brain stimulation reward, and whether pretreatment with a kappa-antagonist would attenuate any such effects. Conditions that have depressive effects in people (e.g., drug withdrawal) increase the threshold amounts of stimulation required to sustain ICSS in rats.
Sprague-Dawley rats with lateral hypothalamic stimulating electrodes were tested in a "curve-shift" variant of the ICSS procedure after systemic administration of the kappa-agonist U-69593 alone, the novel kappa-antagonist 5'-acetamidinoethylnaltrindole (ANTI) alone, or co-administration of both drugs.
U-69593 dose dependently increased ICSS thresholds, suggesting that activation of kappa-receptors reduced the rewarding impact of the brain stimulation. ANTI had no effects on its own, but it attenuated increases in ICSS thresholds caused by the agonist.
These data provide further evidence that stimulation of brain kappa-receptors may trigger certain depressive-like signs, and that kappa antagonists may have efficacy as antidepressants without having reward-related actions of their own.
在大鼠中脑边缘系统内，环磷酸腺苷反应元件结合蛋白（CREB）功能的增强在位置偏爱条件性实验中会降低可卡因奖赏效应，在强迫游泳实验中会增加不动时间。这些行为适应性变化中的每一种都可被解释为类似抑郁的效应（即快感缺失、绝望），这可能反映了大脑奖赏系统活性的降低。此外，每种效应似乎都是由于强啡肽的CREB介导表达增加所致，因为每种效应都可被颅内注射κ-阿片受体拮抗剂norBNI所减弱。
在大鼠中进行颅内自我刺激（ICSS）实验，以确定给予κ-激动剂是否会对脑刺激奖赏产生类似抑郁的效应，以及用κ-拮抗剂预处理是否会减弱任何此类效应。在人类中具有抑郁效应的情况（如药物戒断）会增加大鼠维持ICSS所需的刺激阈值量。
对植入下丘脑外侧刺激电极的Sprague-Dawley大鼠，在单独全身给予κ-激动剂U-69593、单独给予新型κ-拮抗剂5'-乙酰脒基乙基纳曲吲哚（ANTI）或两种药物联合给药后，采用ICSS程序的“曲线偏移”变体进行测试。
U-69593剂量依赖性地增加ICSS阈值，表明κ-受体的激活降低了脑刺激奖赏效应。ANTI单独使用时无作用，但它减弱了激动剂引起的ICSS阈值升高。
这些数据进一步证明，脑κ-受体的刺激可能引发某些类似抑郁的体征，并且κ-拮抗剂可能作为抗抑郁药有效，而自身不具有与奖赏相关的作用。
