Cohen Hagit, Kaplan Zeev, Matar Michael A, Buriakovsky Igor, Bourin Michel, Kotler Moshe
Ministry of Health Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Depress Anxiety. 2004;20(3):139-52. doi: 10.1002/da.20032.
Cholecystokinin (CCK) and its analogs generate anxiety in humans and measurable anxiety-like behaviors in rats. CCK receptor blockers have been reported to have variable effects in the treatment of anxiety disorders. In a prior study, intracerebroventricular administration of CCK-antisense oligodeoxynucleotides (ASODN) for 3 days significantly diminished anxiety-like behavior in rats. Counter to our expectations, intraperitoneal (i.p.) administration of CCK-ASODN significantly increased anxiety-like behavior and impaired retention performance in the Morris water maze. The aim of the present study was to manipulate CCK-mediated anxiety-like behavior and spatial memory in rats by peripheral (i.p.) administration of ASODN to preproCCK in the presence of antagonists to CCK1 and CCK2 receptor subtypes to further elucidate the roles of these two receptors and better understand the effects of i.p. CCK-ASODN. CCK-ASODN was injected i.p. to rats five times at 24-hr intervals with and without administration of CCK1R antagonist PD135158 or CCK2 antagonist benzotrip. Control groups received injections of either a scrambled oligodeoxynucleotide (ScrODN) or vehicle. On Day 6, the rats were assessed in the elevated plus maze paradigm and in the Morris water maze. The rats were sacrificed and their blood was assessed for corticosterone, ACTH, and prolactin levels. The results show that i.p. CCK-ASODN significantly increased anxiety-like behavior and impaired retention performance in the Morris water maze, compared to both control groups, accompanied by increased plasma corticosterone and plasma ACTH concentrations. In contrast, administration of CCK-ASODN together with CCK2R antagonist, but not with CCK1R antagonist, significantly decreased anxiety-like behavior in rats, but still impaired retention performance in the Morris water maze paradigm. Lower levels of plasma corticosterone and ACTH in CCK-ASODN+CCK2R antagonist-treated rats accompanied the reduced anxiety-like behavior. The present study showed an anxiolytic effect of i.p. CCK-ASODN in the presence of CCK2R, but not CCK1R.
胆囊收缩素（CCK）及其类似物会使人类产生焦虑，并在大鼠身上引发可测量的焦虑样行为。据报道，CCK受体阻滞剂在焦虑症治疗中具有不同的效果。在先前的一项研究中，脑室内注射CCK反义寡脱氧核苷酸（ASODN）3天可显著减少大鼠的焦虑样行为。与我们的预期相反，腹腔注射CCK-ASODN显著增加了焦虑样行为，并损害了大鼠在莫里斯水迷宫中的记忆保持能力。本研究的目的是通过在存在CCK1和CCK2受体亚型拮抗剂的情况下，对大鼠外周（腹腔）注射针对前CCK的ASODN来操纵CCK介导的焦虑样行为和空间记忆，以进一步阐明这两种受体的作用，并更好地理解腹腔注射CCK-ASODN的效果。以24小时的间隔对大鼠腹腔注射CCK-ASODN五次，同时给予或不给予CCK1R拮抗剂PD135158或CCK2拮抗剂苯并三氮唑。对照组注射乱序寡脱氧核苷酸（ScrODN）或赋形剂。在第6天，对大鼠进行高架十字迷宫实验和莫里斯水迷宫实验评估。处死大鼠并检测其血液中的皮质酮、促肾上腺皮质激素和催乳素水平。结果表明，与两个对照组相比，腹腔注射CCK-ASODN显著增加了焦虑样行为，并损害了大鼠在莫里斯水迷宫中的记忆保持能力，同时伴随着血浆皮质酮和血浆促肾上腺皮质激素浓度的升高。相比之下，联合注射CCK-ASODN和CCK2R拮抗剂（而非CCK1R拮抗剂）可显著降低大鼠的焦虑样行为，但在莫里斯水迷宫实验中仍会损害记忆保持能力。CCK-ASODN+CCK2R拮抗剂处理的大鼠焦虑样行为减少的同时，血浆皮质酮和促肾上腺皮质激素水平降低。本研究表明，在存在CCK2R而非CCK1R的情况下，腹腔注射CCK-ASODN具有抗焦虑作用。
