Pentkowski Nathan S, Harder Bryan G, Brunwasser Samuel J, Bastle Ryan M, Peartree Natalie A, Yanamandra Krishna, Adams Matt D, Der-Ghazarian Taleen, Neisewander Janet L
School of Life Sciences, Arizona State University , Box 874501, Tempe, Arizona 85287, United States.
ACS Chem Neurosci. 2014 Mar 19;5(3):168-76. doi: 10.1021/cn400155t. Epub 2014 Jan 15.
Studies examining serotonin-1B (5-HT1B) receptor manipulations on cocaine self-administration and cocaine-seeking behavior initially seemed discrepant. However, we recently suggested based on viral-mediated 5-HT1B-receptor gene transfer that the discrepancies are likely due to differences in the length of abstinence from cocaine prior to testing. To further validate our findings pharmacologically, we examined the effects of the selective 5-HT1B receptor agonist CP 94,253 (5.6 mg/kg, s.c.) on cocaine self-administration during maintenance and after a period of protracted abstinence with or without daily extinction training. We also examined agonist effects on cocaine-seeking behavior at different time points during abstinence. During maintenance, CP 94,253 shifted the cocaine self-administration dose-effect function on an FR5 schedule of reinforcement to the left, whereas following 21 days of abstinence CP 94,253 downshifted the function and also decreased responding on a progressive ratio schedule of reinforcement regardless of extinction history. CP 94,253 also attenuated cue-elicited and cocaine-primed drug-seeking behavior following 5 days, but not 1 day, of forced abstinence. The attenuating effects of CP 94,253 on the descending limb of the cocaine dose-effect function were blocked by the selective 5-HT1B receptor antagonist SB 224289 (5 mg/kg, i.p.) at both time points, indicating 5-HT1B receptor mediation. The results support a switch in 5-HT1B receptor modulation of cocaine reinforcement from facilitatory during self-administration maintenance to inhibitory during protracted abstinence. These findings suggest that the 5-HT1B receptor may be a novel target for developing medication for treating cocaine dependence.
研究5-羟色胺-1B（5-HT1B）受体调控对可卡因自我给药及觅药行为的影响，最初结果似乎并不一致。然而，我们最近基于病毒介导的5-HT1B受体基因转移提出，这些差异可能是由于测试前可卡因戒断时间长短不同所致。为了从药理学角度进一步验证我们的发现，我们研究了选择性5-HT1B受体激动剂CP 94,253（5.6毫克/千克，皮下注射）在维持期以及经过一段长时间戒断（无论有无每日消退训练）后对可卡因自我给药的影响。我们还研究了激动剂在戒断期间不同时间点对觅药行为的影响。在维持期，CP 94,253将固定比率5强化程序下的可卡因自我给药剂量效应函数向左移动，而在戒断21天后，CP 94,253使该函数向下移动，并且无论消退历史如何，在累进比率强化程序下的反应也减少。CP 94,253在强制戒断5天而非1天后，也减弱了线索引发和可卡因激发的觅药行为。在两个时间点，选择性5-HT1B受体拮抗剂SB 224289（5毫克/千克，腹腔注射）均阻断了CP 94,253对可卡因剂量效应函数下降支的减弱作用，表明是5-HT1B受体介导的。这些结果支持5-HT1B受体对可卡因强化的调控从自我给药维持期的促进作用转变为长时间戒断期的抑制作用。这些发现表明，5-HT1B受体可能是开发治疗可卡因依赖药物的一个新靶点。
