Cervo L, Carnovali F, Stark J A, Mennini T
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Neuropsychopharmacology. 2003 Jun;28(6):1150-9. doi: 10.1038/sj.npp.1300169. Epub 2003 Apr 2.
Previous studies employed a second-order schedule paradigm maintained by cocaine reinforcement to show that BP897, a dopamine D(3) partial agonist, selectively modulated drug-seeking behavior. We investigated its effect on drug-seeking behavior induced by presentation of stimuli associated with and predictive of cocaine availability after a period of extinction and in the absence of any further cocaine. Male rats were trained to associate discriminative stimuli (S(D)) with the availability of intravenous (i.v.) 0.25 mg/0.1 ml/infusion cocaine (S(D+)) or no-reward (S(D-)) saline solution. Each infusion of cocaine or saline was followed by a response-cue signaling 20-s time-out (TO). After meeting the self-administration training criterion rats were placed on extinction conditions during which i.v. solutions and S(D)s were withheld. Every other 3 days on which rats met the extinction criterion, reinstatement tests were conducted, presenting the S(D+) or S(D-) noncontingently together with a contingent presentation of cocaine- or saline-cues signaling 20-s TO. Regardless of the order of presentation or the nature of the stimuli (auditory or visual), cocaine-associated but not saline-associated stimuli reinstated responding on the previously active lever. Presentation of cocaine-associated stimuli induced lasting drug-seeking behavior for at least eight test sessions. BP897 (1.0 mg/kg i.p.) significantly attenuated this behavior. Since it has been reported that BP897 can interact with a panel of different receptors with high affinity, we evaluated the effects of 7-OH-DPAT, an agonist to D(3) receptors, raclopride, a preferential antagonist to D(2) receptors, and WAY 100,635, an antagonist at 5-HT(1A) receptors, on drug-seeking behavior. 7-OH-DPAT (0.1-3.0 mg/kg i.p.) had biphasic effects on reinstatement induced by the cocaine-associated cues, low dosages reducing and high dosages increasing the impact of cocaine-associated stimuli on rats' behavior. Raclopride (0.1, 0.3 mg/kg s.c.) completely prevented drug-seeking behavior induced by the reintroduction of cocaine-associated stimuli. WAY 100,635 (0.1-1.0 mg/kg s.c.) had no effect on this behavior. These results, while confirming that the partial agonist at the D(3) receptors, BP897, might be a useful medication, also suggest a role of D(2) receptors in cue-induced cocaine-seeking behavior.
以往的研究采用由可卡因强化维持的二阶程序范式，以表明多巴胺D(3)部分激动剂BP897可选择性调节觅药行为。我们研究了其对在一段消退期后且无任何进一步可卡因情况下，由与可卡因可得性相关且可预测其可得性的刺激呈现所诱导的觅药行为的影响。雄性大鼠被训练将辨别性刺激（S(D)）与静脉注射（i.v.）0.25毫克/0.1毫升/次的可卡因（S(D+)）或无奖励（S(D-)）的生理盐水溶液的可得性相关联。每次注射可卡因或生理盐水后都有一个响应提示信号，表示20秒的超时（TO）。在达到自我给药训练标准后，将大鼠置于消退条件下，在此期间停止静脉注射溶液和S(D)。每隔3天大鼠达到消退标准时，进行恢复测试，非偶然地呈现S(D+)或S(D-)，同时偶然呈现表示20秒TO的可卡因或生理盐水提示。无论呈现顺序或刺激性质（听觉或视觉）如何，与可卡因相关而非与生理盐水相关的刺激都会恢复先前活动杠杆上的反应。呈现与可卡因相关的刺激会诱导至少八个测试阶段的持久觅药行为。BP897（腹腔注射1.0毫克/千克）显著减弱了这种行为。由于已有报道称BP897可与一组不同的受体高亲和力相互作用，我们评估了D(3)受体激动剂7-OH-DPAT、D(特别声明：译文内容仅供参考，具体专业术语的准确理解和应用请结合医学专业知识。)
