School of Pharmacy-Pharmacology Unit, University of Camerino, Building of Experimental Medicine, Via Madonna delle Carceri, 62032 Camerino, Italy.
Psychopharmacology (Berl). 2013 Mar;226(2):347-55. doi: 10.1007/s00213-012-2910-y. Epub 2012 Nov 13.
Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)⁵]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat.
Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)⁵]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed.
Intraperitoneal administration of NPSR-QA1 (15-30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15-30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)⁵]NPS (10-30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala.
The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment.
先前的研究表明，大脑神经肽 S 受体（NPSR）的激活有助于恢复可卡因寻求行为，这种行为由预测药物可用性的环境线索引发。这一发现表明，阻断 NPSR 受体可能对可卡因成瘾具有治疗益处。为了评估这一假设，我们研究了两种新合成的 NPSR 拮抗剂，即喹啉酮酰胺衍生物 NPSR-QA1 和 NPS 肽类似物 [D-Cys(tBu)⁵]NPS，对大鼠可卡因自我给药和条件性线索诱导可卡因寻求复发的影响。
分别有几组大鼠在 FR1 和 FR5 （固定比率强化时间表）中自我给药食物和可卡因 0.25mg/kg/inf，每天进行 30 分钟和 2 小时的疗程。在食物和可卡因摄入达到基线水平后，测试 NPSR-QA1 对可卡因和食物自我给药的影响。NPSR-QA1 被腹腔内注射，评估其对条件性线索诱导复吸的影响，而 [D-Cys(tBut)⁵]NPS 被脑内、外侧下丘脑、下丘脑外侧穹窿区和中央杏仁核内注射。还评估了 NPSR-QA1 对可卡因寻求消退的影响。
腹腔内给予 NPSR-QA1（15-30mg/kg）并不影响可卡因自我给药。相反，NPSR-QA1（15-30mg/kg）降低了条件性线索诱导的可卡因复吸。在最低剂量下，这种作用是特异性的，而在最高剂量下，NPSR-QA1 也减少了食物自我给药。用 [D-Cys(tBu)⁵]NPS（10-30nmol/rat）证实了 NPSR 拮抗作用对可卡因寻求的疗效，因为它明显抑制了特异性脑内注射到外侧下丘脑和下丘脑外侧穹窿区后的复发行为，但不抑制中央杏仁核。
NPS/NPSR 系统作为可卡因成瘾生理病理学的一个重要新元素被确定，以及 NPSR 拮抗剂的抗成瘾特性的发现，为探索可卡因成瘾治疗的新机制开辟了可能性。
