Razavi Yasaman, Karimi Sara, Bani-Ardalan Mahtash, Haghparast Abbas
Neuroscience Research Center, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box 19615-1178, Tehran, Iran.
Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
EXCLI J. 2014 Sep 26;13:1120-30. eCollection 2014.
Orexin plays a crucial role in drug-seeking behavior. The lateral hypothalamus (LH) is a central region that produces orexin, and its projections to the ventral tegmental area (VTA) play an important role in reward and addiction-related behaviors. In this study, we investigated the role of LH stimulation and the involvement of the orexin-1 receptor (Ox1r) in the VTA in relation to morphine sensitization. In all animals, cannulae were implanted unilaterally into the LH and VTA to inject different doses of carbachol (62.5, 125 and 250 nmol/0.5 μl saline) as a cholinergic agonist and SB334867 (1, 10 and 20 nmol/0.3 µl DMSO) as a selective Ox1r antagonist for three consecutive days (sensitization period) respectively. These drugs were injected five minutes before administration of an ineffective dose of morphine (0.5 mg/kg; sc) during the sensitization period. In all groups, the sensitization period occurred in a separate room from which the conditioning occurred. After this period, all groups exceeded five days under the conditioned place preference (CPP) paradigm without any treatment. For evaluation of morphine sensitization, place preference was induced by ineffective dose of morphine (0.5 mg/kg) and the CPP score was represented by the difference in time spent in drug- and saline-paired compartments. The results revealed that concurrent intra-LH administration of carbachol (125 nmol/0.5 µl saline) and an ineffective dose of morphine (0.5 mg/kg) significantly induce CPP. Additionally, the blockade of Ox1r in the VTA by SB334867 can attenuate the conditioning score induced by concurrent administration of carbachol and an ineffective dose of morphine. Our findings suggest that LH stimulation potentiates the effect of an ineffective dose of morphine, and induces morphine sensitization. It seems that the chemical stimulation of LH potentiates sensitization to morphine through the orexinergic system in the VTA in rats.
食欲素在觅药行为中起关键作用。下丘脑外侧区（LH）是产生食欲素的中枢区域，其向腹侧被盖区（VTA）的投射在奖赏及成瘾相关行为中起重要作用。在本研究中，我们调查了LH刺激的作用以及VTA中食欲素-1受体（Ox1r）的参与与吗啡敏化的关系。在所有动物中，将套管单侧植入LH和VTA，分别连续三天（敏化期）注射不同剂量的卡巴胆碱（62.5、125和250 nmol/0.5 μl生理盐水）作为胆碱能激动剂，以及SB334867（1、10和20 nmol/0.3 µl二甲基亚砜）作为选择性Ox1r拮抗剂。在敏化期，这些药物在给予无效剂量的吗啡（0.5 mg/kg；皮下注射）前五分钟注射。在所有组中，敏化期在与条件反射发生的房间分开的房间内进行。在此期间过后，所有组在条件性位置偏爱（CPP）范式下超过五天未接受任何处理。为评估吗啡敏化，用无效剂量的吗啡（0.5 mg/kg）诱导位置偏爱，CPP分数由在药物配对隔室和生理盐水配对隔室中花费时间的差异表示。结果显示，同时向LH内注射卡巴胆碱（125 nmol/0.5 μl生理盐水）和无效剂量的吗啡（0.5 mg/kg）可显著诱导CPP。此外，SB334867对VTA中Ox1r的阻断可减弱同时给予卡巴胆碱和无效剂量吗啡所诱导的条件反射分数。我们的研究结果表明，LH刺激增强了无效剂量吗啡的作用，并诱导了吗啡敏化。似乎LH的化学刺激通过大鼠VTA中的食欲素能系统增强了对吗啡的敏化。
