Taraschenko Olga D, Rubbinaccio Heather Y, Shulan Joseph M, Glick Stanley D, Maisonneuve Isabelle M
Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
Neuropharmacology. 2007 Jul;53(1):18-26. doi: 10.1016/j.neuropharm.2007.04.010. Epub 2007 Apr 29.
Owing to multiple anatomical connections and functional interactions between the habenulo-interpeduncular and the mesolimbic pathways, it has been proposed that these systems could together mediate the reinforcing properties of addictive drugs. 18-Methoxycoronaridine, an agent that reduces morphine self-administration and attenuates dopamine sensitization in the nucleus accumbens in response to repeated morphine, has been shown to produce these effects by acting in the medial habenula and interpeduncular nucleus. Acetylcholine, one of the predominant neurotransmitters in the interpeduncular nucleus, may be a major determinant of these interactions. To determine if and how morphine acts in the interpeduncular nucleus, the effects of acute and repeated administration of morphine on extracellular acetylcholine levels in this brain area were assessed. In addition, the motor behavior of rats receiving repeated morphine administration was monitored during microdialysis sessions. Acutely, morphine produced a biphasic effect on extracellular acetylcholine levels in the interpeduncular nucleus such that low and high doses of morphine (i.e., 5 and 20mg/kg i.p.) significantly increased and decreased acetylcholine levels, respectively. Repeated administration of the same doses of morphine resulted in tolerance to the inhibitory but not to the stimulatory effects; tolerance was accompanied by sensitization to morphine-induced changes in locomotor activity and stereotypic behavior. The latter results suggest that tolerance to morphine's effect on the cholinergic habenulo-interpeduncular pathway is related to its sensitizing effects on the mesostriatal dopaminergic pathways.
由于缰核-脚间核与中脑边缘通路之间存在多种解剖学联系和功能相互作用，有人提出这些系统可能共同介导成瘾药物的强化特性。18-甲氧基去甲乌药碱是一种能减少吗啡自我给药并减弱伏隔核中多巴胺对重复给予吗啡的敏感性的药物，已被证明通过作用于内侧缰核和脚间核产生这些效应。乙酰胆碱是脚间核中主要的神经递质之一，可能是这些相互作用的主要决定因素。为了确定吗啡是否以及如何在脚间核中发挥作用，评估了急性和重复给予吗啡对该脑区细胞外乙酰胆碱水平的影响。此外，在微透析过程中监测了重复给予吗啡的大鼠的运动行为。急性给予时，吗啡对脚间核细胞外乙酰胆碱水平产生双相效应，即低剂量和高剂量的吗啡（即腹腔注射5和20mg/kg）分别显著增加和降低乙酰胆碱水平。重复给予相同剂量的吗啡导致对抑制性效应产生耐受性，但对刺激性效应不产生耐受性；耐受性伴随着对吗啡诱导的运动活动和刻板行为变化的敏化。后一结果表明，对吗啡在胆碱能缰核-脚间核通路中作用的耐受性与其对中脑纹状体多巴胺能通路的敏化作用有关。
