Weiss F, Ettenberg A, Koob G F
Research Institute of Scripps Clinic, Department of Molecular and Experimental Medicine, La Jolla, CA 92037.
Psychopharmacology (Berl). 1989;99(3):409-15. doi: 10.1007/BF00445568.
Postsynaptic dopamine-cholecystokinin (CCK) interactions in the nucleus accumbens were studied in two behavioral preparations of DA receptor supersensitivity: chronic-neuroleptic treated and 6-hydroxydopamine (6-OHDA) denervated rats. Subcutaneous (SC) injections of apomorphine (APO; 0.15 mg/kg) in experiment 1 produced marked hyperlocomotion in rats following 12 days of pretreatment with cis-[Z]-flupenthixol (2 mg/kg; twice per day). Bilateral intra-accumbens (N.Acc.) microinjections of CCK-8 (2 ng and 2 micrograms) reliably reduced APO-stimulated hyperlocomotion. An intermediate CCK dose (20 ng) was without effect. No change in APO responsivity following chronic vehicle treatment was observed and the baseline APO response was not altered by CCK at any dose. Denervation of mesolimbic dopamine (DA) terminals by intra-N.Acc. injections of 6-hydroxydopamine (6-OHDA; 8 micrograms/side) in experiment 2 similarly resulted in intense locomotor hyperactivity after APO stimulation (0.1 mg/kg; SC). Bilateral intra-N.Acc. injections of CCK-8 (1, 10, 100 ng, and 1 micrograms) significantly attenuated the supersensitive locomotor response to APO. As in experiment 1, CCK produced "biphasic" dose-response effects with strong attenuation that persisted throughout the entire 60-min test at both high (1 microgram) and low (1 ng) doses. Intermediate CCK doses (10 and 100 ng) produced only short-term reductions in activity. Hypomotility induced by APO in SHAM-lesioned rats was not effectively reversed by CCK treatments. CCK had no effect on unstimulated baseline locomotor activity in either 6-OHDA or SHAM-lesioned rats. These results provide further evidence that CCK-8 modulates mesolimbic DA activity by functionally opposing the postsynaptic effects of DA in the region of the nucleus accumbens.
在两种多巴胺（DA）受体超敏的行为模型中，即慢性给予神经阻滞剂处理的大鼠和6-羟基多巴胺（6-OHDA）去神经支配的大鼠，研究了伏隔核中突触后多巴胺-胆囊收缩素（CCK）的相互作用。在实验1中，皮下（SC）注射阿扑吗啡（APO；0.15mg/kg），在给予顺式-[Z]-氟哌噻吨（2mg/kg；每天两次）预处理12天后，大鼠出现明显的活动亢进。双侧伏隔核（N.Acc.）微量注射CCK-8（2ng和2μg）可可靠地降低APO刺激引起的活动亢进。中等剂量的CCK（20ng）则无作用。慢性给予溶剂处理后，未观察到APO反应性的变化，且任何剂量的CCK均未改变APO的基线反应。在实验2中，通过双侧伏隔核内注射6-羟基多巴胺（6-OHDA；8μg/侧）使中脑边缘多巴胺（DA）终末去神经支配，同样导致APO刺激（0.1mg/kg；SC）后出现强烈的运动活动亢进。双侧伏隔核内注射CCK-8（1、10、100ng和1μg）可显著减弱对APO的超敏运动反应。与实验1一样，CCK产生“双相”剂量反应效应，在高剂量（1μg）和低剂量（1ng）时，在整个60分钟的测试中均持续出现强烈的减弱作用。中等剂量的CCK（10和100ng）仅产生短期的活动减少。CCK处理不能有效逆转假手术大鼠中APO诱导的运动减退。CCK对6-OHDA或假手术大鼠中未受刺激的基线运动活动均无影响。这些结果进一步证明，CCK-8通过在功能上对抗伏隔核区域中DA的突触后效应来调节中脑边缘DA活性。
