Heidbreder C A, Schenk S, Partridge B, Shippenberg T S
Integrative Neuroscience Unit, Behavioral Neuroscience Branch, National Institute of Health, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
Synapse. 1998 Nov;30(3):255-62. doi: 10.1002/(SICI)1098-2396(199811)30:3<255::AID-SYN3>3.0.CO;2-A.
Previous data have shown that the repeated administration of kappa-opioid receptor agonists attenuates the acute behavioral effects of cocaine. The site and mechanism by which kappa-agonists interact with this psychostimulant, however, are unknown. Accordingly, the present microdialysis study characterized the effects of prior, repeated administration of the selective kappa-opioid receptor agonist U69593 on basal and cocaine-evoked DA levels within the nucleus accumbens (NAC) and caudate putamen (CPU). The influence of U69593 treatment on the locomotor-activating effects of an acute cocaine challenge was also assessed. Rats received once daily injections of U69593 (0.16-0.32 mg/kg/day) or vehicle (1.0 ml/kg/day) for 3 days. The behavioral and neurochemical effects produced by an acute cocaine challenge (20 mg/kg i.p.) were assessed 2 days following treatment cessation. Administration of cocaine to control animals increased locomotor activity. This effect was attenuated in animals which had previously received U69593 (0.32 mg/kg/day x 3 days). Prior administration of U69593 failed to modify basal DA levels in either the NAC or CPU. Thus, 2 days following the cessation of U69593 treatment, dialysate DA levels did not differ from that of controls. Administration of cocaine to vehicle-treated animals increased dialysate levels of DA in both brain regions. However, in animals previously exposed to U69593 (0.32 mg/kg/day x 3 days), a significant enhancement in the response of DA neurons to cocaine was seen. These data demonstrate that prior, repeated administration of a selective kappa-opioid receptor agonist attenuates the locomotor-activating effects of cocaine and increases cocaine-evoked DA overflow in terminal projection areas of mesostriatal and mesolimbic DA neurons. These findings indicate that the behavioral interactions of kappa-agonists with cocaine observed in this and previous studies cannot be attributed to a presynaptic inhibition of DA release. Rather, they suggest that postsynaptic or non-DA mechanisms mediate the interaction of these agents with cocaine.
先前的数据表明，反复给予κ-阿片受体激动剂可减弱可卡因的急性行为效应。然而，κ-激动剂与这种精神兴奋剂相互作用的位点和机制尚不清楚。因此，本微透析研究表征了预先反复给予选择性κ-阿片受体激动剂U69593对伏隔核（NAC）和尾状壳核（CPU）内基础和可卡因诱发的多巴胺（DA）水平的影响。还评估了U69593处理对急性可卡因激发的运动激活效应的影响。大鼠连续3天每天注射一次U69593（0.16 - 0.32mg/kg/天）或溶剂（1.0ml/kg/天）。在停止治疗2天后评估急性可卡因激发（20mg/kg腹腔注射）产生的行为和神经化学效应。给对照动物注射可卡因会增加运动活动。在先前接受U69593（0.32mg/kg/天×3天）的动物中，这种效应减弱。预先给予U69593未能改变NAC或CPU中的基础DA水平。因此，在停止U69593治疗2天后，透析液中的DA水平与对照无差异。给溶剂处理的动物注射可卡因会增加两个脑区透析液中DA的水平。然而，在先前暴露于U69593（0.32mg/kg/天×3天）的动物中，观察到DA神经元对可卡因的反应有显著增强。这些数据表明，预先反复给予选择性κ-阿片受体激动剂可减弱可卡因的运动激活效应，并增加中脑纹状体和中脑边缘DA神经元终末投射区域中可卡因诱发的DA溢出。这些发现表明，在本研究和先前研究中观察到的κ-激动剂与可卡因的行为相互作用不能归因于对DA释放的突触前抑制。相反，它们表明突触后或非DA机制介导了这些药物与可卡因的相互作用。
