Chen N H, Reith M E
Department of Basic Sciences, University of Illinois College of Medicine at Peoria.
J Pharmacol Exp Ther. 1993 Dec;267(3):1445-53.
The effects of dopamine (DA) and 5-hydroxytryptamine (5-HT) autoreceptor agents on electrically induced [3H]DA and [3H]5-HT release from superfused slices of striatum, nucleus accumbens and ventral mesencephalon (VM) containing A9 and A10 neurons were investigated in rats made tolerant to the stimulatory effect of cocaine on locomotor behavior by a 14-day continuous infusion of cocaine (29 mg/kg/day) by s.c. implanted osmotic minipumps followed by a 7-day drug-free period. In VM, electrically induced [3H]DA was increased, the ability of pergolide to inhibit this release was abolished, but the ability of sulpiride to facilitate the release was potentiated, implicating a higher concentration of synaptic DA modifying the responsiveness of somatodendritic D2 autoreceptors to D2 agents. Both electrically induced [3H]5-HT release from VM and the stimulatory effect of in vitro cocaine on this release were enhanced whereas the effects of both 5-methoxytryptamine and methiothepin were attenuated, indicating that subsensitivity of 5-HT autoreceptors developed in DA cell body regions. In striatum and nucleus accumbens, no significant changes were observed in [3H]DA and [3H]5-HT release, except for a modest reduction in the effects of both pergolide and sulpiride on electrically induced [3H]DA release from striatum. These results emphasize the importance of pretreatment-induced changes in DA cell body regions, rather than terminal areas, under the present conditions. The observed increase in DA autoinhibitory tone and subsensitivity of 5-HT release-regulating autoreceptors in the VM may contribute to the locomotor tolerance upon cocaine challenge after continuous cocaine.
通过皮下植入渗透微型泵连续14天输注可卡因(29毫克/千克/天),随后经过7天的无药期,使大鼠对可卡因对运动行为的刺激作用产生耐受性,在此基础上研究了多巴胺(DA)和5-羟色胺(5-HT)自身受体激动剂对含有A9和A10神经元的纹状体、伏隔核和腹侧中脑(VM)的灌流切片中电诱导的[3H]DA和[3H]5-HT释放的影响。在VM中,电诱导的[3H]DA释放增加,培高利特抑制这种释放的能力丧失,但舒必利促进释放的能力增强,这意味着突触DA浓度升高改变了树突体D2自身受体对D2激动剂的反应性。VM中电诱导的[3H]5-HT释放以及体外可卡因对这种释放的刺激作用均增强,而5-甲氧基色胺和甲硫哒嗪的作用均减弱,表明DA细胞体区域出现了5-HT自身受体的敏感性降低。在纹状体和伏隔核中,[3H]DA和[3H]5-HT释放未观察到显著变化,只是培高利特和舒必利对纹状体中电诱导的[3H]DA释放的作用略有降低。这些结果强调了在当前条件下,预处理诱导的DA细胞体区域而非终末区域变化的重要性。VM中观察到的DA自身抑制张力增加和5-HT释放调节自身受体的敏感性降低可能导致连续使用可卡因后对可卡因激发的运动耐受性。