NEUROPHARMACOLOGY OF PSYCHOMOTOR STIMULANTS AND NMDA ANTAGONISTS

很明显，药物效应对与可卡因和其他精神运动刺激剂相关的线索的制约在药物诱导敏化的发展和维持以及与这些药理物质相关的成瘾过程中起着非常关键的作用。这项研究的目的之一是进一步确定这些条件性效应背后的神经药理学和神经解剖学底物，并表征与它们的获得、保留和消亡有关的行为变量。除了兴奋作用外，可卡因还具有引发焦虑的特性。我们先前已经发现，与可卡因相关的环境线索可以诱导长期的类似焦虑的作用，这种作用可被CRF拮抗剂α-螺旋-CRF预先逆转。与可卡因相关的线索也被发现引起血浆皮质酮(CORT)的条件性释放，这表明可卡因的一些条件性效应涉及HPA轴的激活。这种条件性内分泌效应也被α-螺旋CRF拮抗，再次暗示CRF参与其中。苯丙胺、吗啡、尼古丁、乙醇和MK-801(一种非竞争性NMDA拮抗剂)被发现以剂量依赖的方式增加血浆皮质醇。然而，只有苯丙胺能够产生皮质醇的条件性增加。用57-二羟色胺耗竭脑内5-羟色胺(5-HT)对可卡因引起的皮质醇升高无影响，提示5-羟色胺能通路可能不参与可卡因对HPA轴活动的无条件或条件性影响。在一系列消退过程之前，用乙氯普利(D2多巴胺拮抗剂)和SCH 23310(D1多巴胺拮抗剂)预处理大鼠可以阻止可卡因条件性行为的表达，但对消退过程没有影响。拮抗剂本身没有产生条件性的效果。阿朴吗啡(一种直接的DA激动剂)也可以防止物种灭绝。与可卡因相关的线索被发现增加了内侧额叶皮质、杏仁基底外侧核、伏隔核的核心和外壳、腹侧被盖区(VTA)和各种丘脑核团的葡萄糖利用。伏隔核中c-fos基因的表达也受到可卡因相关线索的影响。这些结构中活性的增加似乎与条件性可卡因效应的表达有关，并可能是导致渴望的激励动机过程的基础。该项目的第二个重点一直是确定谷氨酸拮抗剂如MK-801和PCP作用的神经生物学底物，已知的是在人类中诱发精神分裂症样症状。一系列利用微透析、微量注射和损毁程序的研究评估了基底节回路的某些成分在调节苯丙胺、阿朴吗啡和MK-801效应中的作用。结果表明，虽然多巴胺激动剂的运动刺激作用依赖于完整的多巴胺，并涉及从伏隔核到腹侧苍白球的GABA能传出，但MK-801s的刺激作用不依赖于这种机制，本质上可能更具全局性。事实上，将MK-801微量注射到伏隔核、额叶皮质、丘脑内侧核、VTA和丘脑底核，都能有效地增加运动活动。-可卡因致敏、血浆皮质酮(CORT)、条件性提示、CRF

It has become apparent that conditioning of drug effects to cues associated with cocaine and other psychomotor stimulants plays a very critical role in the development and maintenance of drug-induced sensitization, as well as the addictive processes related to these pharmacological agents. One aim of this research program was to define further the neuropharmacological and neuroanatomical substrates underlying those conditioned effects and to characterize the behavioral variables involved in their acquisition, retention, and extinction. In addition to its euphorogenic actions, cocaine also has anxiogenic properties. We have previously found that environmental cues associated with cocaine can elicit long-lasting anxiogenic-like actions that are reversed by pretreatment with the CRF antagonist alpha-helical-CRF. Cocaine-associated cues were also found to elicit conditioned release of plasma corticosterone (CORT), suggesting that some of the conditioned effects of cocaine involve activation of the HPA axis. Such conditioned endocrine effects were also antagonized by alpha-helical- CRF, again implicating CRF involvement. Amphetamine, morphine, nicotine, ethanol, and MK-801 (a noncompetitive NMDA antagonist) were found to increase plasma CORT in a dose-dependent fashion. Only amphetamine, however, was able to produce conditioned increases in CORT. Depletion of brain serotonin (5-HT) with 57-DHT had no effect on cocaine-induced increases in CORT, indicating that serotonergic pathways are probably not involved in the unconditioned or conditioned effects of cocaine on HPA axis activity. Pretreatment of rats with eticlopride (a D2 dopamine antagonist) and SCH 23310 (a D1 dopamine antagonist) prior to a series of extinction sessions prevented the expression of cocaine-conditioned behaviors, but had no effect on the extinction process. The antagonists by themselves produced no conditioned effects. Apomorphine (a direct DA agonist) also prevented extinction. Cues associated with cocaine were found to increase glucose utilization in the medial frontal cortex, basolateral amygdala, core and shell of the n. accumbens, ventral tegmental area (VTA), and various thalamic nuclei. Increased expression of c-fos mRNA also was seen in the n. accumbens by cocaine-associated cues. Increased activity in these structures appears to be related to the expression of conditioned cocaine effects and may underlie the incentive motivational processes responsible for craving.A second focus of this project has been on defining the neurobiological substrates underlying the actions of glutamate antagonists such as MK-801 and PCP, which are known to induce schizophrenic-like symptoms in man. A series of studies utilizing microdialysis, micro injection, and lesioning procedures evaluated the role of certain components of the basal ganglia circuits in mediating the effects of amphetamine, apomorphine, and MK-801. The findings indicate that while the locomotor stimulatory effects of dopamine agonists are dependent upon intact dopamine and involve GABAergic efferents from the n. accumbens to the ventral pallidum, MK- 801s stimulatory actions are independent of such mechanisms and may be more global in nature. In fact, micro injections of MK-801 into the n. accumbens, frontal cortex, medial thalamus, VTA, and subthalamic nucleus were all effective in producing increases in locomotor activity. - cocaine sensitization, plasma corticosterone (CORT), conditioned cues, CRF