Morrow B A, Lee E J, Taylor J R, Elsworth J D, Nye H E, Roth R H
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
J Pharmacol Exp Ther. 1997 Nov;283(2):712-21.
This report investigates the effect of the negative enantiomer of 1-hydroxy-3-aminopyrrolidone-2 (HA-966) on behavioral and biochemical changes elicited by pharmacological or experimental paradigms which activate mesocorticolimbic dopaminergic neurotransmission. Several paradigms were used, including cocaine sensitization and two stressors: restraint for 30 min and an aversive conditioning model. (S)-(-)-HA-966 (3 and 5 mg/kg i.p.) prevented restraint stress-induced dopamine utilization in both the medial prefrontal cortex and nucleus accumbens, in contrast to the positive enantiomer. Conditioned fear increased dopamine metabolism in both the core and shell subdivisions of the nucleus accumbens, an effect blocked by (S)-(-)-HA-966. The conditioned stress-induced increase in dopamine metabolism in the medial prefrontal cortex was also blocked by (S)-(-)-HA-966. In addition, (S)-(-)-HA-966 suppressed fear-induced behaviors: immobility and defecation. In other studies, (S)-(-)-HA-966 (3 mg/kg i.p.) prevented locomotor sensitization without altering the acute motoric response elicited by cocaine. The highest dose of (S)-(-)-HA-966 (5 mg/kg i.p.) blocked acute cocaine-induced locomotion but resulted in sedation. In addition, the highest dose of (S)-(-)-HA-966 tested suppressed weight gain in control rats, unlike its enantiomer, (R)-(+)-HA-966. Because (S)-(-)-HA-966 has been proposed to act at the gamma-aminobutyric acid (GABA)B receptor, we examined the ability of (S)-(-) and (R)-(+)-HA-966 to displace [3H]-(-)-baclofen from cortical membranes to assess GABAB receptor binding. Neither enantiomer significantly altered [3H]-(-)-baclofen binding at relevant concentrations, indicating the actions of (S)-(-)-HA-966 reported here are the results of a mechanism apparently independent of the baclofen binding site on the GABAB receptor.
本报告研究了1-羟基-3-氨基吡咯烷-2（HA-966）的负对映体对由激活中脑皮质边缘多巴胺能神经传递的药理学或实验范式所引发的行为和生化变化的影响。使用了几种范式，包括可卡因致敏以及两种应激源：30分钟的束缚和厌恶条件反射模型。与正性对映体相比，（S）-（-）-HA-966（腹腔注射3和5mg/kg）可防止束缚应激诱导的内侧前额叶皮质和伏隔核中的多巴胺利用。条件性恐惧增加了伏隔核核心和壳部亚区的多巴胺代谢，这一效应被（S）-（-）-HA-966阻断。条件性应激诱导的内侧前额叶皮质中多巴胺代谢的增加也被（S）-（-）-HA-966阻断。此外，（S）-（-）-HA-966抑制了恐惧诱导的行为：不动和排便。在其他研究中，（S）-（-）-HA-966（腹腔注射3mg/kg）可防止运动致敏，而不改变可卡因引起的急性运动反应。（S）-（-）-HA-966的最高剂量（腹腔注射5mg/kg）可阻断急性可卡因诱导的运动，但导致镇静。此外，与它的对映体（R）-（+）-HA-966不同，所测试的（S）-（-）-HA-966的最高剂量抑制了对照大鼠的体重增加。由于有人提出（S）-（-）-HA-966作用于γ-氨基丁酸（GABA）B受体，我们检测了（S）-（-）-和（R）-（+）-HA-966从皮质膜上置换[3H]-（-）-巴氯芬以评估GABAB受体结合的能力。在相关浓度下，两种对映体均未显著改变[3H]-（-）-巴氯芬的结合，表明此处报道的（S）-（-）-HA-966的作用是一种明显独立于GABAB受体上巴氯芬结合位点的机制的结果。
