Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: Comparison between cocaine and a potent conventional reinforcer
Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: Comparison between cocaine and a potent conventional reinforcer
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DOI：
10.1523/jneurosci.0176-04.2004
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发表时间：
2004-05-19
影响因子：
5.3
通讯作者：
Weiss, F
中科院分区：
文献类型：
--
作者：
Baptista, MAS;Martin-Fardon, R;Weiss, F
代谢型谷氨酸受体（mGluRs）与调节焦虑、应激反应以及精神兴奋剂的神经行为效应有关。本研究旨在确定强效的mGlu2/3受体激动剂（-）-2 - 氧杂 - 4 - 氨基双环己烷 - 4,6 - 二羧酸（LY379268）对II组mGluR的激活是否能拮抗由可卡因相关刺激诱导的可卡因寻求行为的复燃，以及这种效应是否延伸到由与强效常规强化物（甜炼乳，SCM）相关的刺激所诱导的行为。此外，我们还测试了LY379268对条件性复燃的抑制作用是否延伸到可卡因或SCM的初级强化作用。大鼠被训练将辨别性刺激（S - D）与可卡因或SCM的可得性以及无奖励相关联，然后进行反复的消退训练，在此期间相应的强化物和S - D被取消。随后再次暴露于可卡因或SCM的S - D（而非无奖励的S - D）会使之前活跃的操作杆上的反应恢复。LY379268（0.3 - 3.0 mg/kg，皮下注射）剂量依赖性地减弱可卡因寻求行为的恢复，但仅在最高剂量时减少由SCM的S - D引起的条件性复燃。LY379268不会改变由SCM直接强化的反应，并且只有最高剂量的LY379268会减少可卡因的自身给药。结果表明，LY379268的作用对由可卡因维持的行为具有选择性，而非对可口的常规强化物。更重要的是，结果显示LY379268对由与可卡因或SCM相关的刺激所激发的行为的抑制作用比对由这些物质的非条件作用所维持的摄取行为更有效。因此，结果确定II组mGluRs是与可卡因线索暴露相关的渴求及预防复发的药物治疗靶点。
Metabotropic glutamate receptors (mGluRs) have been implicated in regulating anxiety, stress responses, and the neurobehavioral effects of psychostimulants. The present study sought to determine whether group II mGluR activation by the potent mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), antagonizes reinstatement of cocaine-seeking induced by cocaine-related stimuli and whether this effect extends to behavior induced by stimuli conditioned to a potent conventional reinforcer, sweetened condensed milk (SCM). Also, we tested whether the suppressant effects of LY379268 on conditioned reinstatement extend to the primary reinforcing effects of cocaine or SCM. Rats were trained to associate discriminative stimuli (S-D) with the availability of cocaine or SCM versus non-reward and then subjected to repeated extinction sessions during which the respective reinforcers and SD were withheld. Subsequent reexposure to the cocaine or SCM S-D, but not the non-reward S-D, produced recovery of responding at the previously active lever. LY379268 (0.3 - 3.0 mg/ kg, s.c.) dose-dependently attenuated recovery of cocaine seeking but reduced conditioned reinstatement by the SCM S-D only at the highest dose. LY379268 did not alter responding reinforced directly by SCM, and only the highest LY379268 dose reduced cocaine self-administration. The results suggest that the effects of LY379268 are selective for behavior maintained by cocaine as opposed to palatable conventional reinforcers. More importantly, the results show that LY379268 suppresses behavior motivated by stimuli conditioned to cocaine or SCM more effectively than consummatory behavior maintained by the unconditioned effects of these substances. As such, the results identify group II mGluRs as a pharmacotherapeutic target for craving and relapse prevention associated with cocaine cue exposure.