Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
Eur J Neurosci. 2011 Jul;34(2):177-89. doi: 10.1111/j.1460-9568.2011.07769.x. Epub 2011 Jul 12.
Cocaine relapse can occur when cocaine-associated environmental cues induce craving. Conditioned place preference (CPP) is a behavioral paradigm modeling the association between cocaine exposure and environmental cues. The amygdala is involved in cocaine cue associations with the basolateral amygdala (BLA) and central amygdala (CeA) acting differentially in cue-induced relapse. Activation of metabotropic glutamate receptors induces synaptic plasticity, the mechanism of which is thought to underlie learning, memory and drug-cue associations. The goal of this study was to examine the neural alterations in responses to group I metabotropic glutamate receptor (mGluR) agonists in the BLA to lateral capsula of CeA (BLA-CeLc) pathway in slices from rats exposed to cocaine-CPP conditioning and withdrawn for 14 days. mGluR1, but not mGluR5, agonist-induced long-term potentiation (mGluR1-LTP) in the BLA-CeLc pathway was reduced in rats withdrawal from cocaine for 2 and 14 days, and exhibited an altered concentration response to picrotoxin. Cocaine withdrawal also reduced γ-aminobutyric acid (GABA)ergic synaptic inhibition in CeLc neurons. Blocking cannabinoid receptor 1 (CB(1) ) reduced mGluR1-LTP in the saline-treated but not cocaine-withdrawn group. Response to CB(1) but not CB(2) agonist was altered after cocaine. Additionally, increasing endocannabinoid (eCB) levels abolished mGluR1-LTP in the saline but not cocaine-withdrawn group. However, CB(1) and CB(2) protein levels were increased in the amygdala of cocaine-withdrawn rats while mGluR1 and mGluR5 remained unchanged. These data suggested that the mechanisms underlying the diminished mGluR1-LTP in cocaine-withdrawn rats involve an altered GABAergic synaptic inhibition mediated by modulation of downstream eCB signaling. These changes may ultimately result in potentiated responses to environmental cues that would bias behavior toward drug-seeking.
可卡因复吸会在与可卡因相关的环境线索引起渴望时发生。条件性位置偏爱（CPP）是一种行为范式，可模拟可卡因暴露与环境线索之间的关联。杏仁核参与可卡因线索与基底外侧杏仁核（BLA）和中央杏仁核（CeA）的关联，而 BLA 和 CeA 在线索诱导的复吸中作用不同。代谢型谷氨酸受体的激活诱导突触可塑性，其机制被认为是学习、记忆和药物线索关联的基础。本研究的目的是检查可卡因 CPP 条件暴露并戒断 14 天后大鼠杏仁核外侧被盖区（BLA）到 CeA 外侧被盖区（BLA-CeLc）通路中 I 组代谢型谷氨酸受体（mGluR）激动剂反应的神经变化。mGluR1 但不是 mGluR5 激动剂诱导的长时程增强（mGluR1-LTP）在可卡因戒断 2 天和 14 天的大鼠中减少，并且对 picrotoxin表现出改变的浓度反应。可卡因戒断还降低了 CeLc 神经元中的γ-氨基丁酸（GABA）能突触抑制。阻断大麻素受体 1（CB1）减少了生理盐水处理但不减少可卡因戒断组的 mGluR1-LTP。可卡因后对 CB1 但不是 CB2 激动剂的反应发生改变。此外，增加内源性大麻素（eCB）水平消除了生理盐水组中的 mGluR1-LTP，但可卡因戒断组没有。然而，可卡因戒断大鼠杏仁核中的 CB1 和 CB2 蛋白水平增加，而 mGluR1 和 mGluR5 保持不变。这些数据表明，可卡因戒断大鼠中 mGluR1-LTP 减少的机制涉及由下游 eCB 信号转导调节的 GABA 能突触抑制的改变。这些变化最终可能导致对环境线索的反应增强，从而偏向于觅药行为。
