Departamento de Fisiologia Medica y Biofisica, Universidad de Sevilla, 41009 Sevilla, Spain.
Neuroscience. 2010 May 5;167(2):205-15. doi: 10.1016/j.neuroscience.2010.02.019. Epub 2010 Feb 16.
Reinforcing effects mediated by accumbal CB(1) receptors (CB(1)R) are controversial, as well as their role in the rewarding effects of cocaine. Accumbal glutamate and glutamate receptors have been proposed to be involved in CB(1)R-mediated effects on cocaine reward. Rewarding effects of cocaine can be evaluated with the conditioned place preference or CPP test. Rimonabant, a cannabinoid CB(1)R ligand, lentiviruses aimed at silencing CB(1)R, and selective glutamatergic ligands are good tools for studying the function of accumbal CB(1) and glutamate receptors. The objectives of the present study were (i) to discern the CPP effects of in vivo gene silencing of accumbal CB(1) receptors by means of lentiviruses containing siRNAs; (ii) to discern the CPP effects of intra-accumbens infusions of the cannabinoid CB(1)R ligand rimonabant, and to evaluate whether effects are due to receptor blockade or inverse agonism; (iii) to discern the role of CB(1)R located within the nucleus accumbens shell in the rewarding effects of cocaine, by means of local infusions of rimonabant, and (iv) to discern the role of glutamate receptors (AMPAR, NMDAR, mGluR2/3) in rimonabant-induced effects on CPP in cocaine-treated rats. The findings revealed that in vivo silencing of accumbal CB(1) receptors with Lenti-CB(1)R-siRNAs induced place aversion to cocaine, but intra-accumbal rimonabant induced place preference in its own right, indicating that this compound seems to act as inverse agonist on the CPP. Glutamate receptors participate in rimonabant-mediated place preference because it was abolished after blocking AMPA glutamate receptors, but not NMDAR or mGluR2/3. Finally, in cocaine-treated rats, local rimonabant induced place aversion to the drug (not place preference), and this effect was mediated by glutamate neurotransmission because it was abolished after blockade of AMPA, NMDA or mGlu2/3 receptors, even though only the blockade of mGlu2/3 autoreceptors restored the emergence of place preference to cocaine.
伏隔核内 CB1 受体（CB1R）介导的强化作用存在争议，其在可卡因奖赏效应中的作用也存在争议。伏隔核内谷氨酸和谷氨酸受体被认为参与 CB1R 介导的可卡因奖赏效应。可卡因的奖赏效应可以通过条件位置偏好或 CPP 测试来评估。大麻素 CB1R 配体利莫那班、旨在沉默 CB1R 的慢病毒以及选择性谷氨酸能配体是研究伏隔核内 CB1 和谷氨酸受体功能的良好工具。本研究的目的是：（i）通过含有 siRNA 的慢病毒来辨别伏隔核内 CB1 受体的体内基因沉默对 CPP 的影响；（ii）辨别内伏隔核内给予大麻素 CB1R 配体利莫那班对 CPP 的影响，并评估这些影响是否归因于受体阻断或反向激动作用；（iii）通过局部给予利莫那班来辨别位于伏隔核壳内的 CB1R 在可卡因奖赏效应中的作用，以及（iv）辨别谷氨酸受体（AMPA、NMDAR、mGluR2/3）在利莫那班诱导可卡因处理大鼠 CPP 中的作用。研究结果表明，用 Lenti-CB1R-siRNAs 对伏隔核内 CB1 受体进行体内沉默会导致对可卡因的位置厌恶，但内伏隔核内的利莫那班会自行引起位置偏好，表明该化合物似乎对 CPP 表现出反向激动作用。谷氨酸受体参与利莫那班介导的位置偏好，因为阻断 AMPA 谷氨酸受体后该作用被消除，但阻断 NMDAR 或 mGluR2/3 受体后不会消除。最后，在可卡因处理的大鼠中，局部利莫那班诱导对药物的位置厌恶（而不是位置偏好），并且这种作用是由谷氨酸能神经传递介导的，因为阻断 AMPA、NMDA 或 mGlu2/3 受体后，这种作用被消除，即使仅阻断 mGlu2/3 自身受体也能恢复对可卡因的位置偏好。
