Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Ave., Rm. 115 Crowe, Memphis, TN 38163, USA.
Psychopharmacology (Berl). 2012 May;221(1):91-100. doi: 10.1007/s00213-011-2548-1. Epub 2011 Nov 16.
Glutamatergic projection neurons in the medial prefrontal cortex (mPFC) are hyperexcitable in cocaine-sensitized animals, resulting in increased excitatory output to addiction-associated regions such as the ventral tegmental area (VTA) and nucleus accumbens. Evidence suggests that Group I metabotropic glutamate receptor 5 (mGluR5) is necessary for cocaine sensitization, and stimulation of this receptor in the mPFC potentially alters cell excitability directly through glutamate release or indirectly through downstream signaling cascades.
Experiments in this report examined the role of mPFC mGluR5 in behavioral sensitization to cocaine. Group I mGluR agonist dihydroxyphenylglycine (DHPG) (15 nmol/side), mGluR5 antagonist 3((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) (15 nmol/side), mGluR1 antagonist YM298198 (15 nmol/side), AMPA receptor antagonist CNQX (1 nmol/side), and/or saline were administered through cannulae implanted 1 mm above the mPFC and/or VTA in male rats. Cocaine (15 mg/kg, i.p.) was systemically administered for four consecutive days to induce sensitization and/or once on test day immediately preceding locomotor monitoring.
Intra-mPFC DHPG induced an mGluR5-mediated cross-sensitization to cocaine preventable through the prior administration of an AMPA receptor antagonist in the VTA. Furthermore, mGluR5 blockade in the mPFC failed to prevent the initiation of sensitization. However, intra-mPFC injections of the mGluR5 antagonist MTEP prevented the expression of cocaine sensitization at 21, but not 7, days following daily cocaine injections suggesting a possible role for mPFC mGluR5 in the persistence of the cocaine-sensitized state.
These data suggest that stimulation of mGluR5s in the mPFC is sufficient to induce cocaine sensitization and is necessary for the expression of this sensitized response.
在可卡因敏化动物中，内侧前额叶皮质（mPFC）中的谷氨酸能投射神经元过度兴奋，导致兴奋性输出增加到与成瘾相关的区域，如腹侧被盖区（VTA）和伏隔核。有证据表明，I 组代谢型谷氨酸受体 5（mGluR5）是可卡因敏化所必需的，并且 mPFC 中该受体的刺激可能通过谷氨酸释放直接改变细胞兴奋性，或通过下游信号级联间接改变细胞兴奋性。
本报告中的实验研究了 mPFC mGluR5 在可卡因行为敏化中的作用。I 组 mGluR 激动剂二羟苯甘氨酸（DHPG）（15 nmol/侧）、mGluR5 拮抗剂 3-（2-甲基-4-噻唑基）乙炔基）吡啶（MTEP）（15 nmol/侧）、mGluR1 拮抗剂 YM298198（15 nmol/侧）、AMPA 受体拮抗剂 CNQX（1 nmol/侧）和/或生理盐水通过植入 mPFC 和/或 VTA 上方 1 毫米的套管给药。雄性大鼠连续 4 天系统给予可卡因（15 mg/kg，ip）以诱导敏化，或在运动监测前一天立即给予测试日一次可卡因。
mPFC 内的 DHPG 诱导了可卡因的 mGluR5 介导的交叉敏化，这种敏化可以通过在 VTA 中预先给予 AMPA 受体拮抗剂来预防。此外，mPFC 内 mGluR5 阻断未能阻止敏化的发生。然而，mPFC 内注射 mGluR5 拮抗剂 MTEP 可预防可卡因敏化的表达，但在 21 天而不是 7 天后，这表明 mPFC mGluR5 可能在可卡因敏化状态的持续存在中起作用。
这些数据表明，mPFC 中 mGluR5 的刺激足以诱导可卡因敏化，并且是表达这种敏化反应所必需的。
