Department of Pharmacology and Pharmacodynamics, Medical University, Staszica 4, 20-081 Lublin, Poland.
Neurotox Res. 2011 Jan;19(1):23-30. doi: 10.1007/s12640-009-9136-8. Epub 2009 Nov 21.
Cocaine abuse and dependence is a worldwide health problem. However, there are no currently approved medications to reduce cocaine abuse/relapse and toxicity. The aim of the present study was to test, whether group I metabotropic glutamate receptors (mGluRs) antagonists (mGluR1 and mGluR5) differentially regulate toxic versus behavioral effects of cocaine, both phenomena relevant to the psychopathology of cocaine addiction in humans. In the present study, we assessed the impact of mGluR1 antagonist-EMQMCM and mGluR5 antagonist-MTEP on the cocaine-induced lethality and the expression of sensitization to hyperlocomotor effect of cocaine in mice. Our study indicated that EMQMCM and MTEP, both substances at the doses of 5 and 10 mg/kg (but not 2.5 mg/kg), decreased cocaine-induced lethality produced by 75 mg/kg of cocaine, which was given acutely. The effect of EMQMCM was dose-dependent, and this compound at the dose of 10 mg/kg almost completely abolished the lethality induced by cocaine. MTEP reduced this cocaine effect at the doses of 5 and 10 mg/kg, equally. Furthermore, EMQMCM (1.25-5 mg/kg) at the doses of 2.5 and 5.0 mg/kg, and MTEP (2.5-10 mg/kg) only at the highest dose of 10 mg/kg, significantly reduced the expression of cocaine-induced (10 mg/kg) behavioral sensitization. Our results suggest that stimulation of mGluR1 and mGluR5 is involved in lethal effect of cocaine overdose and cocaine seeking behavior evaluated in behavioral sensitization test. However, the participation of mGluR1 in these cocaine effects seems to be dominant. Therefore, antagonists showing preferences towards mGluR1 might be useful in therapy of cocaine toxicity and abuse.
可卡因滥用和依赖是一个全球性的健康问题。然而，目前没有批准的药物可以减少可卡因滥用/复发和毒性。本研究的目的是测试 I 型代谢型谷氨酸受体（mGluR）拮抗剂（mGluR1 和 mGluR5）是否能调节可卡因的毒性和行为效应，这两种现象都与可卡因成瘾的精神病理学有关。在本研究中，我们评估了 mGluR1 拮抗剂 EMQMCM 和 mGluR5 拮抗剂 MTEP 对可卡因诱导的致死性和可卡因引起的过度运动效应敏化表达的影响。我们的研究表明，EMQMCM 和 MTEP（均为 5 和 10mg/kg 剂量，但 2.5mg/kg 剂量除外）降低了 75mg/kg 可卡因急性给药引起的致死性。EMQMCM 的作用呈剂量依赖性，该化合物在 10mg/kg 剂量下几乎完全消除了可卡因引起的致死性。MTEP 在 5 和 10mg/kg 剂量下降低了这种可卡因效应，效果相等。此外，EMQMCM（2.5-5mg/kg）和 MTEP（2.5-10mg/kg）仅在 10mg/kg 的最高剂量下显著降低了可卡因（10mg/kg）诱导的行为敏化表达。我们的结果表明，mGluR1 和 mGluR5 的刺激参与了可卡因过量的致死效应和行为敏化试验中评估的可卡因寻求行为。然而，mGluR1 在这些可卡因效应中的参与似乎更为重要。因此，对 mGluR1 具有选择性的拮抗剂可能对治疗可卡因毒性和滥用有用。
