Cue-conditioned alcohol seeking in rats following abstinence: involvement of metabotropic glutamate 5 receptors
Cue-conditioned alcohol seeking in rats following abstinence: involvement of metabotropic glutamate 5 receptors
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DOI：
10.1111/j.1476-5381.2009.00562.x
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发表时间：
2010-02-01
影响因子：
7.3
通讯作者：
Lawrence, A. J.
中科院分区：
文献类型：
--
作者：
Adams, C. L.;Short, J. L.;Lawrence, A. J.
背景和目的：本研究设计为：（i）检查已知调节酒精自我给药的受体之间是否发生功能性相互作用;和（ii）表征戒酒后酒精寻求的复发。导致乙醇偏好印第安纳州偏好大鼠乙醇自我给药的剂量依赖性减少。然后将SR 141716 A与选择性谷氨酸代谢型谷氨酸5（mGlu（5））受体拮抗剂3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶（MTEP）或选择性腺苷A（2A）受体拮抗剂SCH 58261共同给药。关键结果：当以单独的阈下剂量给药时，SR 141716 A（0.1 mg中心点kg-1）和SCH 58261（0.5 mg中心点kg-1 i. p.）产生了减少（28%）乙醇自我管理。SR 141716 A（0.3 mg中心点kg-1）和SCH 58261（2.0 mg中心点kg-1，i. p.）导致酒精自我给药基本上增加了减少（68%）。CB 1和mGlu（5）受体拮抗剂单独亚阈值剂量联合给药不影响酒精自我给药;然而，SR 141716 A（0.3 mg中心点kg-1）和MTEP（1.0 mg中心点kg-1 i. p.）确实显著减少了乙醇自身给药（80%）。通过MTEP（1.0 mg中心点kg-1）与SR 141716 A（0.3 mg中心点kg-1 i. p.）联合给药预处理减弱了线索条件性酒精寻求。相比之下，SCH 58261（2.0 mg中心点kg-1）与SR 141716 A（0.3 mg中心点kg-1 i. p.）并没有减少线索条件酒精seeking.Conclusions和影响：腺苷A（2A）和大麻素CB 1受体调节酒精自我管理的加法，但结合低剂量的拮抗这些受体并没有阻止线索条件酒精寻求禁欲后。相比之下，mGlu（5）和CB 1受体的联合低剂量拮抗作用确实可以防止戒断后酒精寻求复发，这表明mGlu（5）受体在这种模式中发挥了重要作用。
Background and purpose:The current study was designed to: (i) examine whether functional interactions occur between receptors known to regulate alcohol self-administration; and (ii) characterize relapse to alcohol seeking following abstinence.Experimental approach:The selective cannabinoid CB1 receptor antagonist SR141716A (0.03-1.0 mg center dot kg-1 i.p.) resulted in a dose-dependent reduction in ethanol self-administration in ethanol-preferring Indiana-preferring rats. SR141716A was then co-administered with either the selective glutamate metabotropic glutamate 5 (mGlu(5)) receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) or the selective adenosine A(2A) receptor antagonist SCH58261.Key results:When administered at individually sub-threshold doses, a combination of SR141716A (0.1 mg center dot kg-1) and SCH58261 (0.5 mg center dot kg-1 i.p.) produced a reduction (28%) in ethanol self-administration. Combinations of threshold doses of SR141716A (0.3 mg center dot kg-1) and SCH58261 (2.0 mg center dot kg-1, i.p.) caused an essentially additive reduction (68%) in alcohol self-administration. A combination of individually sub-threshold doses of CB1 and mGlu(5) receptor antagonists did not affect alcohol self-administration; however, combined threshold doses of SR141716A (0.3 mg center dot kg-1) and MTEP (1.0 mg center dot kg-1 i.p.) did reduce ethanol self-administration markedly (80%). Cue-conditioned alcohol seeking was attenuated by pretreatment with MTEP (1.0 mg center dot kg-1) co-administered with SR141716A (0.3 mg center dot kg-1 i.p.). In contrast, SCH58261 (2.0 mg center dot kg-1) co-administered with SR141716A (0.3 mg center dot kg-1 i.p.) did not reduce cue-conditioned alcohol seeking.Conclusions and implications:Adenosine A(2A) and cannabinoid CB1 receptors regulated alcohol self-administration additively, but combined low-dose antagonism of these receptors did not prevent cue-conditioned alcohol seeking after abstinence. In contrast, combined low-dose antagonism of mGlu(5) and CB1 receptors did prevent relapse-like alcohol seeking after abstinence, suggesting a prominent role for mGlu(5) receptors in this paradigm.