Howard Florey Institute, Parkville, Vic., Australia.
Br J Pharmacol. 2010 Feb 1;159(3):534-42. doi: 10.1111/j.1476-5381.2009.00562.x. Epub 2010 Jan 8.
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.
The selective cannabinoid CB(1) receptor antagonist SR141716A (0.03-1.0 mg.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.
When administered at individually sub-threshold doses, a combination of SR141716A (0.1 mg.kg(-1)) and SCH58261 (0.5 mg.kg(-1) i.p.) produced a reduction (28%) in ethanol self-administration. Combinations of threshold doses of SR141716A (0.3 mg.kg(-1)) and SCH58261 (2.0 mg.kg(-1), i.p.) caused an essentially additive reduction (68%) in alcohol self-administration. A combination of individually sub-threshold doses of CB(1) and mGlu(5) receptor antagonists did not affect alcohol self-administration; however, combined threshold doses of SR141716A (0.3 mg.kg(-1)) and MTEP (1.0 mg.kg(-1) i.p.) did reduce ethanol self-administration markedly (80%). Cue-conditioned alcohol seeking was attenuated by pretreatment with MTEP (1.0 mg.kg(-1)) co-administered with SR141716A (0.3 mg.kg(-1) i.p.). In contrast, SCH58261 (2.0 mg.kg(-1)) co-administered with SR141716A (0.3 mg.kg(-1) i.p.) did not reduce cue-conditioned alcohol seeking.
Adenosine A(2A) and cannabinoid CB(1) 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 CB(1) receptors did prevent relapse-like alcohol seeking after abstinence, suggesting a prominent role for mGlu(5) receptors in this paradigm.
本研究旨在：(i) 检测已知调节酒精自饮的受体间是否存在功能相互作用；及(ii) 描述酒精戒断后觅酒行为的复燃。
选择性大麻素 CB1 受体拮抗剂 SR141716A（0.03-1.0 mg.kg-1 腹腔注射）可剂量依赖性地减少酒精偏爱型印度酒精偏爱大鼠的乙醇自我给药。然后将 SR141716A 与选择性谷氨酸代谢型谷氨酸 5（mGlu5）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 A2A 受体拮抗剂 SCH58261 联合给药。
当以单独的亚阈值剂量给药时，SR141716A（0.1 mg.kg-1）和 SCH58261（0.5 mg.kg-1 腹腔注射）的组合可使乙醇自我给药减少（28%）。SR141716A（0.3 mg.kg-1）和 SCH58261（2.0 mg.kg-1，腹腔注射）的阈剂量组合导致酒精自我给药的减少基本为相加性（68%）。单独亚阈值剂量的 CB1 和 mGlu5 受体拮抗剂的组合不影响酒精自我给药；然而，SR141716A（0.3 mg.kg-1）和 MTEP（1.0 mg.kg-1 腹腔注射）的联合阈剂量可显著减少乙醇自我给药（80%）。MTEP（1.0 mg.kg-1 腹腔注射）预处理可减弱线索诱发的酒精觅酒行为，同时 SR141716A（0.3 mg.kg-1 腹腔注射）也能减弱线索诱发的酒精觅酒行为。相反，SR141716A（0.3 mg.kg-1 腹腔注射）与 SCH58261（2.0 mg.kg-1）联合给药并不减少线索诱发的酒精觅酒行为。
腺苷 A2A 和大麻素 CB1 受体以相加的方式调节酒精自我给药，但这些受体的联合低剂量拮抗并不能防止酒精戒断后的线索诱发的觅酒行为。相比之下，mGlu5 和 CB1 受体的联合低剂量拮抗可防止酒精戒断后的觅酒行为复燃，表明 mGlu5 受体在此模型中起主要作用。
