High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice.
High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice.
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DOI：
10.1016/j.bcp.2015.08.083
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发表时间：
2015-10-15
影响因子：
5.8
通讯作者：
Zaveri NT
中科院分区：
文献类型：
--
作者：
Khroyan TV;Yasuda D;Toll L;Polgar WE;Zaveri NT
中脑边缘回路中烟碱乙酰胆碱受体 (nAChR) 的胆碱能信号传导参与可卡因和阿片类药物等滥用药物的奖赏效应。在小鼠研究中，非选择性 nAChR 拮抗剂美加明可阻断可卡因诱导的条件性位置偏好 (CPP) 和行为敏化。在亚型选择性 nAChR 拮抗剂中，β2 选择性拮抗剂二氢βerythroidine 和 α7 nAChR 拮抗剂甲基化乌头碱 (MLA)，但单独的 MLA 不能预防可卡因行为过敏。由于α3β4 nAChR亚型在可卡因的奖赏和行为效应中的作用尚不清楚，本研究研究了两种有效且选择性的α3β4 nAChR配体AT-1001和AT-1012对小鼠中可卡因诱导的CPP和行为敏化的获得的影响。在 5-30 毫克/公斤时，可卡因会产生强烈的 CPP，而仅在较高剂量（20-30 毫克/公斤）时才观察到运动活动的行为敏化。 AT-1001 (1–10 mg/kg) 或 AT-1012 (3–10 mg/kg) 预处理可阻断 5 mg/kg 可卡因诱导的 CPP，但不能阻断 30 mg/kg 可卡因诱导的 CPP。较低剂量的 AT-1001 (0.3–3 mg/kg) 和 AT-1012 (1–3 mg/kg) 不会影响 5 或 30 mg/kg 可卡因诱导的运动活动的增加。但在这些剂量下，AT-1001 可以阻断 30 mg/kg 可卡因诱导的运动敏化。这些结果表明 α3β4 nAChR 在可卡因的奖赏和行为效应中发挥作用，并且选择性 α3β4 nAChR 配体可以减弱可卡因诱导的行为现象。由于选择性 α3β4 nAChR 功能拮抗剂 AT-1001 也被证明可以阻断大鼠的尼古丁自我给药，因此目前的结果表明 α3β4 nAChR 可能是治疗可卡因成瘾以及可卡因-尼古丁共病成瘾的靶点。
Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 nAChR antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine. Since the role of the α3β4 nAChR subtype in the rewarding and behavioral effects of cocaine is unknown, the present study investigated the effect of two potent and selective α3β4 nAChR ligands, AT-1001 and AT-1012, on the acquisition of cocaine-induced CPP and behavioral sensitization in mice. At 5–30 mg/kg, cocaine produced robust CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20–30 mg/kg). Pretreatment with AT-1001 (1–10 mg/kg) or AT-1012 (3–10 mg/kg) blocked CPP induced by 5 mg/kg cocaine, but not by 30 mg/kg cocaine. Lower doses of AT-1001 (0.3–3 mg/kg) and AT-1012 (1–3 mg/kg) did not affect the increase in locomotor activity induced by 5 or 30 mg/kg cocaine. But AT-1001, at these doses, blocked locomotor sensitization induced by 30 mg/kg cocaine. These results indicate that the α3β4 nAChR play a role in the rewarding and behavioral effects of cocaine, and that selective α3β4 nAChR ligands can attenuate cocaine-induced behavioral phenomena. Since the selective α3β4 nAChR functional antagonist AT-1001 has also been shown to block nicotine self-administration in rats, the present results suggest that α3β4 nAChRs may be a target for the treatment of cocaine addiction as well as for cocaine-nicotine comorbid addiction.