α2 Adrenergic and Imidazoline Receptor Agonists Prevent Cue-Induced Cocaine Seeking
α2 Adrenergic and Imidazoline Receptor Agonists Prevent Cue-Induced Cocaine Seeking
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DOI：
10.1016/j.biopsych.2011.06.010
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发表时间：
2011-10-15
影响因子：
10.6
通讯作者：
Aston-Jones, Gary
中科院分区：
文献类型：
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作者：
Smith, Rachel J.;Aston-Jones, Gary
背景资料：药物相关的线索可以引起成瘾个体的应激样反应，表明线索和应激诱导的药物复吸可能有一些共同的神经机制。目前还不清楚是否α（2）肾上腺素能受体激动剂，这是已知的衰减压力诱导的恢复药物寻求在rats，也减少线索诱导restoration.Methods：大鼠进行了测试恢复药物寻求可卡因自我管理和灭绝。我们首先评估了可乐定（α 2和咪唑啉-1（I-1）受体激动剂）对可卡因寻求复发的影响。为了探索可乐定的作用的可能机制，我们然后测试了更具体的α（2）或I-1激动剂，突触后肾上腺素能受体（α（1）和β）拮抗剂，和促肾上腺皮质激素释放因子受体-1 antagonists.Results：我们发现，可乐定，和更有选择性的α（2）激动剂UK-14，304和guanfacine，减少线索诱导的可卡因寻求的恢复。特异性I-1受体激动剂莫索尼定减少线索诱导以及可卡因诱导的复吸。选择性α（2）受体拮抗剂RS-79948可以逆转可乐定或莫索尼定对线索诱导的恢复的影响，表明α（2）受体的作用。哌唑嗪和普萘洛尔分别是α（1）和β受体的拮抗剂，仅在联合给药时才能减少提示诱导的恢复。最后，促肾上腺皮质激素释放因子受体-1拮抗剂CP-154，526减少线索诱导的恢复，如以前观察到的压力诱导的恢复，表明压力和线索mechanism.Conclusions之间可能存在重叠：这些结果表明，α（2）和I-1受体激动剂是预防线索诱导的可卡因复发的新的治疗选择。鉴于α（2）受体刺激与人体镇静作用有关，I-1激动剂莫索尼定似乎具有治疗成瘾性疾病的巨大潜力。
Background: Drug-associated cues can elicit stress-like responses in addicted individuals, indicating that cue-and stress-induced drug relapse may share some neural mechanisms. It is unknown whether alpha(2) adrenergic receptor agonists, which are known to attenuate stress-induced reinstatement of drug seeking in rats, also reduce cue-induced reinstatement.Methods: Rats were tested for reinstatement of drug seeking following cocaine self-administration and extinction. We first evaluated the effects of clonidine, an agonist at alpha(2) and imidazoline-1 (I-1) receptors, on relapse to cocaine seeking. To explore possible mechanisms of clonidine's effects, we then tested more specific alpha(2) or I-1 agonists, postsynaptic adrenergic receptor (alpha(1) and beta) antagonists, and corticotropin-releasing factor receptor-1 antagonists.Results: We found that clonidine, and the more selective alpha(2) agonists UK-14,304 and guanfacine, decreased cue-induced reinstatement of cocaine seeking. The specific I-1 receptor agonist moxonidine reduced cue-induced as well as cocaine-induced reinstatement. Clonidine or moxonidine effects on cue-induced reinstatement were reversed by the selective alpha(2) receptor antagonist RS-79948, indicating a role for alpha(2) receptors. Prazosin and propranolol, antagonists at the alpha(1) and beta receptor, respectively, reduced cue-induced reinstatement only when administered in combination. Finally, the corticotropin-releasing factor receptor-1 antagonist CP-154,526 reduced cue-induced reinstatement, as previously observed for stress-induced reinstatement, indicating possible overlap between stress and cue mechanisms.Conclusions: These results indicate that alpha(2) and I-1 receptor agonists are novel therapeutic options for prevention of cue-induced cocaine relapse. Given that alpha(2) receptor stimulation is associated with sedation in humans, the I-1 agonist moxonidine seems to have substantial potential for treating addictive disorders.