α(2)肾上腺素能和咪唑啉受体激动剂可预防线索诱导的可卡因觅药行为。
α(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking.
机构信息
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
出版信息
Biol Psychiatry. 2011 Oct 15;70(8):712-719. doi: 10.1016/j.biopsych.2011.06.010. Epub 2011 Jul 23.
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 α(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 α(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 α(2) or I(1) agonists, postsynaptic adrenergic receptor (α(1) and β) antagonists, and corticotropin-releasing factor receptor-1 antagonists.
RESULTS
We found that clonidine, and the more selective α(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 α(2) receptor antagonist RS-79948, indicating a role for α(2) receptors. Prazosin and propranolol, antagonists at the α(1) and β 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 α(2) and I(1) receptor agonists are novel therapeutic options for prevention of cue-induced cocaine relapse. Given that α(2) receptor stimulation is associated with sedation in humans, the I(1) agonist moxonidine seems to have substantial potential for treating addictive disorders.
背景
药物线索会引起成瘾个体的应激样反应，这表明线索和应激诱导的药物复吸可能存在一些共同的神经机制。目前尚不清楚，α2 肾上腺素能受体激动剂是否能减轻大鼠应激诱导的觅药行为复吸，同时也能减少线索诱导的复吸。
方法
通过可卡因自我给药和消退来测试大鼠的觅药行为复吸。我们首先评估了可乐定（α2 和咪唑啉-1（I1）受体激动剂）对可卡因觅药行为复吸的影响。为了探讨可乐定作用的可能机制，我们随后测试了更特异的 α2 或 I1 激动剂、突触后肾上腺素能受体（α1 和 β）拮抗剂和促肾上腺皮质激素释放因子受体-1 拮抗剂。
结果
我们发现，可乐定和更特异的 α2 激动剂 UK-14304 和胍法辛降低了线索诱导的可卡因觅药行为复吸。特异性 I1 受体激动剂莫索尼定降低了线索诱导和可卡因诱导的复吸。选择性 α2 受体拮抗剂 RS-79948 逆转了可乐定或莫索尼定对线索诱导的复吸作用，表明 α2 受体起作用。α1 和 β 受体的拮抗剂哌唑嗪和普萘洛尔仅在联合给药时才降低线索诱导的复吸。最后，促肾上腺皮质激素释放因子受体-1 拮抗剂 CP-154526 降低了线索诱导的复吸，正如先前观察到的应激诱导的复吸一样，这表明应激和线索机制之间可能存在重叠。
结论
这些结果表明，α2 和 I1 受体激动剂是预防线索诱导的可卡因复吸的新的治疗选择。鉴于 α2 受体刺激与人类镇静有关，I1 激动剂莫索尼定似乎具有治疗成瘾障碍的巨大潜力。
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