边缘下皮质脑区微注射克仑特罗对线索诱导海洛因复吸的抑制作用

Infusion of clenbuterol into infralimbic cortex attenuates cue-induced reinstatement of heroin-seeking behavior

目的观察边缘下皮质(IL)脑区注射β2肾上腺素受体激动剂克仑特罗对海洛因自身给药大鼠复吸行为的影响。方法成年雄性SD大鼠采用固定比率F1程序进行海洛因自身给药训练,每天4 h,连续14 d,建立海洛因自身给药模型。随后每天进行2 h环境消退,直至达到消退标准。每侧IL脑区微注射克仑特罗8 ng,15 min后进行线索诱导的海洛因觅药行为的测定,观察大鼠自主运动情况。行为测试结束后立即处死取脑组织,Western蛋白印迹法检测边缘前皮质、IL、伏隔核壳部及核部脑区磷酸化c AMP反应元件结合蛋白(p CREB)表达水平变化。结果在线索诱导的海洛因觅药行为测试中,克仑特罗组的有效鼻触数(8±3)显著低于模型组(45±10)(P<0.01);2 h自发活动度检测中,克仑特罗组大鼠自发活动度(1557±369)和模型组(1514±264)相比无显著性差异;Western蛋白印迹法检测显示,与模型组相比,克仑特罗组大鼠的IL和伏隔核壳部的p-CREB表达均明显减少(P<0.05),而核部的p-CREB表达显著增加(P<0.01)。结论IL脑区微注射克仑特罗可显著抑制海洛因自身给药大鼠的复吸行为,其抑制作用可能与伏隔核壳部和核部p CREB表达改变有关。

OBJECTIVE To investigate the effect of injection of β2- adrenergic receptor agonist clenbuterol into the infralimbic cortex（IL） on drug- seeking behavior triggered by conditioned cues.METHODS Adult male SD rats were trained to self- administer heroin under a FR1 schedule for consecutive 14 d,followed by 2-h extinction training. Cue-induced heroin seeking was measured for 2 h.Clenbuterol was microinjected bilaterally into the IL（8 ng/side）of rats 15 min prior to reinstatement test.Meanwhile,locomotor activity was detected 15 min after clenbuterol or artifial cerebrospinal fluid（model group） was microinjected bilaterally into IL. Western blotting was used to detect the expression of phosphorylated cyclic AMP response element-binding protein（p-CREB）in the prelimbic cortex（PL）,IL,nucleus accumbens core（NACc） and shell（NACsh） of rats immediately after reinstatement test.RESULTS After heroin administration training for 14 consecutive days,these animals exhibited reliable heroin self-administration,indicated by the increase in active nose poke responses and infusions. The rats that had received infusion of clenbuterol into the IL had significantly lower active pokes（8±3）than those in model group（45±10）in cue-induced reinstatement（P〈0.01）,but there was no significant difference between clenbuterol group and vehicle group in the locomotor activity. The expression of p-CREB in either IL or NACsh was significantly decreased in clenbuterol group compared with model group（P〈0.01,P〈0.05）,but significantly increased in NACc（P〈0.01）. CONCLUSION Microinjection of clenbuterol into the IL can attenuate the cue-induced reinstatement of heroin-seeking behavior in rats. The underlying mechanism might be related to the regulation of p-CREB expression in the NACc and NACsh.