Shalev U, Morales M, Hope B, Yap J, Shaham Y
Behavioral Neuroscience Branch, IRP/NIDA/NIH, Baltimore, MD 21224, USA.
Psychopharmacology (Berl). 2001 Jun;156(1):98-107. doi: 10.1007/s002130100748.
Footshock stress reliably reinstates heroin seeking in rats, but the time course of the development of this effect following drug withdrawal is not known. Here we studied the effect of intermittent footshock stress on reinstatement of heroin seeking following different withdrawal periods (1-66 days). We also studied whether changes in corticotropin-releasing factor (CRF) mRNA in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) are correlated with this reinstatement after 1 day and 6 days of heroin withdrawal.
Rats were trained to self-administer heroin (9 h/day; 0.1 mg/kg per infusion) for 10 days. Tests for extinction behavior and footshock-induced reinstatement of heroin seeking were then conducted after 1, 6, 12, 25, or 66 days of heroin withdrawal. On the test day, rats were given five to ten 60-min extinction sessions until they reached the extinction criterion of less than 15 responses per 60 min on the lever previously associated with heroin. Rats were then exposed to intermittent foot-shock (0.8 mA; 10 min), and lever-pressing behavior was recorded for 120 min.
Reinstatement of lever-pressing behavior by footshock followed an inverted U-shaped curve with maximal responding after 6 days and 12 days of heroin withdrawal. Surprisingly, foot-shock did not reinstate lever-pressing behavior on day 1 of withdrawal. Lever pressing during extinction, prior to exposure to footshock, also followed an inverted U-shaped curve, with higher responding after 6, 12, and 25 days of heroin withdrawal. Finally, compared with control groups not exposed to shock, CRF mRNA levels in response to footshock were increased in the CeA (day 1 of withdrawal) and the dorsal BNST (day 1 and day 6), but not in the ventral BNST.
The duration of the heroin withdrawal period is an important factor in the manifestation of (1) footshock stress-induced reinstatement of heroin seeking and (2) extinction of the heroin-reinforced behavior. Finally, the time-dependent changes in footshock stress-induced reinstatement following withdrawal from heroin were not correlated with alterations in CRF mRNA in the CeA and BNST.
足底电击应激能可靠地使大鼠恢复海洛因觅求行为，但药物戒断后这种效应产生的时间进程尚不清楚。在此，我们研究了间歇性足底电击应激对不同戒断期（1 - 66天）后海洛因觅求行为恢复的影响。我们还研究了杏仁核中央核（CeA）和终纹床核（BNST）中促肾上腺皮质激素释放因子（CRF）mRNA的变化与海洛因戒断1天和6天后这种恢复是否相关。
大鼠接受为期10天的海洛因自我给药训练（每天9小时；每次注射0.1mg/kg）。然后在海洛因戒断1、6、12、25或66天后进行消退行为测试以及足底电击诱导的海洛因觅求行为恢复测试。在测试当天，给予大鼠五到十次60分钟的消退训练，直到它们达到在先前与海洛因相关的杠杆上每60分钟反应少于15次的消退标准。然后让大鼠暴露于间歇性足底电击（0.8mA；10分钟），并记录120分钟的杠杆按压行为。
足底电击引起的杠杆按压行为恢复呈倒U形曲线，在海洛因戒断6天和12天后反应最大。令人惊讶的是，在戒断第1天足底电击并未恢复杠杆按压行为。在暴露于足底电击之前的消退过程中的杠杆按压也呈倒U形曲线，在海洛因戒断6、12和25天后反应更高。最后，与未接受电击的对照组相比，CeA（戒断第1天）和背侧BNST（戒断第1天和第6天）中对足底电击反应的CRF mRNA水平升高，但腹侧BNST中未升高。
海洛因戒断期的时长是（1）足底电击应激诱导的海洛因觅求行为恢复和（2）海洛因强化行为消退表现的一个重要因素。最后，海洛因戒断后足底电击应激诱导的恢复的时间依赖性变化与CeA和BNST中CRF mRNA的改变无关。
