Oxytocin treatment in the prelimbic cortex reduces relapse to methamphetamine-seeking and is associated with reduced activity in the rostral nucleus accumbens core
Oxytocin treatment in the prelimbic cortex reduces relapse to methamphetamine-seeking and is associated with reduced activity in the rostral nucleus accumbens core
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DOI：
10.1016/j.pbb.2019.06.002
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发表时间：
2019-08-01
影响因子：
3.6
通讯作者：
Cornish, Jennifer
中科院分区：
文献类型：
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作者：
Everett, Nicholas;Baracz, Sarah;Cornish, Jennifer
对精神刺激剂甲基苯丙胺(冰毒)的上瘾以高复发率为特征。目前还没有被批准的有效的药物疗法来治疗冰毒依赖。神经肽催产素(Oxy)有效地减少了复发啮齿动物模型中的冰毒寻找行为，目前正被用于治疗药物依赖者的临床试验。然而，Oxy在人类体内的给药可能会因其对大脑的渗透能力较差而受到阻碍。因此，确定Oxy减少冰毒复发的神经机制可能会指导改进的基于Oxy的冰毒治疗方法的发展。全身服用Oxy与减弱冰毒诱导的前皮质(PRL)活动有关；PRL是大脑的一个关键区域，控制着大部分奖赏和成瘾回路。然而，目前尚不清楚Oxy是否直接作用于PRL，导致药物寻找和下游大脑活动的减少。因此，本研究试图确定将Oxy注入PRL是否降低了线索诱导和冰毒引发的恢复以及冰毒诱导的伏隔核下游核(NAcc)神经元的活动。雄性SpragueDawley大鼠接受了静脉注射冰毒自我给药、灭绝和随后的恢复测试。在线索诱导(0，1微克/侧)和冰毒恢复(0，0.33，1.0，3.0微克/侧)之前，将Oxy注入双侧PRL。最后，我们量化了NAcc中CFos的免疫荧光，以此作为下游神经元活动的替代指标，在甲基引发的恢复之前，注射Oxy(0.1微克/侧)。PRL中的Oxy显著减少了线索诱导和冰毒引发的恢复。此外，PRL Oxy可减少冰毒诱导的NAcc吻极CFos的表达，但不能减少其尾极CFos的表达。这些发现表明，Oxy在PRL中的作用是减少寻求冰毒的行为和奖赏环路中的冰毒诱导活动。此外，这些结果表明，全身给药Oxy减少冰毒行为的治疗作用可能与PRL-NAC途径有关。
Addiction to the psychostimulant Methamphetamine (METH) is characterised by high rates of relapse. Currently there are no approved effective pharmacotherapies for METH dependence. The neuropeptide oxytocin (OXY) potently reduces METH-seeking behaviours in rodent models of relapse and is now being used in clinical trials to treat drug-dependent individuals. However, OXY administration in humans may be impeded by its poor penetration of the brain. Therefore, identification of the neural mechanisms by which OXY reduces METH relapse may guide the development of improved OXY-based therapies for METH addiction. Systemic OXY administration is associated with attenuated METH-induced activity in the prelimbic cortex (PrL); a key brain region which exerts control over much of the reward and addiction circuitry. However, it is not known whether OXY acts directly in the PrL to cause reductions in drug-seeking and downstream brain activity. Therefore, the present study sought to determine whether OXY infused into the PrL reduces cue-induced and METH-primed reinstatement and METH-induced neuronal activity in the downstream nucleus accumbens core (NAcc). Male Sprague Dawley rats underwent intravenous METH self-administration, extinction, and subsequent reinstatement tests. OXY was infused bilaterally into the PrL prior to cue-induced (0, 1 mu g/side) and METH-primed reinstatement (0,0.33,1.0,3.0 mu g/side). Finally, we quantified cFos immunofluorescence in the NAcc as a proxy for downstream neuronal activity following a PrL infusion of OXY (0,1 mu g/side) prior to METH-primed reinstatement. OXY in the PrL significantly reduced both cue-induced and METH-primed reinstatement. Additionally, intra-PrL OXY reduced METH-induced cFos expression in the rostral but not caudal pole of the NAcc. These findings demonstrate OXY action in the PrL in reducing METH-seeking behaviours and METH-induced activity in the reward circuit. Furthermore, these results suggest that the therapeutic effects of systemically administered OXY on reducing METH-seeking behaviours may involve the PrL-NAc pathway.