Macquarie University, Department of Psychology, North Ryde, 2109, Australia.
Macquarie University, Department of Psychology, North Ryde, 2109, Australia.
Pharmacol Biochem Behav. 2019 Aug;183:64-71. doi: 10.1016/j.pbb.2019.06.002. Epub 2019 Jun 13.
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 μg/side) and METH-primed reinstatement (0, 0.33, 1.0, 3.0 μg/side). Finally, we quantified cFos immunofluorescence in the NAcc as a proxy for downstream neuronal activity following a PrL infusion of OXY (0, 1 μg/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.
对精神兴奋剂冰毒（METH）的成瘾以高复发率为特征。目前，尚无批准的有效药物治疗METH 依赖。神经肽催产素（OXY）可有效减少复发啮齿动物模型中的 METH 觅药行为，目前正在临床试验中用于治疗药物依赖个体。然而，OXY 在人体中的给药可能会受到其对大脑穿透力差的阻碍。因此，确定 OXY 减少 METH 复发的神经机制可能有助于开发改进的基于 OXY 的 METH 成瘾治疗方法。全身 OXY 给药与减轻 METH 诱导的前额皮质（PrL）活性有关；PrL 是一个关键的大脑区域，对奖励和成瘾回路的大部分区域都有控制作用。然而，尚不清楚 OXY 是否直接在 PrL 中作用以减少觅药和下游大脑活动。因此，本研究旨在确定 OXY 注入 PrL 是否会减少线索诱导和 METH 引发的复吸以及下游伏隔核核心（NAcc）中的 METH 诱导的神经元活动。雄性 Sprague Dawley 大鼠接受静脉 METH 自我给药、消退和随后的复吸测试。OXY 双侧注入 PrL 之前进行线索诱导（0、1μg/侧）和 METH 引发的复吸（0、0.33、1.0、3.0μg/侧）。最后，我们在 PrL 注射 OXY（0、1μg/侧）之前进行 METH 引发的复吸后，通过 NAcc 中的 cFos 免疫荧光来量化下游神经元活动。PrL 中的 OXY 显著减少了线索诱导和 METH 引发的复吸。此外，内 PrL OXY 减少了 NAcc 中头侧而非尾侧的 METH 诱导的 cFos 表达。这些发现表明，OXY 在 PrL 中的作用可减少 METH 觅药行为和奖励回路中的 METH 诱导的活动。此外，这些结果表明，系统给予 OXY 减少 METH 觅药行为的治疗效果可能涉及 PrL-NAc 通路。
