Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
Int J Mol Sci. 2022 Jul 23;23(15):8106. doi: 10.3390/ijms23158106.
Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-h, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats exhibited reduced stimulated dopamine release during tonic-like, single-pulse stimulations, but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5-100 Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor agonist responsivity were increased following heroin self-administration. These results reveal a marked low dopamine state following heroin exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.
海洛因的给药会导致多个脑区的参与，奖赏和成瘾效应至少部分通过中脑边缘多巴胺系统的激活来介导。然而，人们对慢性暴露于海洛因后多巴胺系统的功能知之甚少。从慢性海洛因暴露中戒断可能会导致伏隔核（NAc）中的多巴胺水平降低，正如以前观察到的从其他药物类别戒断时一样。因此，我们旨在研究慢性海洛因自我给药后 NAc 多巴胺末梢功能的变化，以确定多巴胺能适应的机制。成年雄性 Long Evans 大鼠被训练进行海洛因（0.05mg/kg/inf，IV）自我给药，然后进行长时间访问（FR1，6 小时，无限剂量，0.05mg/kg/inf）方案，以诱导摄入量增加。与盐水对照组相比，在 NAc 中，与海洛因挑战（0.1mg/kg/inf，IV）相比，海洛因暴露的大鼠的多巴胺基础细胞外水平降低，多巴胺反应减弱。FSCV 显示，与对照组相比，海洛因暴露的大鼠在单脉冲刺激的紧张样刺激期间表现出刺激多巴胺释放减少，但在多脉冲刺激（5 个脉冲，5-100Hz）期间表现出相位样多巴胺释放增加，以及刺激强度释放动态范围改变。此外，我们发现海洛因自我给药后，突触前 D3 自身受体和κ-阿片受体激动剂反应性增加。这些结果揭示了海洛因暴露后明显的低多巴胺状态，并表明多巴胺释放动力学的改变可能导致海洛因寻求增加。
