Pour Mozhgan Ghobadi, Alaei Hojjatollah
Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.
Res Pharm Sci. 2023 Nov 23;18(6):676-695. doi: 10.4103/1735-5362.389957. eCollection 2023 Dec.
Previous research has found that the electrical stimulation of the ventral tegmental area (VTA) is involved in drug-dependent behaviors and plays a role in reward-seeking. However, the mechanisms remain unknown, especially the effect of electrical stimulation on this area. Therefore, this study aimed to investigate how the electrical stimulation and the temporary inactivation of VTA affect the morphine- dependent behavior in male rats.
The adult Wistar male rats were anesthetized with ketamine and xylazine. The stimulation electrode (unilaterally) and the microinjection cannula (bilaterally) were implanted into the VTA, stereotaxically. Then, the rats underwent three-day of repeated conditioning with subcutaneous morphine (0.5 or 5 mg/kg) injections, in the conditioned place preference apparatus, followed by four-day forced abstinence, which altered their conditioning response to a morphine (0.5 mg/kg) priming dose on the ninth day. On that day, rats were given high- or low-intensity electrical stimulation or reversible inactivation with lidocaine (0.5 pL/site) in the VTA.
FINDINGS/RESULTS: Results showed that the electrical stimulation of the VTA with the high intensity (150 μA/rat), had a minimal effect on the expression of morphine-induced place conditioning in rats treated with a high dose (5 mg/kg) of morphine. However, the reversible inactivation of the VTA with lidocaine greatly increased place preference in rats treated with a low dose (0.5 mg/kg) of morphine. Additionally, the reinstatement of 0.5 mg/kg morphine-treated rats was observed after lidocaine infusion into the VTA.
These results suggest that VTA electrical stimulation suppresses neuronal activation, but the priming dose causes reinstatement. The VTA may be a potential target for deep brain stimulation-based treatment of intractable disorders induced by substance abuse.
先前的研究发现，腹侧被盖区（VTA）的电刺激与药物依赖行为有关，并在奖赏寻求中发挥作用。然而，其机制仍不清楚，尤其是电刺激对该区域的影响。因此，本研究旨在探讨VTA的电刺激和暂时失活如何影响雄性大鼠的吗啡依赖行为。
成年Wistar雄性大鼠用氯胺酮和赛拉嗪麻醉。将刺激电极（单侧）和微量注射套管（双侧）立体定向植入VTA。然后，大鼠在条件性位置偏爱装置中接受为期三天的皮下注射吗啡（0.5或5mg/kg）的重复条件训练，随后进行为期四天的强制戒断，这改变了它们在第九天对吗啡（0.5mg/kg）激发剂量的条件反应。在那一天，对大鼠的VTA给予高强度或低强度电刺激或用利多卡因（0.5μL/位点）进行可逆性失活。
结果表明，高强度（150μA/大鼠）电刺激VTA对高剂量（5mg/kg）吗啡处理的大鼠中吗啡诱导的位置条件反射的表达影响最小。然而，利多卡因对VTA的可逆性失活大大增加了低剂量（0.5mg/kg）吗啡处理的大鼠的位置偏爱。此外，在向VTA注入利多卡因后，观察到0.5mg/kg吗啡处理的大鼠的复吸情况。
这些结果表明，VTA电刺激抑制神经元激活，但激发剂量会导致复吸。VTA可能是基于深部脑刺激治疗药物滥用所致顽固性疾病的潜在靶点。
