背景:几种滥用药物(DOA)能够调节神经垂体激素,如催产素(OT)和加压素(VP),可能导致心理异常的发展,比如认知功能障碍,精神病患者,和情感障碍。Efavirenz(EFV),在非洲和全球广泛用于治疗艾滋病毒,引起各种神经精神副作用,而其滥用已成为全球关注的问题。EFV的作用可能涉及神经垂体系统(NS)的破坏,例如已知的DOA。这项研究调查了亚慢性EFV暴露是否,在先前确定的奖励剂量下,与对照组相比,改变外围OT和VP水平,Δ9-四氢大麻酚(Δ9-THC),甲基苯丙胺(MA)和可卡因。
方法:为了模拟以前为EFV建立奖励驱动行为的条件,雄性SpragueDawley大鼠(n=16/暴露)通过交替的16天给药方案接受腹膜内载体(对照)或药物施用。奇数和药物给药(EFV:5mg/kg,Δ9-THC:0.75mg/kg,MA:1mg/kg,或可卡因:20mg/kg)在偶数天,然后安乐死,躯干采血和血浆提取用于神经肽测定。与对照相比,评估药物暴露对外周OT和VP水平的影响,并使用特异性ELISA试剂盒进行定量。统计显著性由Kruskal-WallisANOVA确定,p<0.05。伦理批准:NWU-00291-17-A5。
结果:Delta-9-THC降低了OT和VP血浆水平(分别为p<0.0001,p=0.0141),可卡因降低血浆OT(p=0.0023),而MA降低血浆VP水平(p=0.0001),一切与控制。与对照组相比,EFV降低了OT和VP血浆水平(p<0.0001;OT和VP),类似于Δ9-THC。
结论:EFV显著影响NS,显著降低血浆OT和VP,相当于DOA。重要的是,在药物依赖的背景下进行评估时,EFV对外周OT和VP水平具有明显的影响。数据强调了先前记录的EFV在大鼠中诱导作用的潜在新机制,由此EFV可能在临床上引起神经精神不良反应;还提供了对建议的EFV滥用潜力的更深入的了解。
BACKGROUND: Several drugs of abuse (DOA) are capable of modulating neurohypophysial hormones, such as oxytocin (OT) and vasopressin (VP), potentially resulting in the development of psychological abnormalities, such as cognitive dysfunction, psychoses, and affective disorders. Efavirenz (EFV), widely used in Africa and globally to treat HIV, induces diverse neuropsychiatric side effects while its abuse has become a global concern. The actions of EFV may involve neurohypophysial system (NS) disruption like that of known DOA. This study investigated whether sub-chronic EFV exposure, at a previously-determined rewarding dose, alters peripheral OT and VP levels versus that of a control, ∆9-tetrahydrocannabinol (∆9-THC), methamphetamine (MA) and cocaine.
METHODS: To simulate the conditions under which reward-driven behavior had previously been established for EFV, male Sprague Dawley rats (n = 16/exposure) received intraperitoneal vehicle (control) or drug administration across an alternating sixteen-day dosing protocol. Control administration (saline/olive oil; 0.2 ml) occurred on odd-numbered and drug administration (EFV: 5 mg/kg, ∆9-THC: 0.75 mg/kg, MA: 1 mg/kg, or cocaine: 20 mg/kg) on even-numbered days followed by euthanasia, trunk blood collection and plasma extraction for neuropeptide assay. Effect of drug exposure on peripheral OT and VP levels was assessed versus controls and quantified using specific ELISA kits. Statistical significance was determined by Kruskal-Wallis ANOVA, with p < 0.05. Ethics approval: NWU-00291-17-A5.
RESULTS: Delta-9-THC reduced OT and VP plasma levels (p < 0.0001, p = 0.0141; respectively), cocaine reduced plasma OT (p = 0.0023), while MA reduced plasma VP levels (p = 0.0001), all versus control. EFV reduced OT and VP plasma levels (p < 0.0001; OT and VP) versus control, and similar to ∆9-THC.
CONCLUSIONS: EFV markedly affects the NS in significantly reducing both plasma OT and VP equivalent to DOA. Importantly, EFV has distinct effects on peripheral OT and VP levels when assessed within the context of drug dependence. The data highlights a possible new mechanism underlying previously documented EFV-induced effects in rats, and whereby EFV may induce neuropsychiatric adverse effects clinically; also providing a deeper understanding of the suggested abuse-potential of EFV.