De Vries T J, Jonker A J, Voorn P, Mulder A H, Schoffelmeer A N
Graduate School Neurosciences, Amsterdam, Research Institute Neurosciences Vrije Universiteit, Faculty of Medicine, The Netherlands.
Brain Res Dev Brain Res. 1994 Apr 15;78(2):175-81. doi: 10.1016/0165-3806(94)90024-8.
This study was designed to evaluate the effects of a chronic treatment with the classical neuroleptic drug haloperidol on the preproenkephalin (ppEnk) mRNA synthesis and its consequences for opioid and dopamine (DA) receptor-regulated adenylate cyclase in the developing and adult rat striatum. Prenatal exposure to haloperidol (2 mg/kg, 14 days) caused a 40% reduction of striatal ppEnk mRNA levels, but had no consequences for DA-stimulated or Met-enkephalin-inhibited adenylate cyclase activity in striatal slices from embryonic day 21 (E21) foetal brain. Postnatal treatment of rat pups from day 10 (P10) until P23 and adult rats resulted in significant increases of mRNA levels of 8 and 41%, respectively, a clear reduction of D1 DA receptor-stimulated cAMP production and a profound desensitization of delta-opioid receptors inhibitory coupled to adenylate cyclase. Since striatal D2 receptor-mediated inhibition of adenylate cyclase activity, in contrast to its activation through D1 receptors, is not present in the prenatal period, this study indicates that the tonic inhibitory effect of DA on striatal ppEnk mRNA synthesis is dependent on the presence of adenylate cyclase-coupled D2 receptors which gradually develops postnatally and further supports the idea that striatal D1 and D2 DA receptors have bidirectional effects on enkephalin synthesis in this brain area. The adaptive changes in D1 DA and delta receptor-regulated adenylate cyclase activity are discussed in relation to the well-known increase in the locomotor and reinforcing effects of mu-opioid receptor agonists upon chronic neuroleptic treatment.
本研究旨在评估经典抗精神病药物氟哌啶醇长期治疗对发育中和成年大鼠纹状体中前脑啡肽原（ppEnk）mRNA合成的影响，及其对阿片样物质和多巴胺（DA）受体调节的腺苷酸环化酶的影响。产前暴露于氟哌啶醇（2mg/kg，14天）导致纹状体ppEnk mRNA水平降低40%，但对胚胎第21天（E21）胎儿脑纹状体切片中DA刺激或甲硫氨酸脑啡肽抑制的腺苷酸环化酶活性没有影响。从出生后第10天（P10）至P23对幼鼠及成年大鼠进行产后治疗，结果分别导致mRNA水平显著升高8%和41%，D1 DA受体刺激的cAMP产生明显减少，以及与腺苷酸环化酶偶联的δ-阿片受体明显脱敏。由于纹状体D2受体介导的腺苷酸环化酶活性抑制在产前不存在，与其通过D1受体激活相反，本研究表明DA对纹状体ppEnk mRNA合成的紧张性抑制作用依赖于与腺苷酸环化酶偶联的D2受体的存在，该受体在出生后逐渐发育，并进一步支持了纹状体D1和D2 DA受体对该脑区脑啡肽合成具有双向作用的观点。讨论了D1 DA和δ受体调节的腺苷酸环化酶活性的适应性变化与慢性抗精神病药物治疗后μ-阿片受体激动剂的运动和强化作用众所周知的增加之间的关系。
