Schonfeld Lina, Jaehne Emily J, Ogden Alexandra R, Spiers Jereme G, Hogarth Samuel, van den Buuse Maarten
Department of Psychology and Counselling, School of Psychology and Public Health, La Trobe University, Melbourne, Australia.
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
Prog Neuropsychopharmacol Biol Psychiatry. 2022 Jul 13;117:110552. doi: 10.1016/j.pnpbp.2022.110552. Epub 2022 Mar 22.
Sensitization of dopaminergic activity has been suggested as an underlying mechanism in the psychotic symptoms of schizophrenia. Adolescent stress and chronic abuse of methamphetamine (Meth) are well-known risk factors for psychosis and schizophrenia; however it remains unknown how these factors compare in terms of dopaminergic behavioural sensitization in adulthood. In addition, while Brain-Derived Neurotrophic Factor (BDNF) has been implicated in dopaminergic activity and schizophrenia, its role in behavioural sensitization remains unclear. In this study we therefore compared the effect of chronic adolescent treatment with the stress hormone, corticosterone (Cort), or with Meth, on drug-induced locomotor hyperactivity and disruption of prepulse inhibition in adulthood in BDNF heterozygous mice and their wild-type controls, as well as on dopamine receptor gene expression. Between 6 and 9 weeks of age, the animals either received Cort in the drinking water or were treated with an escalating Meth dose protocol. In adulthood, Cort-pretreated mice showed significantly reduced Meth-induced locomotor hyperactivity compared to vehicle-pretreated mice. In contrast, Meth hyperlocomotion was significantly enhanced in animals pretreated with the drug in adolescence. There were no effects of either pretreatment on prepulse inhibition. BDNF Het mice showed greater Meth-induced hyperlocomotion and lower prepulse inhibition than WT mice. There were no effects of either pretreatment on D1 or D2 gene expression in either the dorsal or ventral striatum, while D3 mRNA was shown to be reduced in male mice only irrespective of genotype. These results suggest that in adolescence, chronically elevated glucocorticoid levels, a component of chronic stress, do not cause dopaminergic sensitization adulthood, in contrast to the effect of chronic Meth treatment in the same age period. BDNF does not appear to be involved in the effects of chronic Cort or chronic Meth.
多巴胺能活性的敏化被认为是精神分裂症精神病性症状的潜在机制。青少年应激和长期滥用甲基苯丙胺（冰毒）是众所周知的精神病和精神分裂症的危险因素；然而，在成年期多巴胺能行为敏化方面，这些因素如何比较仍不清楚。此外，虽然脑源性神经营养因子（BDNF）与多巴胺能活性和精神分裂症有关，但其在行为敏化中的作用仍不清楚。因此，在本研究中，我们比较了在BDNF杂合小鼠及其野生型对照成年期，用应激激素皮质酮（Cort）或冰毒对青少年进行长期治疗，对药物诱导的运动性多动和前脉冲抑制破坏的影响，以及对多巴胺受体基因表达的影响。在6至9周龄之间，动物要么在饮用水中接受Cort，要么接受递增剂量的冰毒治疗方案。成年后，与载体预处理的小鼠相比，Cort预处理的小鼠显示出甲基苯丙胺诱导的运动性多动显著降低。相比之下，在青春期用该药物预处理的动物中，甲基苯丙胺诱导的运动性多动显著增强。两种预处理对前脉冲抑制均无影响。BDNF杂合小鼠比野生型小鼠表现出更大的甲基苯丙胺诱导的运动性多动和更低的前脉冲抑制。两种预处理对背侧或腹侧纹状体中的D1或D2基因表达均无影响，而无论基因型如何，仅在雄性小鼠中显示D3 mRNA减少。这些结果表明，在青春期，慢性应激的一个组成部分，即糖皮质激素水平长期升高，与同一年龄段慢性甲基苯丙胺治疗的效果相反，不会导致成年期多巴胺能敏化。BDNF似乎不参与慢性Cort或慢性甲基苯丙胺的作用。
