Hogarth Samuel, Jaehne Emily J, Xu Xiangjun, Schwarz Quenten, van den Buuse Maarten
School of Psychology and Public Health, La Trobe University, Melbourne, VIC 3086, Australia.
Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.
Biomedicines. 2023 Aug 17;11(8):2290. doi: 10.3390/biomedicines11082290.
The aim of the present study was to gain a better understanding of the role of brain-derived neurotrophic factor (BDNF) and dopamine D3 receptors in the effects of chronic methamphetamine (METH) on prepulse inhibition (PPI), an endophenotype of psychosis. We compared the effect of a three-week adolescent METH treatment protocol on the regulation of PPI in wildtype mice, BDNF heterozygous mice (HET), D3 receptor knockout mice (D3KO), and double-mutant mice (DM) with both BDNF heterozygosity and D3 receptor knockout. Chronic METH induced disruption of PPI regulation in male mice with BDNF haploinsufficiency (HET and DM), independent of D3 receptor knockout. Specifically, these mice showed reduced baseline PPI, as well as attenuated disruption of PPI induced by acute treatment with the dopamine receptor agonist, apomorphine (APO), or the glutamate NMDA receptor antagonist, MK-801. In contrast, there were no effects of BDNF heterozygosity or D3 knockout on PPI regulation in female mice. Chronic METH pretreatment induced the expected locomotor hyperactivity sensitisation, where female HET and DM mice also showed endogenous sensitisation. Differential sex-specific effects of genotype and METH pretreatment were observed on dopamine receptor and dopamine transporter gene expression in the striatum and frontal cortex. Taken together, these results show a significant involvement of BDNF in the long-term effects of METH on PPI, particularly in male mice, but these effects appear independent of D3 receptors. The role of this receptor in psychosis endophenotypes therefore remains unclear.
本研究的目的是更好地理解脑源性神经营养因子（BDNF）和多巴胺D3受体在慢性甲基苯丙胺（METH）对前脉冲抑制（PPI）（一种精神病的内表型）影响中的作用。我们比较了为期三周的青少年METH治疗方案对野生型小鼠、BDNF杂合小鼠（HET）、D3受体敲除小鼠（D3KO）以及同时具有BDNF杂合性和D3受体敲除的双突变小鼠（DM）中PPI调节的影响。慢性METH诱导了BDNF单倍体不足（HET和DM）雄性小鼠PPI调节的破坏，这与D3受体敲除无关。具体而言，这些小鼠表现出基线PPI降低，以及多巴胺受体激动剂阿扑吗啡（APO）或谷氨酸NMDA受体拮抗剂MK - 801急性治疗诱导的PPI破坏减弱。相比之下，BDNF杂合性或D3敲除对雌性小鼠的PPI调节没有影响。慢性METH预处理诱导了预期的运动活动敏化，雌性HET和DM小鼠也表现出内源性敏化。在纹状体和额叶皮质中观察到基因型和METH预处理对多巴胺受体和多巴胺转运体基因表达的性别特异性差异效应。综上所述，这些结果表明BDNF在METH对PPI的长期影响中起重要作用，尤其是在雄性小鼠中，但这些影响似乎与D3受体无关。因此，该受体在精神病内表型中的作用仍不清楚。
