Bennay Mustapha, Gernert Manuela, Schwabe Kerstin, Enkel Thomas, Koch Michael
Department of Neuropharmacology, Brain Research Institute, University of Bremen, POB 330440, 28334 Bremen, Germany.
Eur J Neurosci. 2004 Jun;19(12):3277-90. doi: 10.1111/j.0953-816X.2004.03442.x.
Neurodevelopmental models of schizophrenia posit that early brain damage leads to dys- or misconnection effects possibly altering synaptic transmission in brain sites distal of the lesion. We tested the hypothesis that neonatal medial prefrontal cortex (mPFC) lesions affect the sensitivity of the mesoaccumbal dopamine (DA) system. Using extracellular single-unit recordings combined with systemic application of the DA agonist apomorphine, followed by the D2 receptor antagonist haloperidol or the D1 receptor antagonist SCH23390, we compared electrophysiological properties of nucleus accumbens core and shell neurons after bilateral excitotoxic lesions of mPFC induced at postnatal day 7 or in adult rats. Whereas animals with adult mPFC lesions showed an altered discharge pattern within the core region, neonatal mPFC lesions altered the discharge pattern within the shell region. Subcutaneous administration of apomorphine (4 mg/kg) reduced accumbal firing rate in 77% of all neurons. Onset and magnitude of apomorphine-induced inhibition of neuronal activity was faster and stronger in rats with neonatal but not adult mPFC lesions in both core and shell regions. Apomorphine-induced inhibition was partially reversed by 0.1 mg/kg haloperidol only in core region of neonatal lesioned rats. Apomorphine-induced excitation of neuronal activity (in 21% of all neurons) was reversed by the D1 receptor antagonist SCH23390 (0.1 mg/kg) in all excited neurons. These data support the hypothesis that neonatal but not adult lesions of mPFC alter cortico-striatal networks and suggest that disturbance of mPFC development leads to neurodevelopmental changes in mesoaccumbal DA system during adulthood.
精神分裂症的神经发育模型认为，早期脑损伤会导致功能障碍或连接错误，可能改变损伤部位远端脑区的突触传递。我们验证了如下假说：新生大鼠内侧前额叶皮质（mPFC）损伤会影响中脑伏隔核多巴胺（DA）系统的敏感性。我们采用细胞外单单位记录技术，结合系统应用DA激动剂阿扑吗啡，随后应用D2受体拮抗剂氟哌啶醇或D1受体拮抗剂SCH23390，比较了出生后第7天或成年大鼠双侧兴奋性毒性损伤mPFC后伏隔核核心区和壳区神经元的电生理特性。成年mPFC损伤的动物在核心区内放电模式发生改变，而新生mPFC损伤则改变了壳区内的放电模式。皮下注射阿扑吗啡（4 mg/kg）使所有神经元中77%的伏隔核放电频率降低。在核心区和壳区，阿扑吗啡诱导的神经元活动抑制的起始和幅度在新生mPFC损伤的大鼠中更快、更强，而成年mPFC损伤的大鼠则不然。仅在新生损伤大鼠的核心区，0.1 mg/kg氟哌啶醇可部分逆转阿扑吗啡诱导的抑制作用。阿扑吗啡诱导的神经元活动兴奋（占所有神经元的21%）在所有兴奋神经元中均被D1受体拮抗剂SCH23390（0.1 mg/kg）逆转。这些数据支持如下假说：新生而非成年mPFC损伤会改变皮质-纹状体网络，并提示mPFC发育障碍会导致成年期内中脑伏隔核DA系统发生神经发育变化。
