Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Biol Psychiatry. 2011 May 15;69(10):918-27. doi: 10.1016/j.biopsych.2010.10.030. Epub 2011 Jan 20.
Noncompetitive N-methyl-D-aspartate receptor antagonists are widely used as pharmacological models of schizophrenia. Their neurobiological actions are still poorly understood, although the prefrontal cortex (PFC) appears as a key target area.
We examined the effect of phencyclidine (PCP) on neuronal activity of the mediodorsal (MD) and centromedial (CM) thalamic nuclei, reciprocally connected with the PFC, using extracellular recordings (n = 50 neurons from 35 Wistar rats) and c-fos expression.
Phencyclidine (.25 mg/kg intravenous [IV]) markedly disorganized the activity of MD/CM neurons, increasing (424%) and decreasing (41%) the activity of 57% and 20% of the recorded neurons, respectively (23% remained unaffected). Phencyclidine reduced delta oscillations (.15-4 Hz) as assessed by recording local field potentials. The subsequent clozapine administration (1 mg/kg IV) reversed PCP effects on neuronal discharge and delta oscillations. Double in situ hybridization experiments revealed that PCP (10 mg/kg intraperitoneal [IP]) markedly increased c-fos expression in glutamatergic neurons of several cortical areas (prefrontal, somatosensory, retrosplenial, entorhinal) and in thalamic nuclei, including MD/CM. Phencyclidine also increased c-fos expression in the amygdala; yet, it had a small effect in the hippocampus. Phencyclidine did not increase c-fos expression in gamma-aminobutyric acidergic cells except in hippocampus, amygdala, somatosensory, and retrosplenial cortices. Clozapine (5 mg/kg IP) had no effect by itself but significantly prevented PCP-induced c-fos expression.
Phencyclidine likely exerts its psychotomimetic action by increasing excitatory neurotransmission in thalamo-cortico-thalamic networks involving, among others, PFC, retrosplenial, and somatosensory cortices. The antipsychotic action of clozapine includes, among other actions, an attenuation of the neuronal hyperactivity in thalamocortical networks.
非竞争性 N-甲基-D-天冬氨酸受体拮抗剂被广泛用作精神分裂症的药理学模型。尽管前额叶皮层（PFC）似乎是一个关键的靶区，但它们的神经生物学作用仍知之甚少。
我们使用细胞外记录（来自 35 只 Wistar 大鼠的 50 个神经元，n=50 个神经元）和 c-fos 表达研究了苯环利定（PCP）对与 PFC 相互连接的中脑背侧（MD）和中央内侧（CM）丘脑核的神经元活动的影响。
苯环利定（静脉内 0.25mg/kg，IV）显着打乱了 MD/CM 神经元的活动，分别增加（424%）和减少（41%）记录神经元的 57%和 20%的活动（23%不受影响）。苯环利定还降低了局部场电位记录的 delta 振荡（.15-4Hz）。随后给予氯氮平（1mg/kg，IV）可逆转 PCP 对神经元放电和 delta 振荡的影响。双重原位杂交实验表明，PCP（腹腔内 10mg/kg，IP）显着增加了几个皮质区域（前额叶、体感、 retrosplenial、内嗅）和丘脑核中谷氨酸能神经元的 c-fos 表达，包括 MD/CM。苯环利定还增加了杏仁核中的 c-fos 表达；然而，它在海马体中的作用较小。苯环利定除了在海马体、杏仁核、体感和 retrosplenial 皮质中外，并未增加 GABA 能细胞的 c-fos 表达。氯氮平（5mg/kg，IP）本身没有作用，但能显著阻止 PCP 诱导的 c-fos 表达。
苯环利定通过增加涉及前额叶皮层、 retrosplenial 和体感皮层等的丘脑皮质丘脑网络中的兴奋性神经传递，可能发挥其致精神病作用。氯氮平的抗精神病作用包括减弱丘脑皮质网络中的神经元过度活跃。
