Gronier Benjamin S, Rasmussen Kurt
Lilly Research Centre, Eli Lilly and Co., Windlesham, UK.
Neurosci Lett. 2003 Oct 9;349(3):196-200. doi: 10.1016/s0304-3940(03)00851-6.
Since the prefrontal cortex (PFC) is thought to play an important role in depression and schizophrenia, we studied the effects of fluoxetine and olanzapine on PFC neurons in rats using extracellular, in vivo recordings. Acute or 5-day administration of olanzapine (1-10 mg/kg, iv or 20 mg/kg, sc) did not change the firing rate of PFC neurons. However, a 21-day treatment with olanzapine (20 mg/kg per day, sc) significantly increased the firing rate of PFC neurons and increased their responsiveness to the iontophoretic administration of the GABA(A) antagonist bicuculline. Acute administration of fluoxetine (10 mg/kg, iv) also did not change the firing rate of PFC neurons. However, a 21-day treatment with fluoxetine (10 mg/kg per day) significantly decreased the firing rate of PFC neurons and decreased their responsiveness to the iontophoretic administration of bicuculline. Co-administration of olanzapine (10 mg/kg per day, sc) during the last 5 days of a 21-day fluoxetine treatment (10 mg/kg per day) prevented the suppression of firing and decreased responsiveness to the iontophoretic administration of bicuculline of PFC neurons. In conclusion, chronic, but not acute, olanzapine treatment significantly enhanced the firing and excitability of PFC neurons. In addition, chronic, but not acute, fluoxetine treatment significantly suppressed the firing and excitability of PFC neurons. Further, short-term olanzapine treatment attenuated the suppression of firing and excitability of PFC neurons induced by chronic fluoxetine treatment. These effects of olanzapine, fluoxetine, and the olanzapine/fluoxetine combination in the PFC may play an important role in the beneficial therapeutic effect of these compounds in schizophrenia and depression and may have implications for the treatment of treatment-resistant depression.
由于前额叶皮质（PFC）被认为在抑郁症和精神分裂症中起重要作用，我们使用细胞外活体记录法研究了氟西汀和奥氮平对大鼠PFC神经元的影响。急性或连续5天给予奥氮平（1 - 10 mg/kg，静脉注射或20 mg/kg，皮下注射）并未改变PFC神经元的放电频率。然而，连续21天给予奥氮平（每天20 mg/kg，皮下注射）显著增加了PFC神经元的放电频率，并增强了它们对离子电渗法给予GABA(A)拮抗剂荷包牡丹碱的反应性。急性给予氟西汀（10 mg/kg，静脉注射）也未改变PFC神经元的放电频率。但是，连续21天给予氟西汀（每天10 mg/kg）显著降低了PFC神经元的放电频率，并降低了它们对离子电渗法给予荷包牡丹碱的反应性。在连续21天给予氟西汀（每天10 mg/kg）的最后5天联合给予奥氮平（每天10 mg/kg，皮下注射）可防止PFC神经元放电的抑制，并降低其对离子电渗法给予荷包牡丹碱的反应性。总之，慢性而非急性给予奥氮平治疗可显著增强PFC神经元的放电和兴奋性。此外，慢性而非急性给予氟西汀治疗可显著抑制PFC神经元的放电和兴奋性。此外，短期给予奥氮平治疗可减弱慢性氟西汀治疗诱导的PFC神经元放电和兴奋性的抑制。奥氮平、氟西汀以及奥氮平/氟西汀联合用药在PFC中的这些作用可能在这些化合物对精神分裂症和抑郁症的有益治疗效果中起重要作用，并且可能对难治性抑郁症的治疗具有启示意义。
