title: Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study.
abstract: OBJECTIVE
  3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation.
  
  
  METHODS
  Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na(+) channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability.
  
  
  RESULTS
  SKF83959 (50 μmol/L) shifted the inactivation curve of Na(+) current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 (examined with current injection at the soma) was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability (examined with current injection at the dendrite) was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency.
  
  
  CONCLUSIONS
  SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug's anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.
authors.affiliation: 1] Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Shang-Lin
authors.initials: SL
authors.lastname: Zhou
authors.affiliation: 1] Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Chu
authors.affiliation: Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Guo-Zhang
authors.initials: GZ
authors.lastname: Jin
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Cui
authors.affiliation: 1] Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Xue-Chu
authors.initials: XC
authors.lastname: Zhen
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008959:Models, Neurological; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D061566:Voltage-Gated Sodium Channels; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959