title: (R)-alpha-methylhistamine suppresses inhibitory neurotransmission in hippocampal CA1 pyramidal neurons counteracting propofol-induced amnesia in rats.
abstract: BACKGROUND
  Propofol is a short-acting, intravenous general anesthetic that is widely used in clinical practice for short procedures; however, it causes depressed cognitive function for several hours thereafter. (R)-alpha-methylhistamine (RAMH), a selective histamine H3 receptor agonist, can enhance memory retention and attenuates memory impairment in rats. In this study, we investigated whether RAMH could rescue propofol-induced memory deficits and the underlying mechanisms partaking in this process.
  
  
  METHODS
  In the modified Morris water maze (MWM) test, rats were randomized into the following groups: control, propofol (25 mg/kg, i.p., 30 min before training), RAMH (10 mg/kg, i.p., 60 min before training), and propofol plus RAMH. All randomized rats were subjected to 2 days of training, and a probe test was conducted on day 3. Field excitatory postsynaptic potentials were recorded from CA1 neurons in rat hippocampal slices, and long-term potentiation (LTP) was induced by either theta-burst stimulation (TBS) or high-frequency tetanic stimulation (HFS). Spontaneous and miniature inhibitory (sIPSCs, mIPSCs) or excitatory (sEPSCs, mEPSCs) postsynaptic currents were recorded from CA1 pyramidal neurons by whole-cell patch clamp.
  
  
  RESULTS
  In the MWM task, propofol injection significantly impaired spatial memory retention. Pretreatment with RAMH reversed propofol-induced memory retention. In hippocampal CA1 slices, propofol perfusion markedly inhibited TBS- but not HFS-induced LTP. Co-perfusion of RAMH reversed the inhibitory effect of propofol on TBS-induced LTP reduction. Furthermore, in hippocampal CA1 pyramidal neurons, RAMH significantly suppressed the frequency but not the amplitude of sIPSCs and mIPSCs and had little effects on both the frequency and amplitude of sEPSCs and mEPSCs.
  
  
  CONCLUSIONS
  Our results suggest that RAMH, by inhibiting presynaptic GABAergic neurotransmission, suppresses inhibitory neurotransmission in hippocampal CA1 pyramidal neurons, which in turn reverses inhibition of CA1 LTP and the spatial memory deficits induced by propofol in rats.
authors.affiliation: Department of Anesthesiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.forename: Long-Zhen
authors.initials: LZ
authors.lastname: Cheng
authors.forename: Zui
authors.initials: Z
authors.lastname: Zou
authors.forename: Mou-Li
authors.initials: ML
authors.lastname: Tian
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Abou Dargham
authors.initials: AD
authors.lastname: Raya
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Xue-Yin
authors.initials: XY
authors.lastname: Shi
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018686:Anesthetics, Intravenous / Q000633:toxicity; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology* / Q000473:pathology; D004195:Disease Models, Animal; D017442:Histamine Agonists / Q000627:therapeutic use*; D066298:In Vitro Techniques; D018782:Maze Learning / Q000187:drug effects; D008761:Methylhistamines / Q000627:therapeutic use*; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000633:toxicity; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D018686:Anesthetics, Intravenous; D017442:Histamine Agonists; D008761:Methylhistamines; C069357:alpha-methylhistamine; D015742:Propofol
keywords: (R)-alpha-methylhistamine; Amnesia; Inhibitory transmission; Long-term potentiation; Propofol