Effects of propofol on GABAergic and glutamatergic transmission in isolated hippocampal single nerve-synapse preparations.
We evaluated the effects of propofol on synaptic transmission using a mechanically dissociated preparation of rat hippocampal CA3 neurons to allow assays of single bouton responses evoked from retained functional native nerve endings. We studied synaptic and extrasynaptic GABAA and glutamate receptor responses in a preparation in which experimental solutions rapidly accessed synaptic terminals. Whole-cell responses were evoked by bath application of GABA and glutamate. Synaptic inhibitory and excitatory postsynaptic currents (IPSC and EPSC) were measured as spontaneous and evoked postsynaptic responses. Evoked currents were elicited by focal electrical stimulation. Propofol (1-100 μM) enhanced extrasynaptic GABAA-receptor mediated responses but the increase at clinically relevant concentrations (1 μM) were minor. In contrast, 1 μM propofol significantly increased both the amplitude and frequency of spontaneous IPSCs (sIPSCs) and increased the amplitudes of evoked IPSCs (eIPSCs) while decreasing failure rates (Rf) and paired-pulse ratios (PPR). Decay times of sIPSCs and eIPSCs were significantly prolonged. Although propofol had no effect on extrasynaptic glutamate responses, only supra-clinical propofol concentrations (≥ 10 µM) increased the spontaneous EPSCs (sEPSCs, amplitudes and frequencies) but suppressed evoked EPSCs (eEPSCs decreased amplitudes with increased Rf and PPR). The decay phases of sEPSCs and eEPSCs were not changed. The propofol-induced changes in sEPSCs and eEPSCs resulted from presynaptic GABAA receptor-mediated depolarization, because these actions were blocked by bicuculline. These results suggest that propofol acts at presynaptic and postsynaptic GABAA receptors within GABAergic synapses, but also increases extrasynaptic GABA responses. Our results expand the locus of propofol actions to GABAergic and glutamatergic synapses.
Research Division for Clinical Pharmacology, Medical Corporation, JyuryoGroup, Kumamoto Kinoh Hospital, 6-8-1 Yamamuro, Kitaku, Kumamoto 860-8518, Japan; Research Division for Life Science, Kumamoto Health Science University, 325 Izumi-machi, Kitaku, Kumamoto 861-5598, Japan.
Masahito
M
Wakita
Naoki
N
Kotani
Kiku
K
Nonaka
Min-Chul
MC
Shin
Norio
N
Akaike
D000818:Animals; D002118:Calcium / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D012964:Sodium; D002118:Calcium; D015742:Propofol
Focal electrical stimulation; GABA; Glutamate; Propofol; Synaptic transmission; ‘Synaptic-bouton’ preparation