Suppression of the hyperpolarization-activated inward current contributes to the inhibitory actions of propofol on rat CA1 and CA3 pyramidal neurons
Introduction
2,6 Di-isopropylphenol (propofol) is an intravenous anesthetic used in clinical practice for the last 10 years. Propofol has a variety of known and suspected actions. Propofol's actions on inhibitory synaptic transmission mediated by GABAA receptors (Collins, 1988, Hales and Lambert, 1991, Peduto et al., 1991, Hara et al., 1993, Orser et al., 1994, Albertson et al., 1996, O'Shea et al., 2000) and excitatory synaptic transmission mediated by glutamate receptors (Orser et al., 1995, Yamakura et al., 1995) have been extensively studied. Recent studies also indicate that propofol can modulate intrinsic ionic conductances by directly acting at sodium channels (Rehberg and Duch, 1999), potassium channels (Friederich et al., 2001) and calcium channels (Inoue et al., 1999). We recently showed an inhibitory effect of propofol on the hyperpolarization-activated inward current (IH) in hippocampal CA1 neurons (Funahashi et al., 2001). Such an effect was not found with thiopental, but some volatile anesthetics are known to antagonize IH (Tokimasa et al., 1990, Sirois et al., 1998).
The IH is an inward current that is slowly activated by membrane hyperpolarization (Pape, 1996). The major functional roles of IH are, (1) control of the rhythmic-oscillatory activity by repolarization following membrane hyperpolarization; (2) a substantial contribution to the resting potential; and (3) production of a slow depolarization during the after-hyperpolarization (AHP) phase (Pape, 1996). In view of these functions, we hypothesized that the suppression of IH by propofol would depress some kinds of neuronal activity. To substantiate this speculation, we aimed at providing useful data for an evaluation of how propofol acts on the intrinsic membrane properties and the activity of cells displaying IH in hippocampal CA1 neurons. In the present study, we used intracellular recording techniques in rat brain slices to investigate the action of propofol on the subthreshold behavior, firing properties, and spontaneous activity of hippocampal pyramidal cells displaying IH. This paper describes the effects of propofol on the voltage responses of CA1 and CA3 hippocampal neurons and compares them with the effects of ZD7288.
Section snippets
Slice preparation and maintenance
The Okayama University Animal Use Committee approved all experimental protocols. Brain slices were prepared from male Sprague–Dawley albino rats (150–230 g) as previously described (Funahashi and Stewart, 1997, Funahashi and Stewart, 1998). Briefly, animals were decapitated after halothane anesthesia, and each brain was removed from the skull, bisected, and placed briefly in ice cold artificial cerebrospinal fluid (ACSF) containing (in mM): 124 NaCl, 5 KCl, 2 CaCl2, 1.6 MgCl2, 26 NaHCO3, and 10
Propofol inhibits the conductance underlying IH
Intracellular recordings were taken from 73 hippocampal CA1 neurons having a mean resting potential of −68.3±0.53 mV. Typical voltage responses of these neurons to hyperpolarizing current pulses peaked in the hyperpolarizing direction within 25 ms and then sagged to less negative potentials (Fig. 1A). Such a response is called ‘voltage sag’ and typically results from the activation of a IH (Pape, 1996). CA1 pyramidal cells also showed a depolarizing rebound potential, which could reach firing
Discussion
We studied the actions of propofol on pyramidal cells of the rat hippocampus in brain slices. Propofol affects the voltage responses of hippocampal CA1 neurons as follows: (1) reduction of the magnitude of the ‘voltage sag’, the rebound potential and the hyperpolarizing after-potential; (2) hyperpolarization of membrane potential (about 10 mV) and decreases in the spontaneous discharge rate; and (3) decreases of the duration of epileptiform burst responses. The propofol effects of (1) and (2)
Acknowledgements
We thank Dr. Mark Stewart, Department of Physiology and Pharmacology, SUNY HSC at Brooklyn, for his helpful comments on the manuscript. This research was supported by grants from the Ministry of Education, Science and Culture of Japan.
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