Hippocampus 157

studied general anesthetics on many important synaptic and cellular responses. A common
theme has
emerged for the cellular actions produced by volatile, barbiturate, and propofol anesthetics.
All of
these agents block synaptically evoked discharge activity of CA 1 pyramidal cells and
dentate granule
neurons, but the mechanisms producing the block can differ considerably for volatile vs IV
anesthetics.
Agent specific effects have been observed for actions on excitatory and inhibitory synapses
and for
changes in postsynaptic excitability. For most anesthetics, multiple sites of action combine in
additive
or synergistic ways to depress transmission, but other agents appear to act at only one or
two sites.

Effects on Resting Membrane Potential

One of the earliest studies using hippocampal brain slices to investigate anesthetic effects
found
that some agents could hyperpolarize CA 1 neurons (43). This hyperpolarization was
observed in the
presence of tetrodotoxin, so it was not owing to a generalized depression of synaptic
transmission. It
appeared to result from a direct effect on the cell membrane, since it was associated with an
increase
in membrane conductance. Several studies have provided evidence for anesthetic-induced
increases
in potassium (44,45) and chloride (46,47) currents in hippocampal neurons, which could
account for
this hyperpolarization.
Effects on Membrane Resistance
IV agents like propofol can produce marked increases in chloride currents (36) of
hippocampal
neurons. For volatile anesthetics, relatively small hyperpolarizations are produced (48) and
appear to
be both agent selective and dependent on normal resting membrane potentials (49). Cells
with more
depolarized resting potentials exhibited a greater degree of anesthetic-induced
hyperpolariztion. This
is consistent with anesthetic-induced increases in potassium or chloride currents, since the
reversal
potentials for these ions are near the resting potentials of these cells.
Effects on Action Potential Discharge
The shunting effect of a decrease in membrane resistance produced by anesthetics results
in a
decrease in action potential discharge of hippocampal neurons. This has been observed as
decreased
discharge frequencies (44) and as an increase in discharge thresholds (50) for hippocampal
neurons.
In general, neurons are still capable of firing action potentials in response to depolarizing
current
injection (Fig. 3), and there do not appear to be strong anesthetic effects on spike amplitude,
rise
time, or decay kinetics for most agents (48,51).
Effects on Antidromic Discharge

Consistent with a minimal effect on action potential discharge, anesthetics do not appear to
effect
antidromic spike responses recorded from the pyramidal or granule neuron cell body layers
following
stimulation of their axons (52,53) until high concentrations are achieved, 510 fold higher
than needed
to block synaptically driven discharge.