Synapses
Anesthetics may disrupt normal synaptic transmission by interfering
with the release of neurotransmitter from the presynaptic nerve terminals into the
synaptic cleft, by altering the reuptake of neurotransmitter after its release, by
changing the binding of neurotransmitter to receptor sites on the postsynaptic membrane,
or by influencing the ionic conductance change that follows activation of the postsynaptic
receptor by neurotransmitter.[37]
Presynaptic Action
A presynaptic site of inhaled anesthetic action may be inferred
from electrophysiologic recordings that compare postsynaptic potentials obtained
through presynaptic stimulation compared with those generated by direct application
of neurotransmitter. For example, in mouse hippocampal slices, glutamatergic excitatory
postsynaptic currents are reduced about 50% by approximately 1 MAC of halothane,
whereas halothane (even at concentrations of about 5 MAC) has no effect on the currents
induced by bath application of glutamatergic agonists.[40]
A presynaptic site of action is also implied from studies that
demonstrate an influence of anesthetics on neurotransmitter release.[37]
[41]
Clinical concentrations of inhaled agents
reduce
depolarization-evoked release of norepinephrine but not acetylcholine from slices
of rat cerebral cortex.[42]
In the rat striatum,
isoflurane and halothane increase spontaneous dopamine release[43]
but decrease nicotine-evoked release of dopamine and have no effect on potassium-induced
GABA release.[44]
Isoflurane does not alter potassium-evoked
glutamate release in cerebral cortex, striatum, or hippocampus, but it inhibits Na+
channel-mediated glutamate release.[45]
The ability
of anesthetics to alter neurotransmitter release may depend on the biologic preparation
examined, the method employed to evoke neurotransmitter release, the neurotransmitter,
and the anesthetic and its concentration.
In addition to an effect on the presynaptic release of neurotransmitters,
it is conceivable that inhaled anesthetics may alter the duration of neurotransmitter
action by influencing the reuptake of neurotransmitter into the nerve terminal.[41]
An anesthetic-induced increase in the uptake of glutamate may decrease excitatory
transmission and contribute to the action of some volatile agents.[46]
Postsynaptic Action
Evidence is available for the postsynaptic effects of inhaled
anesthetics on excitatory and inhibitory neurons. Postsynaptic sites of anesthetic
action may be studied by application of putative neurotransmitters thought to act
directly on postsynaptic membrane receptors.[37]
Halothane and isoflurane (0.5 to 2.5 MAC) reduce the depolarizing responses to iontophoretic
applications of acetylcholine or glutamate to dendrites in guinea pig neocortical
slices, with the acetylcholine response being depressed more than the glutamate response.
[47]
Halothane and isoflurane have little or no
effect on the response induced by iontophoretic application of GABA
to perikaryons in these neocortical slices,[47]
whereas in hippocampal neurons[48]
and in neurons
dissociated from the nucleus tractus solitarius of the rat,[49]
volatile anesthetics enhance the currents produced by application of GABA ( Fig.
4-7
). In hippocampal neurons, xenon has no measurable effect on GABA-evoked
postsynaptic currents but inhibits postsynaptic current at glutamatergic excitatory
synapses.[48]
Depending on the particular neuronal
preparation and neurotransmitter examined, anesthetics may depress, have little influence
on, or enhance the postsynaptic response.
A postsynaptic action is also evident from the ability of clinical
concentrations of inhaled agents to modulate current flow through a variety of ion
channels found on postsynaptic membranes (see "Membrane Proteins").[50]
In summary, inhaled anesthetics act on synaptic regions, including
afferent axons at the nerve terminal. Inhaled agents alter axonal and synaptic transmission
in isolated monosynaptic and polysynaptic neuronal systems and may have presynaptic
and postsynaptic effects. Clinical concentrations of inhaled agents can depress,
leave unchanged, or enhance presynaptic neurotransmitter release and the postsynaptic
response. The effect depends on the biologic preparation, the frequency of neuronal
transmission, the particular neurotransmitter, and the anesethetic examined.
