Glutamate is the major excitatory neurotransmitter used by the mammalian CNS, and is especially important in higher brain structures such as the neocortex and hippocampus. Halothane, like other anesthetics, depressed CA1 neuron discharge  (Fig A) and reduced glutamate-mediated excitatory postsynaptic potentials (EPSPs Fig C). This depression was independent of effects on GABA-mediated inhibition, since the effect persisted in the presence of an excess concentration of the GABA antagonist bicuculline (BIC in Fig C).  Propofol, in contrast, required BIC-sensitive GABA-mediated inhibition for much of it's effect.  Abused inhalants, like toluene,  produced a different profile of effects compared to inhaled anesthetics, but appear to share some of the same sites of action at glutamate and GABA synapses.  Even among inhaled anesthetics, agent specific effects were evident, for example, halothane and isoflurane both depress glutamate-mediated synaptic transmission by depressing glutamate release from synaptic terminals, but some of halothane's depression involves partial sodium channel blockade, not produced by isoflurane.

d R

Recordings on top show the halothane & propofol -induced depression of population spike & EPSP responses from hippocampal CA 1 neurons in a brain slice. Note that halothane produced a 50 % EPSP depression which was not reversed by bicuculline (BIC , above Fig A).

Depression of EPSP responses occurred with an increase in paired pulse facilitation (below, Fig A), indicating a presynaptic site of action; a halothane-induced decrease in glutamate release.  Propofol, in contrast, produced an EPSP depression that was completely reversed with a GABA antagonist, bicuclline (BIC), indicating that this anesthetic increases GABA-mediated inhibition to depress the CA1 circuit.

Propofol and halothane produced strikingly different effects on CA1 neuron excitation.  Halothane had no obvious effect (D Figure bottom), but propofol produced a strong depression of action potential discharge.  Each class of anesthetic, from volatile agents like halothane and IV drugs like propofol, produce a unique profile of effects by acting at multiple sites and with differing degrees of effects at these sites.  See Pittson et al 2004 for more details.  The same pharmacologic selectivity appears to be true for abused inhalants and other classes of CNS active drugs.  This selectivity may account for differing effects on memory, cognition and pain systems produced by each class of drug.  Understanding these drug mechanisms will help create better therapeutics with fewer unwanted side effects.