PubMed · 9952175
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P J Cohen. 1999. Plus ça change.. https://doi.org/10.1097/00000542-199902000-00043
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UNLABELLED: General anesthetics cause surgical immobility and oblivion (unconsciousness and amnesia). A class of compounds known as "nonimmobilizers" were predicted to be anesthetic, based on their physiochemical properties, but found to cause only amnesia. In humans, cerebrocortical electrical activity after auditory stimulation is depressed by concentrations of anesthetics which impair auditory recall. We sought to use these evoked responses to characterize the effects of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) and conventional inhaled anesthetics on early sensory processing in rats. Unrestrained rats with chronically implanted epidural silver screw electrodes were put into a chamber. On separate days, the same population of rats were exposed to isoflurane, desflurane, nitrous oxide, or 2N, each at several subminimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus concentrations. After equilibration at each concentration, auditory-evoked responses were obtained. The behavioral state (activity and righting reflex) and electroencephalogram were also examined. 2N did not significantly change the middle latency auditory-evoked response, whereas the anesthetics all slowed conduction and depressed amplitude in a dose-dependent fashion. 2N neither depressed the righting reflex, nor induced epileptiform activity. IMPLICATIONS: Although the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) suppresses learning, we find that 2N does not depress middle latency auditory-evoked responses. This suggests that 2N may suppress learning by depressing transmission through rostral subcortical structures, such as the amygdala, rather than by acting on the brainstem or neocortical structures.
The action of propofol on the rat locus coeruleus was examined using intracellular recording from in vitro brain slice preparations. Concentrations of propofol between 3 and 300 microM were tested. At 100 microM, propofol completely inhibited the firing of all neurons tested (n=34); this was associated with a 5.7-mV hyperpolarization (range 0-16 mV, n=33) and a 35.6% reduction in input resistance (range 7.3-66.1%, n=33). The propofol-induced responses were not affected by 2-hydroxysaclofen (50 microM) or BaCl(2) (300 microM), but were completely blocked by bicuculline methiodide (100 microM) or picrotoxin (100 microM), indicating that propofol acts on GABA(A) receptors. As assessed by inhibition of the spontaneous firing rate, propofol was 5.6-fold more potent than GABA (gamma-aminobutyric acid). Potentiation of the propofol effect by other general anesthetics or other drugs was also investigated. When pentobarbital (100 microM) was tested alone on locus coeruleus cells, no change in membrane potential or input resistance was seen and there was only a 20.3+/-7.2% (n=8) inhibition of firing rate; however, in combination with 30 microM propofol, it caused a 6.1-fold greater increase in membrane hyperpolarization and a 9.7-fold greater reduction in input resistance than 30 microM propofol alone. A relatively low concentration of alphaxalone (10 microM), when tested alone, had little effect on the membrane potential or input resistance and only produced a 46.0+/-8.9% (n=8) inhibition of firing rate; however, in combination with 30 microM propofol, it caused a 9.3-fold greater hyperpolarization and an 8.6-fold greater reduction in input resistance compared with 30 microM propofol alone. In contrast, diazepam caused no potentiation of either propofol- or GABA-induced responses. Our data also indicate that locus coeruleus neuron GABA(A) receptors possess distinctive pharmacologic characteristics, such as blocking of the propofol effects by zinc and insensitivity to diazepam and the direct action of pentobarbital. On the basis of these pharmacologic properties, we suggest that locus coeruleus neuron GABA(A) receptors do not contain the gamma subunit.
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