Acute, chronic and differential effects of several anesthetic barbiturates on glutamate receptor activation in neuronal culture

Abstract

The acute and chronic effects of several anesthetic barbiturates, in therapeutic concentrations, on the excitatory amino acid (EAA)-induced elevation of intracellular calcium levels ([Ca 2+] i) were examined in neuronal tissue culture. The ultrashort-acting barbiturate, thiamylal, was effective in blocking elevations of [Ca 2+] i induced by kainate, N-methyl- d-aspartate (NMDA), and quisqualate or by membrane depolarization with 40 mM KCl. The structurally similar barbiturate, secobarbital which differs from thiamylal only by having an oxygen in place of a sulfur, was able to block elevations induced by the above EAAs but was less effective than thiamylal and did not significantly reduce [Ca 2+] i that resulted from membrane depolarization with KCl. Pentobarbital, while differing from secobarbital by only a methyl group, was without effect on either the NMDA- or 40 mM KCl-induced elevations of [Ca 2+] i. By contrast, cyproheptadine, a compound that has been shown to block Ca 2+ channels, has a different profile from the above barbiturates in that cyproheptadine is more effective in blocking elevation of [Ca 2+] i, induced by membrane depolarization with KCl while the barbiturates are more effective in reducing [Ca 2+] i induced by EAAs. An anticonvulsant barbiturate, phenobarbital, did not reduced elevations of [Ca 2+] i induced by any EAA tested or by membrane depolarization with KCl. When cells were treated chronically with thiamylal for 4 days, 2–6 h after the abrupt drug withdrawal there was a hyperresponsiveness to the elevations of [Ca 2+] i induced by both kainate and NMDA but not by quisqualate. A similar hyperresponsiveness was not seen after the chronic treatment with phenobarbital. Collectively, these results show that the chronic administration of thiamylal affects similar pathways that are affected with the acute drug administration, and also that slight structural changes in the barbiturate side chains result in very significant differences in blocking EAA- and KCl-induced elevations of [Ca 2+] i.