Inhibitory effect of propofol on ketamine-induced c-Fos expression in the rat posterior cingulate and retrosplenial cortices is mediated by GABAA receptor activation

Background: Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine, have psychotomimetic activities and cause neuronal damage in the posterior cingulate and retrosplenial cortices (PC/RS), which are suggested to be the brain regions responsible for their psychotomimetic activities. We previously demonstrated that ketamine induced marked c-Fos (c-fos protein) expression in the rat PC/RS, which was inhibited by propofol, and the expression was closely related to ketamine-induced abnormal behavior. In the present study, we investigated whether the inhibition by propofol was mediated by GABA(A) receptor receptor activation. Methods: Using Wistar rats, propofol alone, propofol with bicuculline or propofol with flumazenil was injected intravenously and then continuously infused. Fifteen minutes later, 100 mg kg(-1) of ketamine or normal saline was injected intraperitoneally. Two hours after the ketamine or saline injection, the brain was extracted and brain sections were prepared, and c-Fos expression was detected using immunohistochemical methods. Results: Ketamine induced marked c-Fos expression in the PC/RS (171+/-9/0.4 mm(2)), which was significantly inhibited by propofol (5+/-5/0.4 mm(2)). The inhibition by propofol was disinhibited dose-dependently by both bicuculline (0.5 and 1.0 mg kg(-1) bicuculline groups: 46+/-15 and 143+/-16, respectively) and flumazenil (0.1 and 1.0 mg kg(-1) flumazenil groups: 79+/-6 and 130+/-15, respectively). Conclusion: These results demonstrate that the inhibitory effect of propofol on ketamine-induced c-Fos expression in the PC/RS is mediated by GABA(A) receptor activation, and suggests that ketamine-induced psychoneuronal adverse effects may be suppressed by propofol via the activation of GABA(A) receptors.