General anesthetic agents have two fundamental properties, an ability to cause immobility in response to pain and an ability to cause amnesia. Understanding anesthesia requires understanding both phenomenon. We recently demonstrated, using inhibitory avoidance learning in rats, that the basolateral amygdala (BL) is critically nvolved with mediating the amnesic effects of propofol general anesthesia. Propofol does not produce amnesia if the BL is lesioned. Further pilot work found that intra-amygdala microinfusions of the GABA antagonist bicuculline also attenuated the amnesic effects of propofol, suggesting that GABAergic mechanisms may underlie this response. This proposal will help fill the gap in knowledge that exists regarding the role of the amygdala as a mediator of anesthetic-induced amnesia. We specifically aim to: 1) determine whether the amygdala mediates the amnesia of volatile anesthetic agents studied under steady-state learning conditions at equivalent MAC% doses, 2) further elucidate the cellular mechanisms of propofol's amnesic effects, and 3) begin to determine how neuroanatomic pathways to and from the amygdala mediate these effects. We will use the rat inhibitory avoidance model to assess, in vivo, the effects of various anesthetics and amygdala manipulations on memory processing. Initial experiments, following appropriate dose-response studies, will determine whether excitotoxic-induced bilateral lesions of the BL will block the amnesia of the volitile anesthetic agents halothane (thought to act preferentially on the amygdala) and isoflurane (a commonly used inhalational agent). Subsequent experiments will use intra-amygdala microinfusion techniques with the specific GABA blocker picrotoxin to assess the contribution played by the GABAergic system in mediating propofol-induced amnesia. Lesions of a main amygdala pathway, the stria terminalis, will also be studied. Collectively, the proposed experiments should provide the most complete understanding to date of specific brain systems mediating anesthetic-induced amnesia and will provide a solid foundation for further work on the mechanisms of drug induced amnesia.
| Alkire, Michael T; Miller, Jason (2005) General anesthesia and the neural correlates of consciousness. Prog Brain Res 150:229-44 |
| Alkire, Michael T; Gorski, Lukasz A (2004) Relative amnesic potency of five inhalational anesthetics follows the Meyer-Overton rule. Anesthesiology 101:417-29 |
