Memory enhancing effect of low-dose sevoflurane does not occur in basolateral amygdala-lesioned rats.

BACKGROUND: Certain anesthetics might enhance aversive memory at doses around 0.1 minimum alveolar concentration. This issue was investigated in a rat model of learning and memory. In addition, evidence for basolateral amygdala (BLA) involvement in mediating memory enhancement was sought. METHODS: First, the memory-enhancing potential of various anesthetics was determined. Rats underwent single-trial inhibitory avoidance training (0.3 mA shock/1 s) during exposure to air, 0.11% sevoflurane, 0.10% halothane, 0.77% desflurane, or 0.12% isoflurane. Memory was assessed at 24 h. Second, the BLA contribution to sevoflurane memory enhancement was determined. Rats received bilateral excitotoxic N-methyl-D-aspartate (12.5 mg in 0.2 microl per BLA) lesions of the BLA 1 week before training. Memory of lesioned and control rats was compared 24 h after training in air or sevoflurane. RESULTS: Sevoflurane exposure during training significantly enhanced 24-h retention performance for both nonoperated and sham-operated rats (P < 0.005 for both vs. their respective controls). Halothane, but not desflurane or isoflurane, also enhanced retention performance (P < 0.05). However, halothane-induced hyperalgesia during learning clouds interpreting enhanced retention performance solely as a memory consolidation effect. BLA lesions significantly reduced and equalized retention performance for both sevoflurane- and air-exposed animals. Lesions blocked memory enhancement without also causing a generalized inability to learn, because additional training revealed essentially normal task acquisition and 24-h memory. CONCLUSIONS: Sevoflurane enhances aversive memory formation in the rat. The BLA likely contributes to this effect. The risk of aversive memory formation may be enhanced during exposure to low-dose sevoflurane.

Does the amygdala mediate anesthetic-induced amnesia? Basolateral amygdala lesions block sevoflurane-induced amnesia.

BACKGROUND: Amnesia for aversive events caused by benzodiazepines or propofol depends on the basolateral amygdala (BLA). Whether the amnesia of volatile anesthesia is also mediated through the BLA is unknown. If so, a general principle of anesthetic-induced amnesia may be emerging. Here, using an inhibitory avoidance paradigm, the authors determine whether BLA lesions prevent sevoflurane-induced amnesia. METHODS: Male Sprague-Dawley rats were separated into two groups: sham-operated controls (n = 22) and rats given bilateral N-methyl-D-aspartate lesions of the BLA (n = 32). After a 1-week recovery, the rats were randomly assigned to be trained during either air or sevoflurane (0.3% inspired, 0.14 minimum alveolar concentration) exposure. Animals learned to remain in the starting safe compartment of a step-through inhibitory avoidance apparatus for 100 consecutive seconds by administering foot shock (0.3 mA) whenever they entered an adjacent shock compartment. Memory was assessed at 24 h. Longer latencies to enter the shock compartment at 24 h imply better memory. RESULTS: Sham-air (n = 10) animals had a robust memory, with a median retention latency of 507 s (interquartile range, 270-600 s). Sham-sevoflurane (n = 6) animals were amnesic, with a latency of 52 s (27-120 s) (P < 0.01, vs. sham-air). Both the air-exposed (n = 5) and the sevoflurane-exposed (n = 8) animals with BLA lesions showed robust memory, with latencies of 350 s (300-590 s) and 378 s (363-488 s), respectively. The latencies for both did not differ from the performance of the sham-air group and were significantly greater than the latency of the sham-sevoflurane group (both P < 0.01). CONCLUSIONS: BLA lesions block sevoflurane-induced amnesia. A role for the BLA in mediating anesthetic-induced amnesia may be a general principle of anesthetic action.

Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala.

Previous findings indicate that administration of abeta-adrenoceptor antagonist systemically blocks glucocorticoid impairment of memory retrieval. Here, we report that beta-adrenoceptor activation in the hippocampus and the basolateral complex of the amygdala (BLA) is implicated in the impairing effects of glucocorticoids on memory retrieval. The specific glucocorticoid receptor (GR) agonist 11beta,17beta-dihydroxy-6,21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one (RU 28362) (15 ng) infused into the hippocampus of male Sprague Dawley rats 60 min before water maze retention testing, 24 hr after training, impaired probe trial retention performance, as assessed by quadrant search time and initial latency to cross the platform location. Because we found previously that RU 28362 infused into the hippocampus does not affect water maze acquisition or immediate recall, the findings suggest that the GR agonist-induced retention impairment was attributable to a selective influence on long-term memory retrieval. Likewise, systemic injections of the beta1-adrenoceptor partial agonist xamoterol (3.0 or 10.0 mg/kg, s.c.) 60 min before the probe trial dose-dependently impaired retention performance. The beta-adrenoceptor antagonist propranolol (2.0 mg/kg) administered subcutaneously before retention testing did not affect retention performance alone, but blocked the memory retrieval impairment induced by concurrent intrahippocampal infusions of RU 28362. Pretest infusions of the beta1-adrenoceptor antagonist atenolol into either the hippocampus (1.25 microg in 0.5 microl) or the BLA (0.5 microg in 0.2 microl) also prevented the GR agonist-induced memory retrieval impairment. These findings suggest that glucocorticoids impair retrieval of long-term spatial memory by facilitating noradrenergic mechanisms in the hippocampus, and additionally, that norepinephrine-mediated BLA activity is critical in enabling hippocampal glucocorticoid effects on memory retrieval.

Basolateral amygdala interacts with other brain regions in regulating glucocorticoid effects on different memory functions.

Extensive evidence indicates that acutely administered glucocorticoid hormones influence cognitive performance. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors dose-dependently enhance long-term memory consolidation. We previously reported that such glucocorticoid effects on memory consolidation rely on noradrenergic activation of the basolateral complex of the amygdala (BLA) and interactions of the BLA with other brain regions. By contrast, memory retrieval and working memory performance are impaired with high circulating levels of glucocorticoids. Although these memory functions depend on the hippocampus and the medial prefrontal cortex, respectively, in recent experiments we found that glucocorticoid-induced impairment of these two memory functions also requires the integrity of the BLA and the noradrenergic system. Thus, these findings suggest that the BLA is a key structure in a memory-modulatory system that regulates, in concert with other brain regions, stress and glucocorticoid effects on different memory functions.