Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala.
alpha(2) adrenergic agonists such as dexmedetomidine generally suppress noradrenergic transmission and have sedative, analgesic, and antihypertensive properties. Considering the importance of the neurotransmitter norepinephrine in forming memories for fearful events, we have investigated the acute and chronic effects of dexmedetomidine on discrete cue and contextual fear conditioning in mice. When administered before training, dexmedetomidine (10-20 microg/kg, i.p.) selectively suppressed discrete cue fear conditioning without affecting contextual memory. This behavioral change was associated with a decrease in memory retrieval-induced expression of c-Fos and P-CREB in the lateral, basolateral, and central nuclei of the amygdala. Dexmedetomidine's action on discrete cue memory did not occur in alpha(2A) adrenoceptor knockout (KO) mice. When dexmedetomidine was administered after training, it suppressed contextual memory, an effect that did not occur in alpha(2A) adrenoceptor KO mice. We conclude that dexmedetomidine, acting at alpha(2A) adrenoceptors, must be present during the encoding process to decrease discrete cue fear memory; however, its ability to suppress contextual memory is likely the result of blocking the consolidation process. The ability of alpha(2) agonists to suppress fear memory may be a valuable property clinically in order to suppress the formation of memories during stressful situations.
Department of Anesthesia, Stanford University of Anesthesiology, Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA, USA. fdavies@stanford.edu
M Frances
MF
Davies
Janet
J
Tsui
Judy A
JA
Flannery
Xiangqi
X
Li
Timothy M
TM
DeLorey
Brian B
BB
Hoffman
D058669:Adrenergic alpha-2 Receptor Antagonists; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology*; D003463:Cues; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D020927:Dexmedetomidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D007266:Inhibition, Psychological; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D013045:Species Specificity
D058669:Adrenergic alpha-2 Receptor Antagonists; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine