memory performance tested within the first 3 h after learn-ing) grows rapidly and then decays within hours, whereasthe LTM trace (
i.e.
memory performance tested at least 3 hafter learning) grows more slowly and is relatively perma-nent(1,27).Boththe
-adrenergicandcorticosteroidsystemshavebeenshowntomodulateshort-(
e.g.
Refs.24and28)andlong-term (
e.g.
Refs. 21–26, 28; see Ref. 5) memory consoli-dation of the stressful events themselves. However, the roleplayed by these two systems in modulating the effects of astressfulexperienceonshort-andlong-termconsolidationofmaterial unrelated to the stressor is to be further defined.Accordingly, the goal of this study was to disentangle andspecifytheroleplayedbythe
-adrenergicandcorticosteroidhormonal systems in modulating short- and long-term de-clarative memory of neutral material learned after stress inhumans. Young men were administered either a blocker ofperipheral and central
-adrenergic receptors (propranolol)or an inhibitor of corticosteroid synthesis (metyrapone) be-fore being exposed to a psychological stress task. Poststressshort-term (5-min delayed recall) and long-term (1-wk de-layed recall) declarative memory was compared with post-stress short- and long-term declarative memory measuredunder a placebo condition.
Subjects and Methods
Experimental subjects
Forty-two healthy English- and French-speaking men participated inthis experiment. The study was conducted according to human researchguidelines and was approved by the Douglas Hospital Research EthicsBoard. Informed consent was obtained from all subjects, who werecompensatedfortakingpartinthestudy.Subjects,agedbetween18and34 yr, were randomly assigned to one of three experimental conditions:oral (p.o.) placebo (n
14); propranolol 80 mg p.o., a blocker of pe-ripheral and central
-adrenergic receptors (n
14); or metyrapone, aninhibitor of corticosteroid synthesis (two doses, 750 mg p.o. each; n
14).Age,bodymassindex,andeducationlevelwerenotdifferentamonggroups(
P
0.27).Allsubjectswerenonsmokers.Subjectswererecruitedin the community and underwent psychological and physical exami-nations as well as blood and urine laboratory routine tests. To be in-cluded in the study, individuals were required to be exempt of a presentor lifetime history of psychiatric disorders (axis I and II disorders) asevaluated with the Structured Clinical Interview for Diagnostic andStatistical Manual of Mental Disorders-IV (29). Participants were alsorequired to be medication free and exempt of current medical problems,clinically significant electrocardiogram abnormalities, and any signifi-cant abnormalities on laboratory tests. Individuals working night shiftswere excluded from the study. Care was also taken not to evaluatesubjectsduringstressfulperiods(suchasexamperiods),andindividualswho had undergone major life changes (
e.g.
death of a close familymember in the past year) were not included in the study. Women wereexcluded from the study to avoid any confounding effects of the men-strualcycleandcontraceptivepillondeclarativememory(30),totalbasalcorticosteroid levels (31), and
-blocker catabolism (32).
Declarative memory task
Subjectsvieweda5-minnarratedseriesof11colorpicturespresentinga neutral story. Specifically, a young girl engaged in a safely organizedwoodworking activity with her grandfather before going, later on, to anoptometrist appointment with her grandmother. Narratives accompa-nying each picture were neutral and matched with regard to the com-prehensibility, complexity, syntax, and grammatical structure.Given the incidental nature of the declarative memory task (
i.e.
sub- jects were not aware of the later memory evaluation; Ref. 33), subjectswere told that they would be viewing pleasant, unpleasant, and neutralpictures and that we were interested in their physiological reactions (
i.e.
heart rate levels, blood pressure levels, and hormone levels) to thesepictures. Participants were asked to relax and simply watch the storypresented as if they were at the movies. Free recall of the story wasassessed at two time points, namely, 5 min after viewing (
i.e.
during thefirst experimental session) and 1 wk later (
i.e.
during the second exper-imental session; see
Psychoneuroendocrine protocol
). At the end of the firstsession,participantsweregivenaphonecallmeeting,tooccur1wklater,to complete a questionnaire on emotions. When called back, subjectswere informed that no questionnaire needed to be completed and wereinstead asked to recall as much information as possible about the storyviewed 1 wk earlier (long-term declarative memory condition). At theend of the phone call meeting, the experimenter asked the subjectswhether they anticipated the declarative memory tests; all reported thatthe declarative memory tests were unsuspected, for both the short- andlong-term free recall. All subjects were debriefed with respect to the realgoal of the study at the end of the second session.For the short- and long-term recall conditions, participants wereencouragedtorememberasmuchastheycouldaboutthemainstorylineas well as any details that would come to mind. Free recall was taperecorded to be analyzed later. The experimenter scoring the results wasunaware of drug conditions. Subjects were credited with the recall of apicture(foratotalofonepointperpicture)iftheyrememberedelementsthat could only have been seen in that particular picture and not in anyother picture or mentioned in the narration. The total declarative mem-ory task procedure, including the viewing of the story and the 5-mindelayedrecall,took15mintobecompleted.FrenchandEnglishversionsof the story were used, and there were no differences in short- andlong-term free recall with regard to the language in which the story waspresented (
P
0.10).
Psychological stress protocol
Subjectsweresubmittedtoapsychologicalstresstask,theTrierSocialStress Test (TSST), developed by Kirschbaum
et al.
(34). This laboratorystressorconsistsofafreespeechandamentalarithmetictaskperformedin front of an audience. The total procedure, including preliminaryinstructionsandapreparationperiod,takes20min.Awealthoffindingsdemonstrated the efficacy of the TSST in substantially increasing freesalivary cortisol levels and cardiac activity (
e.g.
Refs. 9–11, 18, 34, 35).
Psychoneuroendocrine protocol
Subjects were tested individually on two separate occasions. For thefirstexperimentalsession,participants wereaskedtohavealightbreak-fast at no later than 0700 h, during which they were asked not to haveany citrus products, coffee, tea, and sweets. They were also asked toavoid exercising the morning of the initial session and were asked nottoeatanddrinkanythingbutwater1hbeforethestartoftheexperiment.Subjects arrived at the laboratory at 1130 h, and baseline free salivarycortisol samples, heart rate, and blood pressure measures were taken at1150 and 1200 h. Cardiac activity was measured with the Welch AllynAtlas vital signs monitor (Skaneateles Falls, NY). At 1205 h, a first doseof metyrapone 750 mg p.o. was administered, whereas the placebo andpropranolol groups were given placebo pills. A light lunch was givenat 1245 h, and additional saliva samples, heart rate, and blood pressuremeasures were taken at 1225, 1315, 1340, and 1420 h.At 1450 h, heart rate and blood pressure measures were taken andthen, at 1452 h, the placebo group received a placebo, whereas themedication groups received their respective drugs (propranolol 80 mgp.o. or second dose of metyrapone 750 mg p.o.). These specific drugdoses (80 mg propranolol, 2
750 mg metyrapone) were selected be-cause they had proven efficient in blocking peripheral and central
-adrenergic receptors (24, 36) and inhibiting corticosteroid secretion (24,37–40) in humans. No side effects (nausea, dizziness, fatigue, sedation,
etc.
) due to either propranolol (80 mg) or metyrapone (2
750 mg) werereported by subjects. The times of drug administration were also care-fullyselectedtoensurepeakplasmapropranololandmetyraponeeffectsat the time of declarative memory evaluation (24, 37–41). The subjectsand experimenter were unaware of drug conditions.Saliva samples, heart rate, and blood pressure measures were takenat 1520 and 1550 h, and subjects were submitted to the TSST at 1555 h.Additionalsalivasamples,heartrate,andbloodpressuremeasureswerethen taken every 10 min from 1605 to 1705 h. Five minutes after the
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J Clin Endocrinol Metab, March 2005, 90(3):1697–1704 Maheu
et al.
• Modulation of Declarative Memory after Stress
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