2005 Lupien Hormetic Inlfuence Memory

HORMETIC INFLUENCE OF GLUCOCORTICOIDS ON HUMAN MEMORY

Sonia J. Lupien

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Laboratory of Human Stress Research,Douglas Hospital Research Center, Department of Psychiatry, McGill University,Department of Neurology and Neurosurgery, McGill University, Montreal

Claudia Buss

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Department of Psychology, University of Montreal

Tania E. Schramek

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Laboratory of Human Stress Research,Douglas Hospital Research Center, Department of Neurology andNeurosurgery, McGill University, Montreal

Francoise Maheu

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Laboratory of Human Stress Research,Douglas Hospital Research Center, Department of Psychology, University of Montreal

Jens Pruessner

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Laboratory of Human Stress Research,Douglas Hospital Research Center, Department of Neurology and Neurosurgery,McGill University, Montreal

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In this paper, we discuss the effects of glucocorticoids on human learning and memory usingthe recent model of hormesis proposed by Calabrese and collaborators. Although acute increases inglucocorticoids have been shown to impair memory function in humans, other studies report nosuch impairments or, in contrast, beneﬁcial effects of acute glucocorticoid increases on humanmemory function. We summarize these studies and assess whether the wealth of data obtained inhumans with regard to the effects of acute increase of glucocorticoids on human cognition are inline with a hormetic function. We then discuss several factors that will have to be taken into ac-count in order to conﬁrm the presence of a hormetic function between glucocorticoids and humancognitive performance.Keywords.Glucocorticoids, Noradrenergic Hormones, Hippocampus, Frontal, Memory, Recep-tors, Hormesis, Humans

INTRODUCTION

Stress is a popular topic these days. A week seldom passes without hear-ing or reading about stress and its deleterious effects on health and/or cog-nitive functions such as learning and memory. Given these negative conse-quences, many types of stress management therapies have emerged, whichaim to decrease stress and ultimately, prevent its negative impact on learn-ing and memory. The popular idea that stress impairs learning and mem-

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Address correspondence to Sonia J. Lupien, Ph.D., Laboratory of Human Stress Research, Dou-glas Hospital Research Center, 6875 Bld. Lasalle, Verdun (Quebec), H4H-1R3, Canada. Phone: (514)762-3028. Fax: (514) 888-4064. Email: lupson@douglas.mcgill.ca

Nonlinearity in Biology, Toxicology, and Medicine,

ory has been widely confirmed in the scientific literature. Indeed, about 40years of research has shown that the negative effects of stress on learningand memory are due to the fact that stress hormones (particularly gluco-corticoids), released during a stressful experience, easily cross the blood-brain barrier and impact brain structures known to be involved in learningand memory (for a complete review, see Lupien & Lepage, 2001).There is a great paradox, however, in the field of stress research that re-lates to the fact that stress hormones are not consistently linked to impairedlearning and memory. In various animal and human studies, stress hor-mones have been shown to increase the capacity to learn and/or consoli-date new information (for a review, see DeKloet

et al.,

1999 and Roozen-daal, 2002). In fact, in both animals and humans, many studies reveal thepresence of an inverted-U shape function between circulating stress hor-mone levels and memory performance (for a complete review, see Lupien& McEwen, 1997). Although the validity of the inverted-U shape functionbetween glucocorticoids and memory is still called into question, it is of in-terest to note that the observed biphasic effects of glucocorticoids on mem-ory may be part of a larger family of endogenous and exogenous substancesshowing a similar function, i.e. a function that has been termed “hormesis”.

THE CONCEPT OF HORMESIS

The term hormesis refers to how a typically toxic substance can havebeneficial effects at low doses (for a review, see Calabrese and Baldwin,2003). Hormesis has recently been the subject of what has been called the“dose-response revolution” (Calabrese and Baldwin, 2003). This revolutioncame about with the changing perception that the nature of the dose-response observed in toxicology, biology, and radiation data is not linear orthreshold, as originally postulated, but rather U-shaped. Using scientificdata from over 3,000 sources from a variety of research fields, Calabreseand collaborators (Calabrese

et al.,

1999; Calabrese and Baldwin, 2001,2002, 2003; Calabrese, 2002) have shown that the function relating a sub-stance to its effects follows an inverted-U shape. This finding could have atremendous impact on social policies and scientific thinking since it wouldsuggest, for example, that low doses of ionizing radiation, which were pre-viously thought to be harmful (the linear dose effect model), may not beharmful after all or may even have net benefits (see Sagan, 1989).A schematic representation of a hormetic function is depicted in Fig-ure 1. Here, the general form of the U-shaped dose-response curve showsresponse relative to a reference level, which includes a region of apparentimprovement as well as a region of toxic or adverse effects. In this Figure,the hormetic zone is defined as the entire zone of the function related toenhancing and impairing effects. What is important to note in the context

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S. J. Lupien et al

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of this paper is that the deﬁnition of a hormetic function by Calabrese andcollaborators (1999) implies the presence of a reference level that is basedon a control condition (in most cases, a placebo condition). The shape of the dose-response curve is then calculated by taking into account the per-centage of changes in the dependent variable, as a function of the controlcondition or reference level. Consequently, the entire zone above the ref-erence level refers to the stimulatory enhancing zone (the region of ap-parent improvement), while the zone below the reference level refers tothe region of adverse effects. The hormetic zone thus comprises both thestimulatory enhancing zone and the region of adverse effects. Calabreseand Baldwin (2003) reported that in most studies assessed, the amplitudeof the hormetic response almost never exceed a factor of twofold greaterthan the control, and is usually no greater than 130%–160% of the control,regardless of the width of the stimulatory dose range (Calabrese

et al.,

1999). Moreover, the width of the stimulatory dose range is below a 20-foldincrease from placebo in 70% of the cases, and between 20 and 1000-foldincrease from placebo in about 25% of the cases.Among the studies reviewed by Calabrese and collaborators in whichhormesis was observed, were those conducted by Yerkes and Dodson(1908) which showed that learning performance in rodents was optimized

Hormetic Effects of Glucocorticoids on Human Memory

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FIGURE 1

Schematic representation of a hormetic function (Figure adapted from Calabrese and Bald-win, 2003).

Category:	Research > Science
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Upload Date:	06/17/2009
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