Elsevier

Hormones and Behavior

Volume 54, Issue 5, November 2008, Pages 684-693
Hormones and Behavior

Estradiol treatment and its interaction with the cholinergic system: Effects on cognitive function in healthy young women

https://doi.org/10.1016/j.yhbeh.2008.07.007Get rights and content

Abstract

The steroid hormone estradiol has been shown to modulate cognitive function in both animals and humans, and although the exact mechanisms associated with these effects are unknown, interactions with the cholinergic system have been proposed. We examined the neurocognitive effects of short-term estradiol treatment and its interaction with the cholinergic system using the muscarinic receptor antagonist scopolamine in healthy young women. Thirty-four participants (Mean age ± SD = 22.4 ± 4.4) completed baseline cognitive assessment and then received either 100 μg/day transdermal estradiol or transdermal placebo for 31 days. On days 28 and 31 of treatment, further cognitive assessment was performed pre- and 90 min post-scopolamine (0.4 mg) or placebo (saline) injection, under a randomized double-blind placebo-controlled design. Short-term estradiol treatment significantly enhanced spatial working memory with a trend for improvement in long-term verbal learning and memory. Overall, estradiol treatment did not protect against or attenuate the scopolamine-induced impairments in the cognitive domains assessed. Findings suggest that estrogen has minimal effects on cholinergic-mediated cognitive processes following short-term treatment. Effects of estradiol treatment may be dependent on age, dose of estradiol, integrity of cholinergic innervation and baseline endogenous estrogen levels, which may in part explain the inconsistent findings in the literature.

Introduction

Over the past three decades the neuroprotective effects of estradiol in the brain and on cognitive functioning has been extensively investigated. A number of comprehensive reviews and meta-analyses of the literature indicate that hormone therapy (HT; either estrogen only treatment [ET] or combined estrogen-progesterone treatment [EPT]) has a small but significant positive effect on measures of verbal memory, abstract reasoning and information processing in post-menopausal women (for reviews see Hogervorst et al., 2000, Sherwin, 2003, Sherwin, 2006, Zec and Trivedi, 2002), although this continues to be debated with several recent studies reporting minimal, negative or no effects (Almeida et al., 2006, Espeland et al., 2004, Lethaby et al., 2008, Resnick et al., 2006, Yaffe et al., 2006). These inconsistencies may be explained by a number of factors, including age, education, general health, socioeconomic status, type, dosage and duration of treatment, length of time between menopause and initiation of treatment, type of menopause (surgical/natural), and climacetric symptoms. Alternatively, the small and inconsistent findings may suggest minimal effects on cognition (for reviews see Lethaby et al., 2008, Sherwin, 2007). Despite the mixed findings from behavioral studies, there has been growing interest in the molecular mechanisms underlying estrogen's neuroprotective effects and it's influence on cognition, particularly given it's potential implications not only for improving cognitive function in patient with Parkinson's Disease and dementia, but also schizophrenia and other mental illnesses (for reviews see Cyr et al., 2002, Garcia-Segura et al., 2001, Halbreich and Kahn, 2003, Osterlund and Hurd, 2001).

Estradiol's interaction with the cholinergic system in particular, has been suggested to partially explain the possible effects on cognitive function (Gibbs, 2000b, Tinkler and Voytko, 2005, Toran-Allerand et al., 1992). This hypothesis is highly feasible given cholinergic input to fronto-limbic and fronto-striatal regions (Selden et al., 1998), and the abundance on evidence supporting this system's prominent role in modulating fundamental cognitive processes, particularly attention, learning, declarative memory and working memory (Ellis et al., 2006, Everitt and Robbins, 1997, Sarter et al., 2005, Hutchison et al., 2001, Thompson et al., 2000). This is further supported by animal studies which show an increase in choline acetyltransferase activity (Gibbs et al., 1994a, Luine, 1985, McMillan et al., 1996) and high-affinity choline uptake (Gibbs, 2000a, Singh et al., 1994) in cortical and subcortical regions following estradiol administration. In addition, estradiol treatment can enhance working memory via interaction with muscarinic (M2) receptors (Daniel et al., 2005) and can protect against the cognitive-impairing effects of the muscarinic receptor antagonist scopolamine, on measures of learning, declarative memory, and working memory in animals (Dohanich et al., 1994, Fader et al., 1998, Fader et al., 1999, Gibbs, 1999, Gibbs et al., 1998, Savonenko and Markowska, 2003, Tanabe et al., 2004).

The interaction between ET and the cholinergic system in humans is less established. Smith et al. (2001) found that length of ET/HT in post-menopausal women was positively correlated with vesicular acetylcholine transporter (VAChT) binding indexes in certain brain regions including the frontal and cingulate cortices, areas essential for attention, learning and memory. However, they were unable to find a difference in VAChT binding between ET/HT users and non-users (Smith et al., 2001). Using Single Photon Emission Tomography (SPET) and a novel muscarinic ligand (R,R) [123I]-I-QNB, Norbury et al. (2007) recently found higher muscarinic receptor density in the striatum, hippocampus, frontal cortex and thalamus of ET/HT users compared to non-users. To date only one research group has investigated the interaction between ET and the cholinergic system with regard to neurocognitive effects. Dumas et al. (2006) found three months of 1 mg/day oral estradiol treatment in post-menopausal women significantly attenuated scopolamine-induced deficits on measures of attention and reaction time. In addition, estradiol treatment also attenuated deficits caused by mecamylamine (a nicotinic receptor antagonist) on two measures of reaction time. However, no interaction between estradiol treatment and the cholinergic system was found on measures on verbal or visual learning and memory, or any of the accuracy/error measures of the attention tasks. More recently Dumas et al. (2008) reported a protective effect of estradiol treatment on episodic memory in younger (aged 50–62) compared to older (aged 70–81) post-menopausal women following a scopolamine challenge, suggesting the possibility of a critical period for ET's beneficial effects on the cholinergic system for women after the menopause.

The possible modulatory effects of estradiol treatment on the cholinergic system in relation to cognition have yet to be investigated in healthy young women of child-bearing age. The current study therefore examined; (a) the effects of one month of 100 μg/day estradiol treatment on cognitive function in a sample of healthy young women and (b) the interaction between estradiol treatment and the cholinergic system, specifically whether one month of estradiol can attenuate the scopolamine-induced deficits in cognitive function for this age group.

Section snippets

Subjects

34 healthy female volunteers (Mean age = 22.59 ± 4.45) aged between 18 and 38 years (Mean weight = 57.87 kg ± 12.57 kg) were recruited for this study from universities around Melbourne. All participants underwent a semi-structured medical screening by a physician who assessed the individual's physical and mental health. Women were excluded if they were pregnant, lactating, peri- or post-menopausal, had a current or past psychiatric illness, had endocrine abnormalities or suffered from any medical

Subjects

Of the 34 participants who enrolled in the study a total of 30 completed both parts One and Two (3 people withdrew due to time constraints and 1 withdrew due to religious commitments). The majority of participants were Australian born, and all spoke fluent English. There were no significant differences in mean age, weight, predicted WAIS-R IQ (as determined by the NART) or nationality found between the two groups (see Table 1). Independent samples t-tests conducted on each cognitive measure at

Discussion

The current study examined the cognitive effects of one month estradiol treatment and its interaction with the cholinergic system in healthy young women of child-bearing age. The findings showed that estradiol treatment; (1) enhanced accuracy on a measure of working memory, had a tendency to improve long-term verbal memory but had no effect on verbal fluency, cognitive flexibility, attention or information processing and psychomotor functioning, and (2) overall, did not protect against the

Acknowledgments

The authors wish to thank the Australian Rotary Health Research Fund for fellowship support for Cali Bartholomeusz and the National Health and Medical Research Council (NHMRC) for fellowship support for Pradeep Nathan. We would also like to thank Susan Illic for performing medical examinations and all the nurses from the School of Integrative Medicine, Swinburne University who administered the scopolamine and placebo injections, in particular Susan Vitetta who kindly gave up her free time to

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