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Nicotinic Versus Muscarinic Blockade Alters Verbal Working Memory-Related Brain Activity in Older Women

From the Department of Psychiatry (JAD, PAN), Clinical Neuroscience Research Unit, University of Vermont College of Medicine; Department of Radiology (AJS, BCM), Center for Neuroimaging, Indiana University School of Medicine; and Department of Psychiatry (AJS,TWM, BCM, MLH), Brain Imaging Laboratory, Dartmouth Medical School, Dartmouth, NH.

Objectives: An important aspect of furthering our understanding of the central nervous system function after menopause is to examine the cerebral circuitry that appears to be influenced by cholinergic antagonist drugs in the presence and absence of estrogen. This pilot study investigated the effects of two anticholinergic drugs on brain activation and working memory performance in postmenopausal women not taking estrogen. This approach simulates the effects of age- or disease-related neuroreceptor or neuronal loss by temporarily blocking pre- and postsynaptic muscarinic and nicotinic cholinergic receptors.

Design: Six healthy postmenopausal women took part in three drug challenges using the antinicotinic drug mecamylamine (MECA, 20 mg, oral), the antimuscarinic drug scopolamine (SCOP, 2.5 µg/kg, IV), and placebo during functional magnetic resonance imaging. The cognitive measure was a visually presented verbal N-back test of working memory.

Results: Neither MECA nor SCOP significantly impaired performance on the verbal N-back. Functional magnetic resonance imaging results showed greater increases in frontal lobe activation in the placebo condition relative to each drug condition with different specific regional activation for MECA and SCOP.

Conclusions: These preliminary results suggest that brain activation patterns are sensitive to cholinergic modulation in postmenopausal women and that differential effects may be observed following nicotinic versus muscarinic blockade. This approach offers a potentially valuable method for modeling age-related changes in brain function, and the findings may have implications for cholinergic contributions to normal and pathologic aging.

Key Words: Working memory • postmenopausal women • fMRI • cholinergic system

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