Neuroendocrine responses to intravenous infusion of arecoline in patients with Alzheimer's disease.
We have reported that arecoline, a muscarinic receptor agonist replicably enhanced verbal memory in five of nine subjects with Alzheimer's disease (AD). To investigate the mechanism of cognitive improvement, circulating hormone measurements were made during high-dose acute and low-dose chronic intravenous (i.v.) arecoline administration to AD patients. Acute hormone responses were measured during, and for 6 h after, infusion of arecoline 5 mg i.v. over 30 min. Chronic responses were measured in cognitive responders during continuous i.v. infusion of arecoline escalating over 2 weeks (0.5-40 mg/day) and then during a 1 week infusion of the dose optimizing cognition (4-16 mg/day). Acute arecoline administered to 14 subjects produced unpleasant side-effects (e.g. nausea, vomiting), mean adrenocorticotrophic hormone (p = .0006), cortisol (p = .0001) and beta-endorphin (p = .0001) levels were elevated. During chronic arecoline treatment, no side-effects occurred and plasma cortisol, adrenocorticotrophic hormone and beta-endorphin levels were unchanged in nine subjects overall and in five cognitive responders. Thus, high-dose arecoline activates the hypothalamic-pituitary-adrenal (HPA) axis and may increase other anterior pituitary hormone levels, likely representing a 'stress response', but cognition-enhancing, low doses of arecoline do not produce a glucocorticoid response. Hence, arecoline-induced memory improvement is not due to the induction of 'stress' nor to the elevation of peripheral corticosteroid levels.
Asthana
S
S
Unit on Pharmacology and Pharmacokinetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Raffaele
K C
KC
Greig
N H
NH
Berardi
A
A
Morris
P P
PP
Schapiro
M B
MB
Rapoport
S I
SI
Blackman
M R
MR
Soncrant
T T
TT
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D001115:Arecoline / Q000008:administration & dosage* / Q000009:adverse effects; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006728:Hormones / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D009483:Neuropsychological Tests; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D001615:beta-Endorphin / Q000097:blood
D006728:Hormones; D018721:Muscarinic Agonists; D001115:Arecoline; D001615:beta-Endorphin; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone