Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

https://science.sciencemag.org/content/sci/217/4558/408.full.pdf

The Cholinergic Hypothesis of Geriatric Memory Dysfunction

THE CLASSICAL CONCEPT of neuroendocrine control of the pituitary as proposed by Harris stipulates that the endocrine functions of the anterior pituitary are controlled by hypothalamic releasing factors or release-inhibiting factors. It was postulated that these factors are present in hypothalamic neurons which project into the median eminence (ME) of the basal hypothalamus and end in contact with the hypothalamic-hypophyseal portal vessels (1). It has subsequently been shown that growth hormone (GH) secretion is regulated by both stimulatory and inhibitory factors of hypothalamic origin. Like other anterior pituitary hormones, GH is secreted episodically. In all mammalian species so far studied spontaneous episodes of GH secretion occur several times over a 24-h period (2–8). Particularly in the adult male rat there is a striking regularity in the GH pulses which occur at 3- to 4-h intervals and reach levels of several hundred ng/ml.

Sexual dimorphism in the control of growth hormone secretion.

Altered neural-endocrine relations have been proposed as factors in mammalian aging. In the same rats from three age groups we quantified astrocyte reactivity in hippocampus, performed radioimmunoassays for plasma adrenocorticoids, and measured adrenal weight. These variables were correlated in individual animals and generally increased with age. The findings are consistent with recent hypotheses that endocrine levels are related to brain aging, either as cause or effect.

https://science.sciencemag.org/content/sci/202/4372/1098.full.pdf

Hippocampal aging and adrenocorticoids: quantitative correlations

Neurons sensitive to gonadal steroids are located strategically within neural circuits that mediate behaviors broadly related to the reproductive process. Some neuronal events and properties are regulated by these hormones. Variability in the occurrence and distribution of particular neural hormonal sensitivities across species may be related to variations in the hormonal requirements for sexual differentiation and for activation of reproductive behaviors.

http://science.sciencemag.org/content/sci/211/4488/1303.full.pdf

Neural gonadal steroid actions.

Relation of endogenous opioid peptides and morphine to neuroendocrine functions

The steady state concentration of dopamine (DA), norepinephrine (NE), and serotonin (5HT) was determined and turnover estimated in several brain regions of young (3–4 months) and old (21 months) male Wistar rats. An estimate of DA and NE turnover was obtained by determining their depletion rates after treatment with α-methylpara- tyrosine, a tyrosine hydroxylase inhibitor. Serotonin turnover was estimated by determining its rate of increase after monoamine oxidase inhibition with pargyline. In old males, medial basal hypothalamic (MBH) DA concentration and depletion rate were significantly lower than in young males. DA concentration of the remaining hypothalamus also was lower in old than in young males, but depletion rates were not different. DA concentration and depletion rate in the olfactory tubercle were the same in both age groups. The steady state concentration of NE in the MBH and remaining hypothalamus, and the hypothalamic NE depletion rate, were significantly lower in old than in young animals....

Evidence for Depressed Catecholamine and Enhanced Serotonin Metabolism in Aging Male Rats: Possible Relation to Gondotropin Secretion2

The effects of prolactin (PRL) administration on catecholamine turnover in various brain regions of ovariectomized rats were determined by observing the decline of dopamine and norepinephrine concentrations after α-methyltyrosine (αMT) administration PRL had no effect on the steady state concentration of dopamine in the median eminence, anterior hypothalamus and corpus striatum or on the norepinephrine concentration in the anterior hypothalamus However, PRL selectively enhanced dopamine turnover in the median eminence and anterior hypothalamus after a latent period of 10–26 h In addition, PRL administration significantly decreased serum concentrations of LH and FSH These results suggest that the PRL-induced increase in activity of dopaminergic neurons in the median eminence or anterior hypothalamus may be responsible for the reduction of the post-castration rise in serum concentrations of LH and FSH

Selective Actions of Prolactin on Catecholamine Turnover in the Hypothalamus and on Serum LH and FSH

Effects of L-tryptophan and restraint stress on hypothalmic and brain serotonin turnover, and pituitary TSH and prolactin release in rats

The dose-response effects of apomorphine and ET-495 (piribedil), 2 specific dopamine (DA) receptor stimulators, and haloperidol, a DA receptor blocker, were tested on the secretion of prolactin (PRL), thyroid stimulating hormone (TSH), growth hormone (GH) and luteinizing hormone (LH) in male rats. Both apomorphine and piribedil reduced serum PRL and TSH levels, stimulated GH release at low but not at high doses and either had no effect or tended to reduce serum LH levels. The minimal effective dose of apomorphine for reducing PRL by 30 min was 0.01 mg/kg; TSH inhibition was observed with a dose of 0.1-0.3 mg/kg. The inhibitory effects of apomorphine (1.0 mg/kg) on PRL and TSH levels were maximal by 15 min and diminished by 120 min; plasma GH was highest 120 min after injection. Thyroidectomy (10 days) markedLH elevated serum TSH, had no effect on serum PRL and inhibited the ability of apomorphine (0.1 or 0.3 mg/kg) to reduce TSH but not PRL levels. These observations may indicate that separate dopaminergic control mechanisms exist for TSH and PRL secretion. Administration of haloperidol elevated serum PRL, tended to lower TSH, dramatically reduced GH and had no effect on LH levels. Haloperidol pre-treatment blocked the effects of apomorphine on PRL, TSH, and GH secretion. The overall results of this study indicate that DA agonists inhibit PRL and TSH, stimulate GH but do not stimulate LH release in male rats.

Differential Effects of Dopamine Agonists and Haloperidol on Release of Prolactin, Thyroid Stimulating Hormone, Growth Hormone and Luteinizing Hormone in Rats

G.P. Mueller

Papers

Evidence for Depressed Catecholamine and Enhanced Serotonin Metabolism in Aging Male Rats: Possible Relation to Gondotropin Secretion2

Selective Actions of Prolactin on Catecholamine Turnover in the Hypothalamus and on Serum LH and FSH

Effects of L-tryptophan and restraint stress on hypothalmic and brain serotonin turnover, and pituitary TSH and prolactin release in rats

Differential Effects of Dopamine Agonists and Haloperidol on Release of Prolactin, Thyroid Stimulating Hormone, Growth Hormone and Luteinizing Hormone in Rats

Effects of pargyline on hypothalamic biogenic amines and serum prolactin. LH and TSH in male rats.