Biomedical subjects
Publications and source records attributed to S Checkley.
Nocturnal plasma melatonin concentration was significantly increased in ten normal volunteers following the administration of an alpha 2 adrenoceptor antagonist, Org 3770 (30 mg). This result supports the existence of an alpha 2 adrenergic influence on melatonin secretion in man and provides a possible clinical neuroendocrine marker of the action of an alpha 2 antagonist.
Nocturnal plasma melatonin concentrations were reduced following administration of the alpha 1 adrenoceptor antagonist, prazosin (2 mg orally at 1900h), to 10 normal men. These data indicate that alpha 1 adrenoceptors are involved in the physiological control of melatonin secretion in man.
The noradrenergic control of melatonin secretion in rat and man appears to have the property of a typical central noradrenergic system. Using the pineal as a model, increases and decreases in plasma melatonin levels are used to monitor the respective changes in noradrenergic transmission. Although in rats chronic imipramine treatment reduced pineal adrenoreceptor binding sites and melatonin levels, in depressed patients chronic treatment with desimipramine results in increases in plasma melatonin levels. These data support the classical view that in man antidepressants act by increasing monoamine transmission. The author postulates in depression a primary lesion distal to the monoaminergic projections but proximal to the hypothalamic nuclei, and further, that antidepressants may have a common effect on an as yet unidentified, hypothalamic neuropeptide.
The term 'psychopharmacology' was coined as early as 1920, by David Macht, but it was not until three decades later that the discipline started to develop in a substantial way. The fortuitous discovery of the first antipsychotics and antidepressants, in the 1950s, presented new horizons and gave impetus to the study of drug treatments in psychiatry. In the 1980s, advances in the basic neurosciences, and especially in the characterisation of neurotransmitter receptors, are presenting new opportunities for understanding the biology of mental illness and for designing new drug treatments. This article reviews the evidence linking the action of antidepressant drugs to the regulation of neurotransmitter receptors. We then show how this information has led to a pharmacologic model (melatonin secretion by the human pineal) for the study of antidepressants in depressed patients. Finally, we outline how pharmacologic exploitation of neurotransmitter receptors might lead to new approaches for the design of novel antidepressant drugs.
Acute administration of the antidepressant drug desipramine (DMI) in man, increased evening melatonin secretion, which reached peak plasma levels 2-4 h earlier than after placebo administration. The increase at set time points 21.00 h-22.00 h was directly proportional to an individual's integrated night-time secretion of melatonin. We have shown that this stimulation was not an effect of DMI inhibition on the hepatic metabolism of melatonin to 6-sulphatoxy melatonin (aMT6s), indeed aMT6s is in itself a good index of the evening melatonin rise. The stimulation of early evening melatonin by DMI might be exploited as a simple pineal function test.
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In an era when it is generally believed that the acute symptoms of schizophrenia can be controlled pharmacologically, the case of a young man who has remained almost continuously floridly psychotic for 13 years, despite treatment, is disquieting. Conventional psychiatric treatment appears to be rendered impotent. It is in this context that it may be of interest to report a summary of the proceedings of a Special Problems Conference held at the Institute of Psychiatry on 18 February 1985 to discuss such a case.
Growth hormone and prolactin responses to diazepam were measured in eight male patients who had been receiving long-term treatment with benzodiazepines and eight age-matched drug-free controls. The growth hormone response was significantly attenuated during benzodiazepine administration, but increased significantly after benzodiazepine treatment was discontinued. Growth hormone responses four days after the drug therapy withdrawal in patients, however, were still significantly less than in drug-free controls. Prolactin levels were unaltered after diazepam challenge, both in patients and in controls. The results clearly demonstrate tolerance to the growth hormone-releasing effect of diazepam, but do not suggest receptor supersensitivity after withdrawal of benzodiazepine therapy. It is possible that pituitary mammotropes lack benzodiazepine receptors.
The autonomic effects of mianserin were tested in seven depressed patients by comparing pupillary responses to adrenergic and cholinergic agonists before and after treatment. Mianserin failed to affect pilocarpine-evoked miosis and tyramine- or phenylephrine-evoked mydriasis, despite adequate plasma levels of the drug. There was, however, a significant reduction in resting pupillary size after 1 and 3 weeks of treatment: this could result either from a central action, or from interactions at receptors other than cholinergic or adrenergic ones in the pupil of the eye. It is concluded that in clinical dosage mianserin is devoid of effects upon muscarinic receptors, alpha 1 adrenoceptors and noradrenaline uptake in the pupil.
Six depressed patients were treated routinely with desipramine, a relatively selective noradrenergic uptake blocking drug. After 0, 1 and 3 weeks' treatment, pupillary responses to tyramine, phenylephrine and pilocarpine were measured using a photographic techniques. Both 1 and 3 weeks' treatment significantly inhibited tyramine and phenylephrine-induced mydriasis, but did not inhibit pilocarpine-induced miosis; in fact the longer treatment enhanced miosis due to pilocarpine. Resting pupil size was significantly increased after 1 and 3 weeks' treatment. The findings can be explained by the known ability of desipramine to block noradrenaline uptake and alpha adrenoceptors: they provide no evidence of muscarinic receptor blockade or of a slowly developing adaptation at alpha adrenoceptors.
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OBJECTIVE: This study was conducted to determine whether an increase in salivary free cortisol would be reliably elicited by a midday meal, thus providing a convenient physiological challenge to the hypothalamic-pituitary-adrenal (HPA) axis, and whether this cortisol release depended on the protein content of the meal. METHOD: In healthy men, free cortisol was measured in saliva samples taken before and after two identical protein-rich midday meals (39% energy as protein) and compared with a day on which no meal was eaten. Next, in healthy women in a nonclinical setting, salivary cortisol was measured before and after a protein-rich meal (32% energy as protein) on one day and a low-protein meal (5% energy as protein) on another day. Measures of mood, appetite, and psychological well-being were also taken. RESULTS: An acute meal-dependent increase in salivary cortisol occurred, which was reliable over 2 test days. This increase in cortisol depended on the proportion of protein in the meal, increasing after the high-protein but not the low-protein meal. The extent of this increase in cortisol correlated significantly with poor psychological well-being in women. Some postmeal improvement of mood (positive affect) was associated with the high- but not the low-protein meal. CONCLUSIONS: The cortisol response to meals may have implications for the effects of meal composition on mood, cognitive function, and food choice. The measurement of free cortisol in saliva provides a psychologically stress-free and reliable technique to assess the cortisol response to a standard protein-rich meal, ie, a physiological challenge to the HPA axis in men and women that could be investigated in naturalistic settings outside the laboratory.