Walter E. Müller

Cholinergic REM induction test: Muscarinic supersensitivity underlies polysomnographic findings in both depression and Schizophrenia

Disinhibition of rapid eye movement (REM) sleep (e.g. shortening of REM latency, heightened REM density) is frequently encountered in patients with a major depressive disorder (MDD). Administration of cholinomimetics prior to or during sleep leads to a more pronounced advance of REM sleep in depressed patients compared to healthy controls and patients with other psychiatric disorders. The present study tested whether the cholinergic REM induction test (CRIT) with 1.5 mg RS 86 (an orally acting muscarinic agonist) differentiates patients with MDD (n = 40) from those with schizophrenia (n = 43) and healthy controls (n = 36). The most pronounced shortening of REM latency after cholinergic stimulation occurred in patients with MDD. However, a significant number of patients with schizophrenia also displayed short REM latencies (REM latency < 25 minutes) under placebo conditions and after cholinergic stimulation. REM density measures more clearly differentiated patients with MDD from those with schizophrenia. It is concluded that a subgroup of patients suffering from schizophrenia displays signs of a muscarinic receptor supersensitivity.

Influence of the Cholinesterase Inhibitor Galanthamine Hydrobromide on Normal Sleep

Evidence from animal experiments has suggested that the triggering and maintenance of rapid eye movement (REM) sleep is mainly under the control of cholinergic neurons in the brain stem. Correspondingly, studies in humans have demonstrated that the application of cholinergic agonists or cholinesterase inhibitors provokes an earlier onset of REM sleep. The present study investigated the influence of galanthamine hydrobromide, a reversible cholinesterase inhibitor, on REM sleep regulation in 18 healthy volunteers. After an adaptation night, the subjects were given two doses of galanthamine (10 mg and 15 mg) or placebo at 10 p.m. in a randomized double-blind design. Both doses of galanthamine shortened REM latency (with statistical significance depending on the definition of REM latency used), increased REM density, and reduced slow wave sleep mainly in the first non-REM cycle. Higher doses of galanthamine (15 mg) seem to be accompanied by unwanted side effects that warrant the application of a peripheral antidote. These results are comparable to those for other cholinomimetics and stress the usefulness of galanthamine for pharmacological challenge studies in healthy subjects and depressed patients.

Muscarinic cholinergic receptors on intact human lymphocytes. Properties and subclass characterization.

Saturable specific binding of tritiated N-methyl-scopolamine (3H-NMS) can be demonstrated on intact circulating human lymphocytes, with an average KD of 7 nmol/liter and an average density of about 15 fmol/10(6) cells. Specific 3H-NMS binding can be inhibited by cholinergic antagonists and agonists, is highly stereospecific for the enantiomers of the cholinergic antagonist quinuclidinyl benzilate (QNB), and is modulated by the stable guanosine triphosphate (GTP) analog GppNHp in a fashion similar to the specific binding of the same radioligand to rat heart membranes. The results indicate the presence of muscarinic cholinergic receptors on intact human lymphocytes, with a predominance of the M2 subtype. As central muscarinic cholinergic receptors have been reported to play an important role in the pathogenesis of affective disorders, the lymphocyte might represent a suitable model for the study of muscarinic receptor functions in humans.

The influence of carbamazepine on sleep-EEG and the clonidine test in healthy subjects: Results of a preliminary study

A study of healthy volunteers was peformed with the aim of testing the hypothesis that carbamazepine suppresses REM sleep. Concerning GH secretion in the clonidine test, our study was considered exploratory

Platelet and lymphocyte free intracellular calcium in affective disorders

SummaryMany studies have demonstrated pharmacologic similarities between platelet and brain 5-HT2 binding sites. Therefore it may be possible to use platelets as a model for the central serotonergic neuron. Accordingly, a previcus report (Kusumi et al. 1991b) about elevated [Ca2+]i after serotonin stimulation in platelets of depressed patients was interpreted as further evidence for enhanced serotonergic sensitivity in depression. However, a very recent study showed an enhanced thrombin-induced platelet Ca2+ response, rather suggesting abnormalities of intracellular Ca2+ regulation in affective disorders. In the present study we have determined 5-HT2-and thrombin-induced Ca2+ responses in platelets and additionally phytohemagglutin (PHA)-induced Ca2+ increase in lymphocytes of medicated depressed patients (8 mono- and 2 bipolar, HRSD>17) and of ten sex- and age-matched controls. The results showed no significant difference in basal calcium levels between the two groups and no significant difference in the Ca2+ response to thrombin although the response was higher in the patients. The Ca2+ increase after serotonin stimulation in depressed patients was significantly (P<0.05) higher than in healthy controls. By contrast, the Ca2+ response to PHA in lymphocytes was significantly decreased in the patients. Our data confirm elevated Ca2+ responses after 5-HT2 receptor activation even in medicated depressed patients. However, Ca2+ responses in lymphocytes were decreased. Together with the observations of an enhanced Ca2+ response in platelets after thrombin stimulation, we speculate that the findings rather suggest alterations of [Ca2]i regulation in depression than specific changes of serotonergic sensitivity.

The Effect of Carbamazepine on Endocrine and Sleep EEG Variables in a Patient with 48-Hour Rapid Cycling, and Healthy Controls

Carbamazepine treatment of a patient with 48-hour rapid cycling led to a dampening of mood cycling, and prolonged rapid eye movement (REM) sleep latency. No effect on central alpha-receptors as measured by growth hormone (GH) secretion after clonidine stimulation or on spontaneous 48-hour GH secretion was observed. In 12 healthy subjects given 400 mg carbamazepine daily for a period of 5 days, improved sleep continuity and increased slow-wave sleep occurred with treatment. REM sleep percentage and REM latency remained uninfluenced, whereas REM density decreased. GH secretion after clonidine stimulation was not altered. Data from the single-case longitudinal study emphasize that carbamazepine is effective in treating rapid-cycling affective psychosis. Furthermore, neuroendocrine and sleep EEG data from the study in healthy subjects indicate a different profile of action for carbamazepine compared to most other antidepressants or antimanic drugs.

Growth hormone response to growth hormone-releasing hormone and clonidine in depression

Growth hormone (GH) responses to the alpha 2-adrenoceptor agonist clonidine and to GH-releasing hormone (GHRH) were measured in 12 patients fulfilling DSM-III-R criteria for major depressive disorder and in 12 age- and sex-matched controls. GH responses to clonidine correlated significantly with the GH responses to GHRH in the depressed patients as well as in the controls. Neither the responses to clonidine nor the responses to GHRH were significantly lower in depressed patients than in controls. Similarly, somatomedin-C (Sm-C) plasma concentrations and baseline GH concentrations were not different between the two groups. The data do not suggest that blunted GH responses to clonidine and/or GHRH represent specific features of depression.

Stereospecific3H-QNB binding to human erythrocyte membranes associated with muscarinic cholinergic receptors

Specific binding of the muscarinic antagonist3H-QNB can be demonstrated on human erythrocyte membranes. Specific3H-QNB binding is stereospecific and can be inhibited by a variety of cholinergic agonists and antagonist with affinities similar to their affinities for muscarinic cholinergic receptor binding in other tissues. Accordingly, the data indicate the presence of muscarinic cholinergic receptors on human erythrocyte membranes. Their density is very low, varies between healthy persons, but seems to be an individual characteristic. The data reported are consistent with the assumption that the muscarinic cholinergic receptors on human erythrocyte membranes are mainly of the M1 receptor subtype.

Personality factors predisposing to depression correlate significantly negatively with M1-muscarinic and β-adrenergic receptor densities on blood cells

SummaryA relationship between psychological and neurobiological predisposition factors for affective disorders has been suggested. The aim of the present study was to test this hypothesis. As predisposition measures of affective disorders, muscarinic and β-adrenergic receptors densities on blood cells and personality traits were determined in 16 male volunteers. The Minnesota Multiphasic Personality Inventory (MMPI), Freiburger Personality Inventory (FPI), and Premorbid Personality Inventory (PPI) were used for personality assessment. The erythrocyte muscarinic receptor density (mainly M1 subtype) correlated highly significantly negatively with depression on the MMPI (r = −0.71; P < 0.001) as well as significantly positively with reactive aggressiveness (dominance) on the FPI (r = 0.48; P < 0.05) and extraversion on the PPI (r = 0.46; P < 0.05). The β-adrenoceptor density on lymphocytes correlated significantly negatively with spontaneous aggressiveness (r = −0.51; P<0.05) on the FPI. These results are the first evidence that premorbid personality traits of depressives are related to M1-muscarinic and β-adrenergic receptors densities. It is speculated that decreased β-adrenergic receptor densities might predispose an individual to major depression whereas a decrease of M1-muscarinic receptor densities could play a role in the development of minor depressions. The findings of the present study are compatible with the postulated relationship between personality and neu robiological predisposition factors of depressive disorders. They suggest the participation of neurobiological factors in the development of personality traits predisposing to depression. However, they seem to be nonspecific for depression and are probably neither a sufficient nor a necessary cause of this disorder. Additional biological or psychological factors seem to be required for the development of clinical depressions.

DL-sodium lactate reduces alpha1-adrenergic receptor binding in rat and mouse brain

DL-Sodium lactate decreases the density of alpha 1-adrenergic receptors in rat brain membranes in vitro, an effect that is not present for several other neuroreceptors under similar conditions. Moreover, similar effects on specific 3H-prazosin binding to alpha 1-adrenergic receptors can be seen in the mouse brain after intravenous (i.v.) administration of DL-sodium lactate. Since these effects can be observed with i.v. doses of DL-sodium lactate only slightly higher than the doses needed to provoke panic attacks in susceptible patients, it seems possible that similar changes in central neurotransmission might be involved in the biological mechanism underlying the induction of panic attacks by DL-sodium lactate.