Harderian gland: an extraretinal photoreceptor influencing the pineal gland in neonatal rats?

The circadian rhythm of pineal serotonin and the influence of light on that rhythm have been confirmed. Removal of the Harderian gland abolishes the response to light in blinded animals, which suggests that this gland may act as the extraretinal transducer involved in the persistence of the pineal rhythm in blinded suckling rats.

Harderian gland: development and influence of early hormonal treatment on porphyrin content.

The porphyrin content of the rat Harderian gland remains low until 12 days of age at which time both porphyrin content and concentration rapidly increase. Intraperitoneal administration of tetraiodothyronine (thyroxine) into newborn animals advances the appearance of porphyrin in the gland. Conversely, a single injection of cortisol acetate into newborns retards the appearance of porphyrin. The time of porphyrin appearance in the gland parallels the time for maturation of the evoked cortical response to visual stimulation in normal and hormone-treated animals.

Harderian gland: influence on pineal hydroxyindole-O-methyltransferase activity in neonatal rats.

A circadian rhythm has been found in hydroxyindole-O-methyltransferase activity of the pineal gland of blinded 12-day-old rats. Five additional hours of lighting can partly prevent the nocturnal increase in pineal hydroxyindole-O-methyltransferase activity in such rats. Removal of the Harderian gland abolishes this response to light in 12-day-old blinded animals, giving further support to the suggestion that this gland may function as an extraretinal photosensitive organ influencing the pineal gland in blinded suckling rats.

Ontogenesis of somatomedin and insulin receptors in the human fetus.

This study examines the ontogenesis of somatomedin and insulin receptors in man. Particulate plasma membranes were prepared by ultracentrifugation from various tissues removed from fetuses after abortion and classified as less than 17, 17-25, and greater than 25 cm in length. The binding of iodinated insulinlike growth factors 1 (IGF-1) and 2 (IGF-2), somatomedin A (SMA), multiplication-stimulating activity (MSA), and insulin was examined at the different ages. In the liver, cross-reaction studies revealed separate insulin and IGF-2 receptors. The Scatchard plots of insulin binding to liver membranes were curvilinear and showed an increase in the concentration of insulin receptors with advancing age. A single IGF-2 receptor was found on liver and no alteration was observed during development. The brain contained a lower concentration of insulin receptors. A change in the brain receptors for somatomedins occurred during development. Early in gestation, a high concentration of a low-affinity IGF-1 receptor was found. After approximately the 17th wk of gestation a higher affinity IGF-1 receptor appeared, which then increased in concentration. Cross-reaction studies also revealed changes in the specificity of these receptors during development. In the youngest fetal group IGF-2 was preferentially bound. Around midgestation a separate IGF-1 receptor, indicated by the preferential displacement of iodinated IGF-1 by IGF-1, appeared. In contrast, iodinated IGF-2 bound to a receptor where IGF-1 and IGF-2 were equipotent.

N-Acetyltransferase activity of the rat Harderian gland.

Harderian gland extracts from male rats catalyze the conversion of serotonin to N-acetylserotonin and of tryptamine to N-acetyltryptamine. The reaction is linear up to 14 mg tissue and departs from linearity after 10 min. The pH otpimum with tryptamine as substrate is between 8 and 9. Enzymic activity of the gland in vivo does not show diurnal variations. Enzymic activity of tissue in organ culture is not stimulated by 10 micrometer isoproterenol or 100 micrometer dibutyryl cyclic AMP. Harderian gland tissue in culture can acetylate tryptamine and serotonin and can O-methylate the N-acetylserotonin to form melatonin.

Propranolol in schizophrenia. Clinical, metabolic, and pharmacological findings.

Six schizophrenic patients received propranolol hydrochloride to evaluate pharmacological, endocrinological, and antipsychotic properties of the drug. They had previously been unsuccessfully treated with phenothiazines. After a drug-free period of two weeks, propranolol was administered in gradually increasing doses. After two to four weeks, a low dose of phenothiazines was added. The clinical effect was evaluated using the Comprehensive Psychopathological Rating Scale. Three of the six patients showed a definite improvement with propranolol therapy given as a sole treatment. Propranolol in plasma was positively correlated to dosage. The proportion of its major metabolite, 4-hydroxy-propranolol, decreased with increasing drug dose. Melatonin and prolactin levels in serum decreased noticeably with propranolol treatment. When phenothiazines were added, prolactin increased above drug-free levels. These results support the view that propranolol has an antipsychotic potential that needs further evaluation in clinical trials.

Exclusion of linkage between the serotonin2 receptor and schizophrenia in a large Swedish kindred.

Family, twin, and adoption studies suggest that genetic factors play an important role in the etiology of schizophrenia. Detection of single gene(s) involved in a higher susceptibility to a hereditary disease is possible with linkage analysis. The effects of serotonin2-receptor antagonists on symptoms of schizophrenia suggest that a mutation in the gene coding for this receptor subtype might be involved in the pathophysiology of this disease. Recently a copy DNA encoding the serotonin 5-HT2 receptor has been isolated and with a human 5-HT2 receptor copy DNA probe the HTR2 locus has been mapped to chromosome 13. Using multipoint linkage analysis between schizophrenia and genetic markers spanning the region of the HTR2 locus, we were able to exclude linkage between this candidate gene and schizophrenia in a Swedish kindred. Given this result, we conclude that the serotonin 5-HT2 receptor gene itself is not a major susceptibility gene for schizophrenia in this family.

No linkage between D2 dopamine receptor gene region and schizophrenia.

The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance, we were able to exclude the DRD2 locus with a lod score of -4.14 for the penetrance of 0.72 and with a lod score of -3.05 for the lower bound penetrance of 0.56. The area of exclusion (lod score, less than -2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.

Human serum melatonin changes during the menstrual cycle.

Serum melatonin concentration in early morning during the menstrual cycle, studied in five healthy women, showed that melatonin was elevated at the time of menstrual bleeding and had its nadir at the time of the menstrual cycling in humans.

The circadian covariation of fatigue and urinary melatonin.

Twelve healthy male subjects were kept under constant conditions (no sleep, isolation from time cues, controlled activity, etc.) for 64 hr. Urinary melatonin values, self-rated sleepiness, and vigilance performance scores were obtained every 3 hr. All variables showed a pronounced circadian rhythmicity. Vigilance performance and self-rated sleepiness showed, in addition, a gradual decrease and increase, respectively, with increasing sleep deprivation. The correlation of melatonin with performance and ratings was highly significant, high melatonin levels being associated with reduced performance and increased sleepiness. Aligning self-ratings and behavioral data with respect to the melatonin troughs and peaks showed that the former coincided with performance and alertness peaks and the latter with the troughs. It was concluded that under these conditions there is a strong circadian covariation between melatonin and indices of fatigue/sleepiness.

Plasma prostaglandin E2 metabolite--measured as 11-deoxy-15-keto-13,14-dihydro-11 beta,16 xi-cyclo-PGE2--in twins with schizophrenic disorder.

Blood samples were obtained from 18 twin pairs, and the major prostaglandin E2 (PGE2) plasma metabolite 15-keto-13,14-dihydro-PGE2 was measured by RIA after its conversion to 11-deoxy-15-keto-13,14-dihydro-11 beta,16 xi-cyclo-PGE2. Significant positive correlations were found in all the twin pairs, in 11 pairs diagnosed as DSM-III schizophrenic disorder and schizoid/schizotypal personality disorder, and in the 5 nonschizophrenic pairs. These results indicate that synthesis of prostaglandins (PGs) is in part genetically determined. With regard to absolute PGE2 metabolite levels, the data did not support the hypothesis of increased PGE2 in schizophrenia. Thus, seven of eight schizophrenic probands had lower metabolite concentrations than their healthy twin siblings, and in one pair they were similar. Furthermore, schizophrenic probands and their healthy sibling controls, taken as a group, had lower PGE2 metabolite levels than the group comprised of affective disorder probands and their respective controls. These findings raise the possibility that a change in PGE2 may be associated with schizophrenic and also possibly with affective disorders.

Somatomedins in aging and dementia disorders of the Alzheimer type.

Serum levels of somatomedins were determined in apparently healthy aged individuals and dementia patients primarily with clinically suspected Alzheimer type disorder. Serum somatomedin values, determined by radioreceptorassay and radioimmunoassay, fell with advancing age in normal subjects. A significant elevation in serum somatomedins was observed in dementia patients. CSF somatomedin levels were also increased in the only two patients with suspected Alzheimer type disease examined. Since somatomedins are believed to act as anabolic hormones, it was suggested that the elevated levels represent a compensatory mechanism to overcome receptor insensitivity in patients with dementia disorders of the Alzheimer type.

Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia.

OBJECTIVE: To describe symptoms, signs, neuroimaging results, and neuropathologic findings in patients from a family with chromosome 17q21-linked autosomal dominant frontotemporal dementia. DESIGN: Multiple case report with genetic investigations. SUBJECTS: The disease was observed in a Swedish family and documented in 3 generations. Four siblings are described in this article. RESULTS: A rapidly progressive dementia with genetic linkage to chromosome 17q21 was observed. The mean age of onset was 51 years and the average duration of disease to death was 3 years. Two patients started with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia and akinesia and muscular rigidity, and in 1 patient reckless driving was the first symptom. Loss of spontaneous speech developed later in all patients and emotional bluntness in 3 of the patients. Cerebral perfusion was decreased in the frontal areas in all patients. In the person with apraxia as the onset symptom, the cerebral blood flow was also diminished in the left hemisphere, where a slight atrophy was detected on magnetic resonance imaging scans. At the postmortem examination, slight gliosis of the parietal lobes was observed in this patient. In all patients there was a frontocentral degeneration of the cortex with discrete microvacuolation and gliosis. CONCLUSION: Clinical features of frontotemporal dementia, parkinsonism, an early age of onset, a rapid disease progression, and variable onset symptoms were seen in these patients. Two other clinically distinct diseases, dementia with pallido-ponto-nigral degeneration and a disinhibition-dementia-parkinsonism-amyotrophy complex, have recently been mapped to chromosome 17q21. In the family described in this article, genetic linkage was detected to the same region, suggesting the possibility that these diseases may originate from pathogenic mutations in the same gene.

Catecholaminergic activity in idiopathic torsion dystonia.

Day and nighttime melatonin and dopamine-beta-hydroxylase activity were measured in blood from 10 Jewish and 9 non-Jewish dystonics and from 22 nondystonic family members. Groups did not significantly differ on either of these measures. These results do not support a generalized abnormality of noradrenergic release in dystonia.

Melatonin secretion and excretion in patients with obstructive sleep apnea syndrome.

Melatonin (MT) secretion and excretion were investigated in patients with obstructive sleep apnea syndrome (OSAS). Nine men, mean age 55.1 years, mean body mass index 31.2, with a previously confirmed diagnosis of moderate to severe OSAS, were tested on two occasions: immediately before initiation of continuous positive airway pressure (CPAP) treatment and again after at least 4 weeks of continuous nocturnal use of CPAP. Serum MT concentrations were determined every second hour between 2000 and 0800 hours. Urine was collected between 2200 and 0700 hours for determination of urinary MT excretion. Sleep apnea recordings included ear oximetry, respiration and body movements, body position, and breathing sounds. Nine healthy male controls were tested on one occasion. We found that the MT secretion, as reflected by the area under the curve (AUC), among the OSAS patients did not differ from that found in healthy controls (MT AUC 1.68 vs. 1.92 nmol/l x h). Sleep apnea recordings were normalized during CPAP treatment. Moreover, the excessive daytime sleepiness disappeared in all patients. Neither MT secretion (MT AUC 1.68 vs. 1.56 nmol/l x h) nor urinary excretion of MT (0.122 vs. 0.108 nmol/9 h) changed significantly as a result of the CPAP treatment.

Progress in a genome scan for linkage in schizophrenia in a large Swedish kindred.

Genetic linkage studies of a kindred from Sweden segregating for schizophrenia have been performed using a genetic model (autosomal dominant, f = 0.72, q = 0.02, phenocopies = 0.001) as described in Kennedy et al., 1988. Analyses of the restriction fragment length polymorphism (RFLP), allele-specific oligonucleotides (ASO), and short tandem repeat (STR also called microsatellite) data for 180 polymorphisms (individual probe-enzyme, ASO, or STR systems) at 155 loci have been completed using the MLINK and LIPED programs. Linkage to schizophrenia was excluded, under the given model, at 47 loci; indeterminate lod scores occurred at 108 loci. The total exclusion region across 20 chromosomes is estimated at 330 cM; 211 cM excluded by pairwise analyses and 119 cM previously excluded by multipoint analyses (Kennedy et al., 1989: Schizophr Bull 15:383-391; Moises et al. 1991: Genet Epidemiol 2:99-110; Hallmayer et al., 1992: Arch Gen Psychiatry 49:216-219).

Alleles at the dopamine D4 receptor locus do not contribute to the genetic susceptibility to schizophrenia in a large Swedish kindred.

The discovery of a functional polymorphism within the dopamine D4 receptor gene (DRD4) has not only strengthened the hypotheses implicating DRD4 in the etiology of neuropyschiatric disorders, but also provided a genetic marker for testing these hypotheses. The possibility of the dopamine D4 receptor as a candidate gene for schizophrenia was investigated in a large Swedish kindred segregating for schizophrenia. Linkage to schizophrenia was tested by linkage analyses of 6 polymorphic markers (at 4 loci) in chromosome 11p15.5 including the dopamine D4 receptor (DRD4) and the tyrosine hydroxylase (TH) loci. Schizophrenia was excluded from close linkage to the DRD4 locus using two of the polymorphisms located within the dopamine D4 receptor gene. The first DRD4 polymorphism consists of variation in the number of a 48 bp imperfect direct repeat in the third exon; the second consists of a variable number of repeated G nucleotides in the first intron. In addition, some of the individuals homozygous for four or seven copies of 48 bp repeat alleles were tested for previously reported sequence variation among repeats. No single haplotype of the DRD4 alleles or haplotype of other markers in chromosome 11p15.5 was found to be common to the schizophrenic individuals in this family. Therefore, we find no evidence for linkage of the D4 receptor, or this region of 11p15.5, with genetic susceptibility to schizophrenia in this kindred.

The relationship between the pineal gland and the pituitary--adrenal axis in health, endocrine and psychiatric conditions.

Evidence is reviewed in favour of a close relationship between the pineal hormone, melatonin and ACTH--cortisol in man. Subgroups of patients with Cushing's disease as well as with major depressive disorder have low levels of nocturnal serum melatonin. Depressed patients with an abnormal dexamethasone suppression test (DST) have lower melatonin levels than do patients with a normal DST. Low melatonin levels may be a genetic trait marker for vulnerability to depression. The mechanism may be related to increased corticotropin-releasing factor (CRF), secondary to hypofunction of a pineal factor which physiologically inhibits CRF.

Normative melatonin excretion: a multinational study.

The present study on overnight urinary melatonin was conducted on the most geographically dispersed population to date, over a 1 year period, also covering a broad age range (18-62 years). An inverse relationship between melatonin and age, as well as between melatonin and weight was observed for both genders. Females as a whole, had higher melatonin values than males. Furthermore, the excretion of melatonin exhibited a bimodal distribution, distinguishing two groups of individuals: low and high melatonin excretors. The cut-off point was set at 0.25 nmol/l for ages up to 40 years and at 0.20 nmol/l for subjects above this age. Since melatonin may be involved in several physiological and pathological processes, it could be of importance to detect the type of melatonin excretion that prevails in various conditions, using a simple noninvasive procedure such as the overnight urinary measurement. For that purpose, this large sample could serve as a worldwide reference databank across different ages and locations.

Melatonin, cortisol and ACTH in patients with major depressive disorder and healthy humans with special reference to the outcome of the dexamethasone suppression test.

The 24 hr profiles of melatonin and cortisol in serum, morning levels of ACTH in plasma, and the dexamethasone suppression test (DST) were investigated in 32 acutely ill patients with a RDC diagnosis of major depressive disorder, 24 patients with a history of longlasting unipolar or bipolar major depressive disorder studied in remission, and 33 healthy subjects. A significant decrease in maximum nocturnal melatonin level (MTmax) was found in the acutely ill depressed patients with abnormal DST compared to both those with normal DSTs and the healthy subjects. The MTmax levels were unaltered when these patients were reinvestigated in remission. A decrease of MTmax was also seen in the group of unipolar and bipolar patients studied in remission. Low nocturnal melatonin is proposed to be a trait marker for major depressive disorder and depressive states with abnormalities in the hypothalamic--pituitary--adrenal (HPA) axis. A significant decrease of ACTH levels at 0800 hr after dexamethasone administration the preceding evening was found in the healthy subjects, the unipolar--bipolar patients in remission, and the acutely ill depressed patients with normal DSTs, but was not found in the acutely ill depressed patients with abnormal DSTs. These findings support the hypothesis that pituitary ACTH regulation is altered in depressed patients with abnormal DST. Morning plasma ACTH before the administration of dexamethasone did not significantly differ between the acutely ill depressed patients with abnormal DSTs, normal DSTs, the patients with unipolar--bipolar disease in remission, or the healthy subjects. Thus, the abnormalities in the HPA axis in depresséd patients are proposed to be due to a hypersecretion of corticotrophin releasing factor (CRF) with a subsequent stimulus-induced pituitary desensitization. A significant decrease of melatonin after dexamethasone was seen at 0800 hr in the unipolar--bipolar patients in remission as well as in the healthy subjects, at 1600 hr and 2200 hr in the acutely ill depressed patients in remission, but not at 0800 hr in the acutely ill depressed patients in relapse. A significant regression was found between MTmax levels and the degree of non-suppression of cortisol at 0800 hr in the DST in the acutely ill depressed patients both in relapse and in remission. Melatonin thus is proposed to be an inhibiting factor for CRF during depression. A trend to a phase-advance of cortisol nadir and melatonin peak was seen in the acutely ill depressed patients with abnormal DST, possibly indicating an involvement of the suprachiasmatic nuclei in the hypothalamus.