Ank C. Frankhuijzen-Sierevogel

Anxious–Retarded Depression: Relation with Plasma Vasopressin and Cortisol

Dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis is related to melancholic or endogenous depression; however, the strength of this relationship depends on the definition of the specific depression subcategory. A two-dimensionally defined subcategory, anxious–retarded depression, is related to melancholic depression. Since arginine vasopressin (AVP) activates the HPA axis, and both major depression and the melancholic subcategory are associated with elevated plasma AVP levels, we investigated whether the plasma AVP level is also elevated in anxious–retarded depression, melancholic depression and anxious–retarded melancholic depression, and whether plasma AVP and cortisol levels are correlated in these subcategories. A total of 66 patients with major depression not using oral contraception were investigated. Patients with anxious–retarded depression had a highly significant AVP–cortisol correlation, while no such correlation was found in patients with nonanxious–retarded depression. Log-transformed mean plasma AVP values were higher in patients with anxious–retarded depression than in patients with nonanxious–retarded depression. Patients with anxious–retarded melancholic depression also had a significantly elevated level of plasma AVP and a highly significant correlation between plasma AVP and cortisol levels. The correlation was low in patients with melancholic depression. Anxious–retarded depression may be a useful refinement of the melancholic subcategory with regard to dysregulation of the HPA axis and plasma AVP release.

Plasma Arginine Vasopressin and motor activity in major depression

BACKGROUND Previously, we found that mean plasma concentrations of arginine vasopressin (AVP), but not of oxytocin (OT), were higher in depressed patients than in healthy controls. Plasma AVP concentrations were positively correlated to clinically rated psychomotor retardation. To further explore this previously reported relation we studied psychomotor retardation by means of an activity monitor, which is a more fine-focused and more objective instrument to analyze motor retardation than a clinical rating scale. METHODS Plasma AVP and OT concentrations, and day- and nighttime wrist activity were measured in 48 in- and outpatients with major depression and 30 healthy controls during a period of 5 consecutive days and nights. RESULTS Principal components analysis revealed three components of motor activity: motor activity during wakefulness, motor activity during sleep, and the awake/sleep time ratio. In patients and controls an inverse relationship between plasma AVP concentrations and motor activity during wakefulness was found. Patients with elevated AVP plasma levels showed increased motor activity during sleep. CONCLUSIONS These results suggest that high plasma AVP levels are related to the clinical picture of daytime psychomotor retardation and nighttime motor activity in major depression. Mean plasma OT concentrations were not related to measures of motor activity.

Distribution of glucuronidation capacity (1-naphthol and morphine) along the rat intestine

The distribution of glucuronidation capacity along the rat intestine was investigated using mucosal cells, isolated from the small intestine, the caecum, and the colon plus rectum. The glucuronidation capacity for 1-naphthol decreases from 787 +/- 75 (duodenum) to 128 +/- 13 (colon plus rectum) pmoles/min X mg cell protein. The ratio between 1-naphthol and morphine glucuronidation was constant throughout the intestine (7.15 +/- 0.37). The distribution of maximal activity of UDP-glucuronosyltransferase in intestinal cell homogenates follows the same pattern. The maximal activity of UDPglucose dehydrogenase in homogenates corresponds closely to the glucuronidation rate in mucosal cells. The activity of beta-glucuronidase in intestinal cell homogenates is constant along the duodenum and jejunum but increases throughout the terminal ileum, caecum, colon and rectum. Subcellular fractionation studies using marker enzymes indicate that UDPglucose dehydrogenase and beta-glucuronidase are cytosolic enzymes in intestinal mucosal cells. Although UDP-glucuronosyltransferase activity is found in both the mitochondrial and the microsomal fractions, no indications for a mitochondrial localization of this enzyme can be found. Activity in the mitochondrial fraction appears to be due to endoplasmic reticulum, associated with the mitochondrial fraction.

Depression with above-normal plasma vasopressin: Validation by relations with family history of depression and mixed anxiety and retardation

An anxious-retarded subtype of depression has been derived from the DSM-IV category of melancholia. It is defined by combined high scores for anxiety and retardation, and is related to family history of depression and increased plasma vasopressin (AVP) levels. Central problems concerning this hypothesized subcategory are whether elevated plasma AVP is related to family history, whether it would be better operationalized by a cut-off level for plasma AVP than as continuous variable, and whether the anxious-retarded phenotype would be better described in terms that account for full variability of mixed anxiety and retardation. A previous study suggested that above-normal plasma AVP was a more useful endophenotypic parameter than plasma AVP as a continuous variable. To answer these and related questions, 81 patients were investigated. Receiver Operating Characteristic analyses yielded a cut-off value of 5.56 pg/ml for above-normal plasma AVP, log-transformed plasma AVP (ln (AVP)) was used as continuous variable, and the correlation between anxiety and retardation was used to account for full variability of the anxious-retarded phenotype. Family history was related to above-normal plasma AVP (n = 16) and non-significantly to ln (AVP). Depression with above-normal plasma AVP, as well as familial depression with above-normal plasma AVP, showed a high correlation between anxiety and retardation, and this correlation was significantly higher than that found in the depressed patient control groups. The data support the delimitation of a largely familial depression with above-normal plasma AVP, vasopressinergic activation of the hypothalamus-pituitary-adrenal axis and a variable anxious-retarded phenotype.

Distribution of Lys-γ2-melanocyte-stimulating hormone- (Lys-γ2-MSH)-like immunoreactivity in neuronal elements in the brain and peripheral tissues of the rat

Abstract Using an antiserum raised against Lys-γ 2 -melanocyte-stimulating hormone (Lys-γ 2 -MSH), with a high specificity for this peptide and its des-Lys derivative, γ 2 -MSH, we found Lys-γ 2 -MSH-like immunoreactivity to have a widespread distribution in the rat brain. In colchicine-treated rats, groups of immunopositive cell bodies were found in the intermediate and anterior lobes of the pituitary gland, in the hypothalamic arcuate nucleus and in the commissural part of the nucleus of the solitary tract (NTS). Immunopositive fibers were found to originate from the latter two cell body regions. The distribution of these fibers was similar to that of the pro-opiomelanocortin-containing cell bodies and projections as it has been described previously. Immunopositive terminals were found in brain regions containing neurons which have been shown to express mRNA for melanocortin receptors, though the distribution of Lys-γ 2 -MSH-like immunoreactivity is considerably more widespread than that of mRNA for the ‘γ-MSH receptor’ (the melanocortin MC 3 receptor), which has been reported to be mainly expressed in the hypothalamus. In the periphery Lys-γ 2 -MSH immunoreactivity was localized in the adrenal medulla and in neuronal fibers and varicosities in the heart. The vascular system, the bronchi and kidney were immunonegative. The occurrence of Lys-γ 2 -MSH immunoreactivity in many of the brain regions which are involved in cardiovascular regulation offers leads for further studies on the putative role of γ-MSHs in cardiovascular control. The occurrence in the rat heart of Lys-γ 2 -MSH-containing fibers suggests a role of the γ-MSHs in cardiac function.

Kinetics of in vitro O-deethylation of phenacetin and 7-ethoxycoumarin by rat intestinal mucosal cells and microsomes: The effect of induction with 3-methylcholanthrene and inhibition with α-naphtoflavone

A novel, sensitive (0.5 ng) assay for acetaminophen, using HPLC with selective electro-chemical detection, enabled us to study rat small intestinal O-deethylation of phenacetin and compare it with corresponding 7-ethoxycoumarin-O-deethylation. Two in vitro systems, i.e. isolated intestinal mucosal cells and microsomal fractions thereof, were used to study kinetics for the O-deethylation of both substrates. Kapp m- and Vmax-values are similar for 7-ethoxycoumarin- and phenacetin-O-deethylation. Apparent Km-values varied between 50 and 70 microM in control rats and decreased after 3-methylcholanthrene pretreatment to 20-45 microM. Vmax-values were increased by 3-methylcholanthrene pretreatment. O-Deethylation was inhibited equally in cells and microsomes by alpha-naphthoflavone, but is inhibited more markedly in intestinal preparations after pretreatment with 3-methylcholanthrene. It is suggested that 7-ethoxycoumarin and phenacetin are O-deethylated by different forms of cytochrome P-450 with almost identical Kapp m and that these enzymes have a different distribution along the villus.

Cytochrome P-450 and ethoxycoumarin-deethylation in rat gastric microsomes: Induction by 3-methylcholanthrene and inhibition by cimetidine

Summary Gastric microsomal preparations from the rat showed a considerable cytochrome P-450.content, which is inducible by oral dosing of 3-methylcholanthrene. Preparations were able to dealkylate 7-ethoxycoumarin. A typical ligand spectrum by interaction with ferricytochrome P-450 upon addition of the anti-ulcer drug cimetidine to gastric microsomes was observed. Cimetidine also inhibited 7-ethoxycoumarin deethylation. This inhibition was more pronounced in control microsomes than in microsomes from 3-methylcholanthrene pretreated rats.

Comparison of microsomal drug-metabolizing enzymes in 14 rat inbred strains

Drug metabolic capacity in liver microsomes of 14 rat inbred strains was investigated. Cytochrome P-450 content as well as the following enzyme activities were measured: NADPH cyt. c(P-450) reductase (Red.), aminopyrine N-demethylase (APDM), ethoxycoumarin O-deethylase (ECOD), 1-naphthol: UDP-glucuronosyltransferase (NGT) and hydrolysis of acetylsalicylic acid (ASA; measured at pH 5.5 and pH 7.4). All enzymes measured were found to exhibit statistically significant inter-strain differences. In males the enzyme activities varied over a 7.3-fold (ECOD) to 1.4-fold (cytochrome P-450) range. Other inter-strain differences were generally larger than 2-fold: ASA-hydrolysis at pH 5.5 and 7.4 (3.9- and 3.3-fold variation, respectively), NGT and Red. (2.1-fold variation) and APDM (1.8-fold variation). In females similar, but somewhat smaller inter-strain differences were observed. Correlations between different enzyme activities were generally poor (correlation coefficients r less than 0.7). An exception was the correlation between ASA-hydrolysis at pH 5.5 and pH 7.4 (r = 0.79). We conclude that ASA hydrolysis at pH 5.5 and 7.4 is mediated by the same enzyme or by coregulated enzymes and that all other activities are mediated by different or differentially regulated enzymes. Based on analysis of variance and subsequent inter-strain comparisons, all strains appear to express a unique profile of liver microsomal drug metabolism. No two strains are identical with respect to all activities measured. We suggest that differences between inbred rat strains and particularly the difference in balance between different enzymes in various strains can be used advantageously in pharmacological and toxicological experiments.