Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain.

The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

Influence of having a male twin on body mass index and risk for dyslipidemia in middle-aged and old women.

BACKGROUND: Animal experiments suggest that exposure to elevated levels of androgens during development by means of so-called hormonal programming causes metabolic aberrations at adulthood. An indirect strategy to address the possible importance of such an influence also in humans would be to study female dizygotic twins, presuming that those with a twin brother--due to diffusion of testosterone--have been exposed to higher androgen levels prenatally. DESIGN: We have compared 8409 women with a male twin with 9166 women with a dizygotic female twin with respect to self-reported indices of anthropometry and metabolic aberrations at age 42 or older. RESULTS: Body mass index (BMI), body weight and rate of dyslipidemia were moderately, but significantly, higher in women from opposite-sexed (OS) twin pairs; splitting for age revealed this difference to be present in those ≥ 60 years of age only. CONCLUSION: The results (i) support the notion that comparisons of women with a twin brother with women from same-sexed twin pairs may be used to shed light on possible long-term effects of interindividual variations in early androgen exposure, and (ii) suggest that the effects of early androgen exposure on metabolism previously observed in animal experiments are of relevance also for humans.

A missense polymorphism in the putative pheromone receptor gene VN1R1 is associated with sociosexual behavior.

Pheromones regulate social and reproductive behavior in most mammalian species. These effects are mediated by the vomeronasal and main olfactory systems. Effects of putative pheromones on human neuroendocrine activity, brain activity and attractiveness ratings suggest that humans may communicate via similar chemosignaling. Here we studied two samples of younger and older individuals, respectively, with respect to one nonsynonymous polymorphism in the gene encoding the human vomeronasal type-1 receptor 1, VN1R1, and one nonsynonymous polymorphism in the gene encoding the olfactory receptor OR7D4. Participants in both samples had self-reported their sociosexual behavior using the sociosexual orientation inventory, including questions regarding lifetime number of one-night stands, number of partners last year and expected number of partners the coming 5 years. In women, there was a significant association between the VN1R1 polymorphism and sociosexual behavior in both samples, driven specifically by the question regarding one-night stands. Our results support the hypothesis that human social interaction is modulated by communication via chemosignaling.

Polyamine metabolism in the kidneys of castrated and testosterone-treated mice after administration of methylglyoxal bis(guanylhydrazone).

The effects of methylglyoxal bis(guanylhydrazone) on S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50) activity were studied in the mouse kidney stimulated to growth by testosterone administration. The drug was found a potent inhibitor of the enzyme in vitrol Administration of methylglyoxal bis(guanylhydrazone) in vivo resulted in a transient inhibition followed by a strong enhancement of the enzyme activity. Dialysis of the kidney extract, to remove remaining methylglyoxal bis(guanylhydrazone), revealed a great and rapid increase in the activity of S-adenosyl-L-methionine decarboxylase. Injections of testosterone to castrated mice resulted in a marked increase in kidney weight and an accumulation of renal putrescine, spermidine and spermine. These effects of testosterone could not be blocked by simultaneous injections of methylglyoxal bis(guanylhydrazone). It appears that due to secondary effects by which the inhibition of methylglyoxal bis(guanylhydrazone) on S-adenosyl-L-methionine decarboxylase activity is circumvented the inhibitor seems to be of uncertain value in attempts to decrease selectively the in vivo levels of polyamines.

Role of emotional processing in depressive responses to sex-hormone manipulation: a pharmacological fMRI study.

Sex-hormone fluctuations may increase risk for developing depressive symptoms and alter emotional processing as supported by observations in menopausal and pre- to postpartum transition. In this double-blinded, placebo-controlled study, we used blood-oxygen level dependent functional magnetic resonance imaging (fMRI) to investigate if sex-steroid hormone manipulation with a gonadotropin-releasing hormone agonist (GnRHa) influences emotional processing. Fifty-six healthy women were investigated twice: at baseline (follicular phase of menstrual cycle) and 16 ± 3 days post intervention. At both sessions, fMRI-scans during exposure to faces expressing fear, anger, happiness or no emotion, depressive symptom scores and estradiol levels were acquired. The fMRI analyses focused on regions of interest for emotional processing. As expected, GnRHa initially increased and subsequently reduced estradiol to menopausal levels, which was accompanied by an increase in subclinical depressive symptoms relative to placebo. Women who displayed larger GnRHa-induced increase in depressive symptoms had a larger increase in both negative and positive emotion-elicited activity in the anterior insula. When considering the post-GnRHa scan only, depressive responses were associated with emotion-elicited activity in the anterior insula and amygdala. The effect on regional activity in anterior insula was not associated with the estradiol net decline, only by the GnRHa-induced changes in mood. Our data implicate enhanced insula recruitment during emotional processing in the emergence of depressive symptoms following sex-hormone fluctuations. This may correspond to the emotional hypersensitivity frequently experienced by women postpartum.

The effect of nandrolone, an anabolic steroid on putrescine metabolism in the mouse.

1 The catabolism of injected 14 C-putrescine was studied in mice treated with nandrolone phenpropionate, an anabolic steroid. 2 The putrescine was rapidly metabolized; almost 50% of the injected radioactivity was recovered within 2 h as 14 CO2 in the expired air. 3 Considerable amounts of radioactive gamma-aminobutyric acid (GABA) and an unidentified compound were found in the kidney and in the urine in addition to radioactive putrescine, spermidine and spermine both in controls and nandrolone-treated mice. 4 Nandrolone elevated the concentration of endogenous putrescine in the kidney and urine, eightfold and twentyfold, respectively, and the concentrations of spermidine and spermine were also increased 5 after the injection of 14C-putrescine the incorporation of 14C into spermidine was significantly increased in the kidney of mice receiving nandrolone.

Alterations of histamine metabolism after injections of sex hormones in mice.

1. Urinary excretion of histamine in female mice was determined after the injection of oestradiol, progesterone or testosterone. Histamine excretion was increased by oestradiol but was not affected by progesterone. Testosterone administration, by contrast, effected a striking reduction of histamine excretion.2. After injection of oestradiol, the kidney histamine forming capacity was greatly elevated, but in the other tissues investigated no significant change occurred.3. Testosterone administered in vivo but not in vitro reduced the histidine decarboxylase activity of female mouse kidney to a small fraction of normal.4. On thin-layer chromatography, after extraction and coupling of the amines to 2,4-dinitrofluorobenzene, the amount of histamine and to a lesser extent, methyl histamine in urine was reduced after testosterone administration. On the chromatogram of urine from untreated mice, an unidentified yellow spot appeared and the quantity of this spot was increased during testosterone treatment.

Alterations in the activities of ornithine and histidine decarboxylases provoked by testosterone in mice.

1. The urinary excretion of putrescine has been determined in female mice before and during repeated injections of testosterone.2. Testosterone administration effected a striking increase in the excretion of free putrescine.3. Ornithine decarboxylase (L-ornithine carboxy-lyase; E.C. 4.1.1.17) and histidine decarboxylase (L-histidine carboxy-lyase; E.C. 4.1.1.22) activities of mouse kidney and liver were examined. In the kidney, following testosterone administration, ornithine decarboxylase activity was found to be substantially elevated, whereas that of histidine decarboxylase was depressed. In the liver, by contrast, the activity levels of these enzymes were not significantly altered by testosterone treatment.4. The possibility of a functional interrelation between putrescine and histamine, via the two enzyme activities investigated, is discussed.

Comparison of human fetal hepatic and adrenal cytochrome P450 activities with some major gestational steroids and ethylmorphine as substrates.

The immunoidentified human fetal liver and adrenal microsomal contents of cytochromes P450IIIA and P450XVIIA1 were compared to the metabolism of steroids and ethylmorphine. In fetal liver microsomes, 16 alpha-hydroxylation of dehydroepiandrosterone (DHA) was catalyzed at a high rate in almost all investigated specimens and accompanied by a high ethylmorphine N-demethylase activity. Progesterone 16 alpha- and 17 alpha-hydroxylation was found only in the livers with the highest DHA 16 alpha-hydroxylation activities, while 21-hydroxylation of progesterone was catalyzed only occasionally in these samples. In fetal adrenal microsomes, 21-hydroxylation of progesterone to 11-desoxycorticosterone (DOC) and 11-desoxycortisol (DOCOL) was catalyzed. In contrast to fetal liver, the adrenals also catalyzed the 17 alpha-hydroxylation of pregnenolone and the formation of DHA from 17 alpha-OH-pregnenolone. 16 alpha-hydroxylation of DHA and ethylmorphine N-demethylation were modest in the adrenals. P450IIIA/HLp was immunoidentified in all investigated liver specimens except two (18/20) in which no ethylmorphine N-demethylation or 16 alpha-hydroxylation of DHA was found. P450XVIIA1 bands were observed in 8/20 blots of liver specimens, but there was no correlation between the density of these bands and the 17 alpha-hydroxylation of progesterone. All 11 fetal adrenal samples catalyzed DHA 16 alpha-hydroxylation, although only 8 were positive for P450IIIA/HLp. All investigated adrenals were positive in regard of the P450XVIIA1 band, except one (8/9) with a low 17 alpha-hydroxylation of progesterone. All adrenal specimens catalyzed 21-hydroxylation of progesterone and contained P450C21 bands in immunoblots and all samples catalyzed the formation of DOC and DOCOL from progesterone. Our findings in the fetal livers show a correlation between the DHA 16 alpha-hydroxylation and immunoidentified P450IIIA/HLp bands. In adrenals, there was a correlation between the immunoidentified P450XVIIA1 bands and the 17 alpha-hydroxylation of progesterone.

Association between amygdala reactivity and a dopamine transporter gene polymorphism.

Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [(15)O]water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.

Genetic variability within the innate immune system influences personality traits in women.

Raised levels of inflammation markers have been associated with several mental disorders; however, studies regarding the relationship between inflammation or the immune system and various aspects of human behaviour are not numerous. The aim of the present study was to investigate whether an association exists between personality traits and two single nucleotide polymorphisms located in genes that are associated with the innate immune system. The studied population consisted of 42-year-old women recruited from the population registry that had been assessed by means of Karolinska Scales of Personality, a self-reported inventory. The first polymorphism, +1444C>T (rs1130864), is located in the gene coding for C-reactive protein (CRP), a marker of low-grade inflammation. The T-allele has previously been suggested to be linked to raised serum levels of CRP. The second polymorphism, Y402H (1277T>C, rs1061170), is located in the gene coding for complement factor H, an important regulator of the complement system. The C-allele has consistently been associated with age-related macular degeneration. While the +1444T allele was associated with higher scores in the personality traits impulsiveness, monotony avoidance and social desirability, the 1277C polymorphism was associated with higher scores in verbal aggression and lower scores in social desirability. In conclusion, the associations between the personality traits and the studied polymorphisms further support the possible influence of the immune system on mental functions.

Biosynthesis of histamine and putrescine in mice during post-natal development and its hormone dependence.

1. Histidine decarboxylase and ornithine decarboxylase activities were determined in mouse kidney and liver during post-natal development. 2. The content of histamine, putrescine, spermidine and spermine was examined in kidney and liver and in the urine of adult male and female mice. 3. Histamine formation by the kidney was high in both sexes when determined a few days after birth but decreased during weaning. Thereafter, a distinct sex difference was established in that in the female kidney the level of histidine decarboxylase rose several-fold during adolescence while in the male the level was still further reduced. 4. Putrescine formation by mouse kidney was low in both sexes up to three weeks of age whereafter the amine formation in the male increased conspicuously whereas that of the female kidney remained low. 5. The observed sex differences in tissue enzyme activities were reflected in concomitant differences in the amount of the diamines excreted in the urine. 6. No correlation was found between the actual enzyme levels and the assayed tissue content of histamine, putrescine, spermidine and spermine. 7. Following gonadectomy, the activities of both decarboxylases were significantly altered. Ornithine decarboxylase activity of male kidney and histidine decarboxylase activity of female kidney were strikingly reduced. 8. In the mouse liver, the two decarboxylases displayed no changes comparable with that of the kidney during development.

Biosynthesis and accumulation of cadaverine and putrescine in rat ovary after administration of human chorionic gonadotrophin.

In the ovaries of pre-pubertal rats stimulated by human chorionic gonadotrophin (hCG) the temporal changes in cadaverine and putrescine formation were investigated. In addition, the dose-response relationship of hCG and its effect on the diamine formation and the effect of hCG on the content of diamines and polyamines in the ovaries and the urine were studied. The results show that the ovary stimulated by hCG, in addition to putrescine, forms cadaverine at a highly increased rate. The elevated diamine formation was parallelled by an increased content of cadaverine and putrescine in the ovary. Treatment with aminoguanidine elevated the content of cadaverine in the ovary, suggesting that diamine oxidase has a role as a regulator of the intra-ovary level of cadaverine. These results confirm that cadaverine can be synthesized in an inducible manner in mammalian tissues. This is, virtually, the first report of elevated formation of cadaverine in response to an exogenous gonadotrophin.

Metabolism of putrescine in the pregnant rat.

The in vivo metabolism of 14C-putrescine injected to rats before, during and after pregnancy was studied. Within 30 min of the administration of the isotope 9-12% of the injected radioactivity was recorded as 14CO2 in the expired air and after 5 h 60% was expired. The radioactivity excreted in the urine during the first day following the 14C-putrescine administration consisted of unmetabolized putrescine, gamma-aminobutyric acid (GABA) and some unidentified compound(s). No radioactive polyamines were detected in the urine. After treatment of pregnant rats with the diamine oxidase inhibitor aminoguanidine the expiration of 14CO2 was almost completely inhibited. In the urine increased amounts of unmetabolized putrescine were excreted while the excretion of GABA and the unidentified compound(s) were decreased. In addition 14C-spermidine appeared in the urine. The in vitro metabolism of putrescine was determined by the incubation of different tissues of pregnant and non-pregnant rats with 14C-putrescine. The 14C-metabolites derived via the diamine oxidase pathway (delta 1-pyrroline, GABA, some unidentified compound(s) and carbon dioxide) varied in magnitude with the tissue investigated. GABA was found to be a main metabolite of putrescine in several tissues of the pregnant rat. The content of putrescine and spermidine was elevated in several tissues as well as the blood on the 19th day of pregnancy in rats treated with aminoguanidine, while the content of spermine was unchanged.

Polyamines and nucleic acids in the mouse kidney induced to growth by testosterone propionate.

Daily injections of testosterone propionate to castrated mice resulted in a striking increase in kidney weight. Renal putrescine rose sharply and the amounts of spermidine were also increased. The activity or ornithine decarboxylase was enhanced to values of more than 1 000 times the control level within a few days of testosterone substitution. A moderate and temporary increase in the activity of the putrescine-activated S-adenosyl-L-methionine decarboxylase was observed. Testosterone injections produced a large increase of renal RNA but only a minor change in DNA. It is apparent that in mice distinct alterations in polyamine metabolism occur during the development of renal hypertrophy induced by testosterone administration.

On the biogenesis of diamines and polyamines in the pregnant rat.

The urinary excretion of the diamines histamine, methylhistamine, putrescine and cadaverine and the polyamines spermidine and spermine was studied in rats which on the 19th day of pregnancy were subjected to various ectomizing operations. In sham-operated rats the urinary excretion of all the amines studied except spermine was highly elevated on the day preceding the sham-operation and on the 3 days studied post-operatively, i.e. sham-operation did not affect the elevated urinary amine excretion during pregnancy. Foetectomy resulted in an abolished increase in the urinary excretion of histamine and methylhistamine while the excretion of putrescine, cadaverine and spermidine was still significantly increased. Removal of both the foetuses and placentae reduced the excretion of putrescine, cadaverine and spermidine towards the level of non-pregnant rats. Combined hysterectomy and ovariectomy did not cause any additional effects to those after removal of the foetuses and the placentae except for cadaverine, the excretion of which was further reduced.

In vitro metabolism of putrescine by diamine oxidase in tissues of the pregnant rat.

The metabolism of 14C-putrescine by diamine oxidase was tested on the 19th day of pregnancy in different organs of rats. The highest turnover was found in maternal placenta and uterus where 94% of the reaction product was identified as delta 1-pyrroline. Considerable deamination rates were also observed in ovary, liver and fetal placenta where, however, gamma-aminobutyric acid was the predominant product. In the kidney only a small diamine oxidase activity was measured. No formation of spermidine or spermine from 14C-putrescine was detected.