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.

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.

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.

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.

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.

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.

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.

Cerebrospinal fluid exchange after intrathecal methotrexate overdose. A report of two cases.

Two patients aged 11 and four years, were accidentally given a 10-fold overdose of intrathecal methotrexate while being treated for malignant disease. Neither patient developed any signs of neurotoxicity and exchange of lumbar cerebro-spinal fluid was started 3 and 5 h later, respectively. In one of the patients, who received 120 mg of methotrexate intrathecally, 31% of the given dose was recovered during 2 h of cerebrospinal fluid exchange that was started 3 h after the accidental overdosage. No sequelae were observed in any of the patients. Cerebrospinal fluid exchange is safe and can be recommended in all cases of intrathecal methotrexate overdosage. Ventriculo-cisternal perfusion is not necessary in cases of a 10-fold overdose if the patient has no signs of acute neurotoxicity.

Autoradiography of 3H-alpha-fluoromethyl histidine in mice: correlation with the kidney histidine decarboxylase activity.

Tritium-alpha-fluoromethyl histidine (3H-alpha-FMH), designed as a kcat-inhibitor of mammalian histidine decarboxylase (EC 4.1.1.22), was administered intravenously in male and pregnant female mice of the NMRI strain and the distribution of tritium in the body recorded by whole-body and microautoradiography. The results showed penetration of radioactivity into most tissues within 5 min. after the injection. After 4 hrs the highest levels of radioactivity were present in the intestinal content and in the kidneys. In the pregnant animal there was also a high labelling of the foetal tissues. When whole-body sections were washed in TCA prior to the autoradiographic exposure to retain only protein-bound radioactivity, a distinct labelling pattern was seen in the kidneys of the pregnant female mice but not in those of the male mice. Microautoradiography of the kidneys showed that the cells involved were located within the proximal convoluted tubuli. In several mouse strains, including the NMRI, the activity of kidney histidine decarboxylase is low in the males but high in females during a transient period of pregnancy. Incorporation of tritium into kidney protein after treatment with 3H-alpha-FMH, was correlated to a loss in histidine decarboxylase activity. The isotopic labelling was confined mainly to a component which cofractionated with histidine decarboxylase in polyacrylamide gel electrophoresis (PAGE) under non-denaturing conditions. Our data indicate that the cells described above represent the location of kidney histidine decarboxylase.

Hyperplasia and hypertrophia in the denervated and distended rat urinary bladder.

The parasympathetically denervated and distended rat urinary bladder was found to have increased fourfold in weight when examined 3 weeks postoperatively. Both in muscularis and mucosa of such a bladder the synthesis of proteins, RNA and DNA was increased severalfold. An increase in the polyamines putrescine, spermidine and spermine was also found; these polyamines are usually linked to protein synthesis. The results suggest that the cells of the two layers increase both in size and number. Hyperplasia was, in a previous study, suggested as a possible explanation for a right-ward shift of the active length-tension curve of muscle strips in the denervated rat urinary bladder.

In vitro metabolism of cadaverine in the pregnant rat.

The in vitro metabolism of 14C-cadaverine by diamine oxidase was investigated in various tissues of pregnant and non-pregnant rats. The metabolites formed were: delta 1-piperideine, delta-aminovaleric acid, carbon dioxide and some unidentified compound(s). In most of the tissues investigated delta 1-piperideine was the predominant metabolite, but considerable amounts of delta-aminovaleric acid and the unidentified compound(s) were also formed. The oxidative products of cadaverine might be of importance in various physiological and pathophysiological connections associated with elevated diamine oxidase levels.

Effect of His-Phe, a competitive inhibitor of histidine decarboxylase, on gastric acid secretion in chronic gastric fistula rats: delay in acid secretion response to pentagastrin.

The dipeptide His-Phe, earlier shown to inhibit mammalian histidine decarboxylase, was analysed concerning its effect in vivo on pentagastrin-induced gastric acid secretion. Chronic gastric fistula rats were used and the effectors in saline were given as continuous i.v. infusions while acid was collected from the fistula. Addition of pentagastrin to the infusion solution resulted in an immediate increase in the acid output of the control runs. In the His-Phe experiments the dipeptide was introduced one hour before pentagastrin. A significant decrease in the acid output was obtained. This effect was optimal at a dose of about 6 mg/h and during the first few hours of the experiments. In spite of the continuous His-Phe infusion the acid secretion increased with time to the control values. These results are discussed in relation to preliminary observations on effects of alpha-fluoromethyl histidine on gastric acid secretion and the effect of this and His-Phe on gastric histamine content and histidine decarboxylase activity.

Changes in cadaverine and putrescine metabolism in the mouse kidney induced to growth by an anabolic steroid.

The formation of cadaverine and putrescine was studied in the kidneys of gonadectomized male mice stimulated to growth by nandrolone, an anabolic steroid with low androgenic activity. Administration of nandrolone resulted in an increased kidney weight and elevated activities of lysine and ornithine decarboxylase (assayed by measurement of the formation of 14CO2 from the 1-14C-labelled amino acids). The responses were dose and time dependent. The elevated enzyme activities were reflected by an increased endogenous kidney content of cadaverine and putrescine as well as in an increased urinary excretion of the diamines. Further, the kidney content and the urinary excretion of the polyamines spermidine and spermine were elevated on nandrolone treatment. Fractionation of kidney extracts on pore gradient electrophoresis revealed an apparent molecular weight of about 95 000 Daltons of the lysine decarboxylase as well as of the ornithine decarboxylase. On electrofocusing it was evident that both enzymes were present as more than one isoelectric form. However, the main form in both cases focused at a pH of about 5.0.

Polyamine metabolism as related to growth and hormones.

Previous work had revealed a connection between high histamine formation and certain types of rapid growth. Since then evidences have accumulated that diamines abd polyamines affect an impressive number of reactions pertinent to cell growth and proliferation. In studies on polyamine metabolism as related to growth and hormones we have preferentially been working with three types of biological model systems, i.e. the pregnant rat, the gonadotrophin stimulated rat ovary and the mouse kidney induced to growth by androgenic or anabolic steroids.

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.

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.

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.