Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs)... more
Melanocortin 4 receptor (MC4R) plays a key role in regulation of appetite activated by its main ligand α-melanocyte-stimulating hormone (α-MSH) in both central and peripheral targets. α-MSH also binds to circulating immunoglobulins (Igs) but the functional significance of such immune complexes (ICs) in MC4R signaling in normal and pathological conditions of altered appetite has remained unknown. To address this question, we analyzed plasma levels, affinity kinetics, and binding epitopes of α-MSH-reactive IgG extracted from plasma samples of female patients with hyperphagic obesity, anorexia nervosa, bulimia nervosa, binge-eating disorder, and healthy controls. Ability of α-MSH/IgG IC to bind and activate human MC4R were studied in vitro and to influence feeding behavior in vivo in rodents. We found that α-MSH-reactive IgG were low in obese but increased in anorectic and bulimic patients and displayed different epitope and kinetics of IC formation. Importantly, while α-MSH/IgG IC fro...
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The molecular mechanisms at the origin of eating disorders (EDs), including anorexia nervosa (AN), bulimia and binge-eating disorder (BED), are currently unknown. Previous data indicated that immunoglobulins (Igs) or autoantibodies... more
The molecular mechanisms at the origin of eating disorders (EDs), including anorexia nervosa (AN), bulimia and binge-eating disorder (BED), are currently unknown. Previous data indicated that immunoglobulins (Igs) or autoantibodies (auto-Abs) reactive with α-melanocyte-stimulating hormone (α-MSH) are involved in regulation of feeding and emotion; however, the origin of such auto-Abs is unknown. Here, using proteomics, we identified ClpB heat-shock disaggregation chaperone protein of commensal gut bacteria Escherichia coli as a conformational antigen mimetic of α-MSH. We show that ClpB-immunized mice produce anti-ClpB IgG crossreactive with α-MSH, influencing food intake, body weight, anxiety and melanocortin receptor 4 signaling. Furthermore, chronic intragastric delivery of E. coli in mice decreased food intake and stimulated formation of ClpB- and α-MSH-reactive antibodies, while ClpB-deficient E. coli did not affect food intake or antibody levels. Finally, we show that plasma lev...
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This study examined the effect of chronic diazepam administration on central benzodiazepine and CCK-8 receptor binding in rat brain. After a two-week treatment with diazepam (5 mg/kg per day) tolerance developed towards the sedative but... more
This study examined the effect of chronic diazepam administration on central benzodiazepine and CCK-8 receptor binding in rat brain. After a two-week treatment with diazepam (5 mg/kg per day) tolerance developed towards the sedative but not towards the anxiolytic action of this drug as determined using elevated plus-maze and open field tests. The % entries the rats made onto open arms and % time the rats spent in open arms were markedly decreased 24 h after the last dose of diazepam, probably indicating withdrawal anxiety. There were no changes in [3H]flunitrazepam binding either 30 min or 24 h after the last diazepam dose. However, 30 min after the last diazepam administration the apparent number of sulphated [3H]CCK-8 binding sites was significantly increased in the primary olfactory cortex. Acute diazepam treatment (5 mg/kg) had no influence on [3H]flunitrazepam or sulphated [3H]CCK-8 binding in any brain region studied. Cessation of chronic diazepam treatment was followed after 24 h by an increase in the number of CCK-8 receptors in frontal cortex and hippocampus as compared to the vehicle group. These results demonstrate that certain alterations in CCK-8 receptor characteristics may be important in the anti-anxiety effect, tolerance, and withdrawal reaction reaction after benzodiazepine administration.
Research Interests: Pharmacology, Chemistry, Animal Behavior, Medicine, Animals, and 15 moreMale, Open Field, Rat Brain, Rats, Radioligand Assay, Anxiolytic, Exploratory Behavior, Benzodiazepine, Diazepam, Brain Chemistry, Cholecystokinin, Flunitrazepam, Pharmacology and pharmaceutical sciences, In Vitro Techniques, and Substance Withdrawal Syndrome
Research Interests: Intelligence, Neuropsychopharmacology, Mitochondria, Medicine, Energy Metabolism, and 15 moreNucleus Accumbens, Emotions, Humans, Internal Medicine, Caudate Nucleus, Female, Male, Cytochrome c oxidase, Frontal Cortex, Aged, Middle Aged, Globus Pallidus, Neuronal Activity, Medical and Health Sciences, and Cognitive Deficit
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The effect of DSP-4, a neurotoxin selectively affecting the projections of the locus coeruleus, upon exploratory behaviour of rats was studied in a complex exploration test, including a choice between open and enclosed areas and both... more
The effect of DSP-4, a neurotoxin selectively affecting the projections of the locus coeruleus, upon exploratory behaviour of rats was studied in a complex exploration test, including a choice between open and enclosed areas and both inquisitive and inspective exploration elements. One week after DSP-4 (50 mg/kg i.p.) administration, the neurotoxin-treated rats did not explore a novel open area to any extent on the first exposure to the apparatus; however, on the third day of testing, these animals began to explore the area and the novel objects. Diazepam (0.5 mg/kg) treatment did not change the behaviour of control rats, but significantly increased the exploratory activity of the DSP-4-treated animals. LY 288513, a selective CCKB receptor antagonist (0.01 mg/kg), prevented the increase in exploratory activity in the DSP-4-treated rats, but increased the exploratory activity of controls on the third exposure to the test situation. The results of this investigation suggest that DSP-4 treatment reduces neotic behaviour by increasing neophobia rather than by decreasing exploratory drive. The divergence reported between the relative potencies of CCKB receptor antagonists in exploratory activity and other anxiety tests may in part be due to the effects of these drugs on exploratory drive.
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Noradrenaline (NA) has been implicated in both increase and reduction of anxiety. Selective destruction of nerve endings of the locus coeruleus projections by DSP-4 has been shown to reduce active behaviour in novel situations by... more
Noradrenaline (NA) has been implicated in both increase and reduction of anxiety. Selective destruction of nerve endings of the locus coeruleus projections by DSP-4 has been shown to reduce active behaviour in novel situations by enhancing anxiety. In the present study, DSP-4 (50 mg/kg) treatment reduced locomotor activity and time spent in social interaction in rats placed into a novel environment together with an unfamiliar rat, indicating an anxiogenic-like effect. The effect of DSP-4 on time spent in social interaction was completely antagonized by intracerebroventricular administration of neuropeptide Y (NPY) (1 microg) which had no effect of its own on this measure. The present study thus supports the idea that DSP-4 pretreatment is anxiogenic in novel situations and suggests a functional relationship of NA- and NPY-using neural mechanisms in the regulation of social behaviour.
Research Interests: Psychology, Social Interaction, Social Behaviour, Medicine, Social behavior, and 15 moreNeuropeptides, Animals, Male, Denervation, Neurotoxins, Clinical Sciences, Rats, Neuropeptide Y, Rat, Locus coeruleus, Wistar Rats, Locomotor Activity, Social Behavior, Neurosciences, and Biochemistry and cell biology
Research Interests: Reward, Dopamine, Hippocampus, Animals, Cocaine, and 15 moreMale, Projection, Denervation, Norepinephrine, High Pressure Liquid Chromatography, Rats, Analysis of Variance, Rat, Locus coeruleus, Neural pathways, Frontal Lobe, Motor activity, Conditioned place preference, Psychology and Cognitive Sciences, and Medical and Health Sciences
This study aimed to examine the structure of fears of youth, and its associations with gender, genetic variation of the serotonin transporter (5-HTTLPR), and perceived maternal acceptance/rejection and control, in a... more
This study aimed to examine the structure of fears of youth, and its associations with gender, genetic variation of the serotonin transporter (5-HTTLPR), and perceived maternal acceptance/rejection and control, in a population-representative sample. Participants were 453 adolescents and 540 young adults. Fears were assessed by a 18-item Fear Questionnaire, and perceived maternal relationships by the Mother Acceptance-Rejection/Control Questionnaire. A structured psychiatric interview was used to assess current and lifetime psychiatric disorders in participants from the older cohort. A principal component analyses indicated 2 components, named Fear/Phobia and Panic/Despair. Females expressed higher level of fears and symptoms of despair regardless of the serotonin transporter genotype. The 5-HTTLPR genotype nevertheless played a role in the association between fears and perceived relationships: in S/S-genotype, more Fear/Phobia was reported by the participants who perceived greater m...
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Rats display persistent behavioural phenotypes of low (LE) versus high (HE) exploratory activity in the exploration box paradigm. LE rats that prefer passive coping strategies show differential dopaminergic activity in the striatum. The... more
Rats display persistent behavioural phenotypes of low (LE) versus high (HE) exploratory activity in the exploration box paradigm. LE rats that prefer passive coping strategies show differential dopaminergic activity in the striatum. The main hypothesis of this study was that chronic variable stress (CVS) would have a higher impact on LE rats. Animals were submitted to a CVS regimen lasting 32 days that was followed by a behavioural test battery. The functional states of their dopamine D(1) and D(2) receptors were measured in the striatum and nucleus accumbens (NAcc). Cerebral oxidative metabolism was assessed via cytochrome c oxidase histochemistry in 65 brain regions. CVS decreased weight gain, to a higher extent in LE rats, and lowered the sucrose preference after the first week, but habituation to the anhedonic effect had developed by the end of the experiment. CVS did not change the behavioural phenotypes initially assigned. No effect of stress on D(2) receptor function was foun...
Research Interests: Cognitive Science, Coping Strategies, Social Interaction, Swimming, Nucleus Accumbens, and 26 moreSocial behavior, Vitamin D receptor, cyclic AMP, Chronic Disease, Animals, Male, Reaction Time, Cytochrome c oxidase, Sucrose, Cytochrome oxidase, Clinical Sciences, Rats, Analysis of Variance, Time Factors, Chronic Stress, Food Preferences, Body Weight, Wistar Rats, Social Behavior, Exploratory Behavior, Individual Difference, Protein Binding, Weight Gain, Maze Learning, Neurosciences, and Choice Behavior
To examine the associations of insulin resistance at childhood with adiposity changes over a 6-year period (from 9 to 15 years) in a sample of 659 Swedish and Estonian children (52.7% girls) participating in the European Youth Heart... more
To examine the associations of insulin resistance at childhood with adiposity changes over a 6-year period (from 9 to 15 years) in a sample of 659 Swedish and Estonian children (52.7% girls) participating in the European Youth Heart Study. We measured weight, height, waist circumference, biceps, triceps, subscapular, suprailiac, and medial calf skinfolds, and we calculated body mass index (BMI), sum of five skinfolds, and body fat percentage. Fasting plasma glucose and insulin were measured and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Changes in puberty stage, sex, centre and the corresponding baseline adiposity values were used as confounders in all analysis. HOMA-IR at childhood was significantly and positively associated with changes in BMI (β=0.265; P=0.024), sum of five skinfolds (β=0.3445; P=0.003), body fat percentage (β=1.042; P=0.016) and waist circumference (β=0.806; P=0.002) from childhood to adolescence. These relationships persisted w...
Research Interests: Education, Research Design, Obesity, Adolescent, Sweden, and 16 moreInsulin Resistance, Adipose tissue, Prospective studies, Humans, Child, Blood Glucose, Estonia, Female, Male, Body Mass Index, Waist Circumference, Body mass index (BMI), Body Weight, Abdominal Fat, Body fat percentage, and Skinfold Thickness
Brain-derived neurotrophic factor (BDNF) regulates food intake and energy metabolism. It has also been suggested that mutations in the human BDNF gene and its receptor TrkB account for disturbed eating and obesity. The Met-allele of the... more
Brain-derived neurotrophic factor (BDNF) regulates food intake and energy metabolism. It has also been suggested that mutations in the human BDNF gene and its receptor TrkB account for disturbed eating and obesity. The Met-allele of the BDNF Val66Met polymorphism has been associated with eating disorders, but the underlying mechanism of its contribution is not known. We report herewith that the effect of BDNF Val66Met polymorphism on binge eating in adolescent girls is dependent on severe food restriction. The scores on EDI-2 Bulimia subscale were significantly higher in BDNF Met-allele carriers who made attempts to regulate their body weight by reducing their meal frequency or by starving. This finding may help to explain why some people develop binge eating in response to dieting and others do not.
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Several lines of evidence suggest that alterations in serotonergic activity contribute to the pathophysiology of abnormal eating behaviors. Since platelet monoamine oxidase (MAO) activity and the 5-HT transporter gene promoter... more
Several lines of evidence suggest that alterations in serotonergic activity contribute to the pathophysiology of abnormal eating behaviors. Since platelet monoamine oxidase (MAO) activity and the 5-HT transporter gene promoter polymorphism (5-HTTLPR) have been associated with eating disorders, the knowledge from a population-based sample may provide useful information which changes in 5-HT function observed in eating disorders represent trait vs. state effects. The sample was based on both cohorts of the Estonian Children Personality, Behavior and Health Study (ECPBHS). The current study was conducted during the second follow-up where altogether 82% from the original sample was recruited. EDI-2 subscales--Drive for Thinness and Bulimia--were used to determine eating attitudes and behaviors. Platelet MAO activity was measured and the participants were genotyped for the 5-HTTLPR. Allelic variation of 5-HTTLPR or platelet MAO activity were not independently associated with drive for th...
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Twin studies suggest that substance use initiation in children and adolescents is determined primarily by environmental influences, whereas the establishment of use patterns is strongly controlled by genetic factors. The present study... more
Twin studies suggest that substance use initiation in children and adolescents is determined primarily by environmental influences, whereas the establishment of use patterns is strongly controlled by genetic factors. The present study analysed the effects of the serotonin transporter promoter polymorphism [5-HT transporter gene-linked polymorphic region (5-HTTLPR)] and the α(2A)-adrenoceptor C-1291G genotype (ADRA2A C-1291G) as well as their interaction effects on alcohol, tobacco and drug use from preadolescence to the late adolescence. Initial sample of 9-year-old children of Estonian Children Personality Behaviour and Health Study (n = 583) was recalled at ages 15 and 18. Participants reported in all waves how frequently they smoked and used alcohol and illicit drugs. 5-HTTLPR had age-dependent effects on alcohol, tobacco and drug use: substance use did not differ by genotype at age 9, but at age 15, the participants with the short (s)/s genotype had higher tobacco use, and at age 18, they were more active alcohol, drug and tobacco users. Effects of ADRA2A C-1291G on drug use were dependent on gender, age and 5-HTTLPR. Males (age 18) with ADRA2A CG genotype, when compared to other participants, tended to have higher drug use especially when they had s/s genotype of 5-HTTLPR. Our results reveal that expression of genetic vulnerability for substance use in children and adolescents may depend on age, gender, interaction of genes, and type of substance.
Research Interests: Genetics, Psychopharmacology, Polymorphism, Tobacco, Adolescent, and 20 moreDrug Use, Humans, Child, Substance Use, Estonia, Tobacco Use, Female, Serotonin Transporter, Male, Children and Adolescents, Longitudinal Studies, Genotype, Sex Factors, Analysis of Variance, Longitudinal Study, Illicit Drugs, Age Factors, Twin Study, Interaction effect, and Substance-Related Disorders
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Neuropeptide S is involved in anxiety and arousal modulation, and the functional polymorphism Asn107Ile (rs324981, A > T) of the neuropeptide S receptor gene (NPSR1) is associated with panic disorder and anxiety/fear-related traits.... more
Neuropeptide S is involved in anxiety and arousal modulation, and the functional polymorphism Asn107Ile (rs324981, A > T) of the neuropeptide S receptor gene (NPSR1) is associated with panic disorder and anxiety/fear-related traits. NPSR1 also interacts with the environment in shaping personality and impulsivity. We therefore examined whether the NPSR1 A/T polymorphism is associated with affective and anxiety disorders in a population-representative sample. Lifetime psychiatric disorders were assessed by MINI interview (n = 501) in the older cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study (ECPBHS). Anxiety (STAI), self-esteem (RSES), depression (MÅDRS), suicide attempts and environmental factors were self-reported in both the younger (original n = 583) and the older cohort (original n = 593). Most of the NPSR1 effects were sex-specific and depended on environmental factors. Females with the functionally least active NPSR1 AA genotype and expos...
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Much data has accumulated over the past decade supporting the hypothesis that CCK plays a role in the neurobiology of anxiety and panic attacks. These data originated from animal studies and human studies that were initiated... more
Much data has accumulated over the past decade supporting the hypothesis that CCK plays a role in the neurobiology of anxiety and panic attacks. These data originated from animal studies and human studies that were initiated independently, but the conclusions are remarkably consistent. In this review, Jacques Bradwejn and colleagues examine the evidence for a role of CCK in anxiety and panic attacks, and highlight the consistencies between animal and human studies.
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Systemic treatment with caerulein (0.25-5 micrograms/kg SC), non-selective agonist of cholecystokinin (CCK) receptors, dose-dependently suppressed the exploratory behaviour of rats in an elevated plus-maze without producing remarkable... more
Systemic treatment with caerulein (0.25-5 micrograms/kg SC), non-selective agonist of cholecystokinin (CCK) receptors, dose-dependently suppressed the exploratory behaviour of rats in an elevated plus-maze without producing remarkable changes in the locomotor activity of animals in an open field test. Ondansetron, a selective antagonist of 5-HT3 receptors, increased the number of open arm entries in the plus-maze test only at a dose 10 micrograms/kg. The other doses of ondansetron (0.1, 1 and 100 micrograms/kg IP) did not significantly change either the locomotor activity or the exploratory behaviour of rats. Pretreatment of rats with ondansetron (at 10 micrograms/kg, but not at 0.1, 1 or 100 micrograms/kg) completely reversed the anti-exploratory effect of caerulein (5 micrograms/kg). The concomitant treatment with caerulein and ondansetron did not cause any major change in the locomotor activity of animals in open field. Consequently, we propose that 5-HT-ergic mechanisms are involved not only in the regulation of CCK release in the cerebral cortex and nucleus accumbens, but also in the modulation of the anti-exploratory effect of caerulein, a CCK agonist, in the elevated plus-maze.
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Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism... more
Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic functioning. The effect of the two markers for serotonin system efficiency on performance in a visual comparison task (VCT) and self-reported impulsiveness (Barratt Impulsiveness Scale, BIS-11) were investigated in healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study. Possible confounding effect of general cognitive abilities on the performance in VCT was controlled for. Low platelet MAO activity and carrying of the S allele of 5-HTTLPR were both associated with higher error-rate and more impulsive performance in VCT. Platelet MAO activity and 5-HTTLPR S allele had a significant interactive effect on self-reported impulsivity (BIS-11). The effect of platelet MAO activity on both self-reported and performance impulsivity was significant only in the S allele carriers. The effect of 5-HTTLPR S allele on impulsive performance remained significant after controlling for general cognitive abilities. The two markers of lower serotonergic capacity, 5-HTTLPR S allele and low platelet MAO activity, have a similar and partly synergistic influence on self-reported as well as performance measures of impulsivity.
Research Interests: Psychopharmacology, Polymorphism, Cognition, Visual perception, Adolescent, and 18 moreCognitive Style, Information Processing, Serotonin, Humans, Female, Serotonin Transporter, Male, Reaction Time, Information Processing in Visual System, Mental processes, Bit Error Rate, Psychological Tests, Genotype, Cognitive Ability, Interaction effect, Impulsive Buying Behavior, Monoamine oxidase, and Performance Measure
Major depressive disorder is predicted by enduring anxiety-related personality traits, in particular by neuroticism, which have genetic foundations. Neuroticism in turn is strongly related with the genetic risk for depression. Search for... more
Major depressive disorder is predicted by enduring anxiety-related personality traits, in particular by neuroticism, which have genetic foundations. Neuroticism in turn is strongly related with the genetic risk for depression. Search for gene variants associated with neuroticism and depression has led to some good candidates, but the consistency of findings is very far from ideal. Adverse life events are causal to development of mood disorders, and often the vulnerability genes can be detected only when environmental impact has been objectively assessed. Yet the continuity of depression diagnosis from early childhood to adulthood is limited, while childhood depression increases odds of other affect-related disorders such as substance abuse and personality disorders. Whether specific genes have an impact seems to depend on the period of life both because of biological maturation and differences in major environmental factors, but also active engagement--or the failure to do so--of the vulnerable subjects with their environment. It is proposed that subjects with genetically determined neurotic tendencies are likely to attempt to select coping strategies that reduce events perceived as harmful and can by this means develop resilience towards affective disorders.
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1. The effect of gender, smoking and pubertal development on platelet monoamine oxidase (MAO) activity was described in a randomly selected, large sample of 9- and 15-years old healthy children. 2. Platelet MAO activity was measured in... more
1. The effect of gender, smoking and pubertal development on platelet monoamine oxidase (MAO) activity was described in a randomly selected, large sample of 9- and 15-years old healthy children. 2. Platelet MAO activity was measured in 1129 children by a radioenzymatic method with beta-phenylethylamine as the substrate. Smoking habits were reported in an anonymous questionnaire. Pubertal status was assessed visually using Tanner's stages. 3. Boys, younger children and smokers had significantly lower platelet MAO activity than girls, older children and non-smokers, respectively. Girls in Tanner's stage V for breast and pubic hair development had significantly lower MAO than girls in stage IV. 4. Differences in gender, age, pubertal status and smoking habits must be taken into account if the relationship between platelet MAO activity, personality and psychiatric disorders is studied in children.
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The short (S) allele of the 5-HTT gene promoter region polymorphism (5-HTTLPR), in combination with adverse environmental influence, leads to higher likelihood of depression. Impulsivity has been related to low serotonin turnover, poor... more
The short (S) allele of the 5-HTT gene promoter region polymorphism (5-HTTLPR), in combination with adverse environmental influence, leads to higher likelihood of depression. Impulsivity has been related to low serotonin turnover, poor regulation of affect, and problems in the family, including child maltreatment. The current study explored the effect of the 5-HTTLPR polymorphism in the serotonin transporter gene and adverse family environment on impulsivity in adolescents. Healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study (n=483) filled the Adaptive and Maladaptive Impulsivity Scale (AMIS), Barratt Impulsiveness Scale (BIS-11), a scale measuring family relations, and were genotyped. While genotype alone was not associated with thoughtlessness, BIS-11 impulsiveness, fast decision-making or excitement seeking, 5-HTTLPR S allele carriers, however, had higher scores of disinhibition. In girls carrying the S allele, scores of thoughtlessness and disinhibition depended on family relations, being higher with less warmth in the family. Adverse family relations had no effect on impulsivity in girls with LL genotype. In boys, the effects of family relations on maladaptive impulsivity did not depend on genotype. However, the S allele and high maltreatment in the family both independently increased disinhibition and the BIS-11 score in boys. Family environment and the 5-HTTLPR genotype had no interactive effect on excitement seeking or fast decision-making. In summary, carrying the S allele may lead to high maladaptive impulsivity due to higher sensitivity to environmental adversity, which is more significantly expressed in girls.
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This study was designed to compare growth hormone, cortisol and prolactin responses to physical exercise in depressed patients and healthy comparison subjects. Patients fulfilled the DSM-IV diagnostic criteria for current major depressive... more
This study was designed to compare growth hormone, cortisol and prolactin responses to physical exercise in depressed patients and healthy comparison subjects. Patients fulfilled the DSM-IV diagnostic criteria for current major depressive disorder; subjective depressive symptoms were rated with Montgomery-Asberg Depression Rating Scale (MADRS) immediately before the experiment. Growth hormone, cortisol and prolactin were measured before and immediately after physiologically stressful bicycle cardiopulmonary exercise test. After exercise, there were three additional hormone measurements, with 30-min intervals. No significant difference was found in baseline growth hormone, cortisol or prolactin levels between patients and the control group. Plasma growth hormone and cortisol levels increased significantly during physical exercise in both patients and controls and returned to baseline in 90 min. There was no significant difference in growth hormone or cortisol responses to physical exercise between the two groups. However, prolactin levels increased only in the depressed patients group during the exercise. We hypothesize that acute exercise may have a stronger effect on serotonin (5-HT) release in depressed patients, which is reflected in increased plasma prolactin concentration.
Research Interests: Serotonin, Growth Hormone, Cortisol, Humans, Prolactin, and 17 moreMajor Depressive Disorder, Male, Exercise, Depressive Disorder, Rating Scale, Aged, Middle Aged, Adult, Analysis of Variance, Time Factors, Immunoassay, Age Factors, Physical Exercise, Depressive Symptoms, Exercise Test, Cardiopulmonary Exercise Testing, and Control Group
The C-1291G polymorphism (rs1800544) in the promoter region of the alpha(2A)-adrenoceptor gene (ADRA2A) has been associated with attention deficit and hyperactivity in clinical samples. We have examined the effect of ADRA2A C-1291G on... more
The C-1291G polymorphism (rs1800544) in the promoter region of the alpha(2A)-adrenoceptor gene (ADRA2A) has been associated with attention deficit and hyperactivity in clinical samples. We have examined the effect of ADRA2A C-1291G on inattentive, hyperactive and aggressive behaviour in a population representative cohort of healthy schoolchildren, and possible interaction of genotype with family relations. Ratings on aggressiveness, motor restlessness and concentration difficulties were obtained from the class teachers by using the Hyperactivity Scale of af Klinteberg, and the teacher-report version of SNAP-IV. The relations in the family were reported by children. Symptom scores, self-reports and genotype data of 429 15-years old children (196 boys, 233 girls) were available for analysis. There was a significant interaction effect of maltreatment and the ADRA2A genotype on behavioural functioning in 15years old boys. Boys with CC genotype and higher score of maltreatment demonstrated more overactive behaviour and concentration difficulties than boys with CC genotype and low maltreatment score. They also had more inattentive symptoms measured by SNAP-IV. Among boys with low maltreatment score, subjects with CC genotype demonstrated less overactivity than G allele carriers. In girls, the G allele carriers did not differ from the CC genotype, but in maltreated girls with GG genotype aggression and inattention symptoms were reduced, and the score of aggressive behaviour was also lower compared to maltreated girls with CC genotype. Our data suggest that family environmental factors may act together with the alpha(2A)-adrenoceptor genotype to increase the expression of hyperactive and inattentive symptoms in adolescents.
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Research Interests: Immunohistochemistry, Multidisciplinary, Anorexia Nervosa, Bulimia Nervosa, Oxytocin, and 13 moreNeuropeptides, Humans, Estonia, Stress response, Female, Oxycodone, Adult, Analysis of Variance, Adrenocorticotropic Hormone, Eating Disorder, Enzyme Linked Immunosorbent Assay, Autoantibodies, and Behavioral symptoms
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Platelet monoamine oxidase (MAO) activity is a peripheral marker of central serotonergic activity, and has been associated with psychiatric vulnerability. This longitudinal investigation studied the relationship between aggressive and... more
Platelet monoamine oxidase (MAO) activity is a peripheral marker of central serotonergic activity, and has been associated with psychiatric vulnerability. This longitudinal investigation studied the relationship between aggressive and hyperactive behaviour and platelet MAO activity in adolescents at age 15 and 18 years. The psychological data were obtained from teachers by using the Hyperactivity Scale (af Klinteberg, 1988) and, at
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Research Interests: Obesity, Polymorphism, Adolescent, Type 2 Diabetes, Multidisciplinary, and 18 moreInsulin Resistance, Adipose tissue, Humans, Blood Glucose, Insulin, Female, Male, Phenotype, Transcription Factor, Introns, Adiponectin, Coronary heart disease, Sex Factors, Linkage Disequilibrium, Health surveys, Genetic Variability, Glucose Uptake, and Skinfold Thickness
Platelet monoamine oxidase (MAO) activity is a peripheral marker of central serotonergic activity, and has been associated with aggressive, impulsive and hyperactive behaviour, alcohol and drug abuse. Central serotonergic activity has... more
Platelet monoamine oxidase (MAO) activity is a peripheral marker of central serotonergic activity, and has been associated with aggressive, impulsive and hyperactive behaviour, alcohol and drug abuse. Central serotonergic activity has also been associated with plasma cholesterol levels. In the present longitudinal investigation in adolescents (n = 320) changes in platelet MAO activity and in plasma cholesterol levels over three years were measured, and their possible association with changes in aggressive and hyperactive behaviour, smoking, alcohol and drug use was studied. The measures were taken at age 15 and 18 years. Psychological data were obtained from teachers by using the Hyperactivity Scale [B. af Klinteberg, Studies on Sex-related Psychological and Biological Indicators of Psychosocial Vulnerability: A Developmental Perspective, University of Stockholm, Department of Psychology, 1988]. The results of the study show that in most of the tested individuals, platelet MAO activity is a relatively stable measure, however, there was a significant number of subjects with a noticeable change in MAO activity. In subjects with decreased platelet MAO activity, total and HDL cholesterol levels were significantly increased. Also, changes in HDL cholesterol and in platelet MAO activity were inversely associated with changes in the score of Concentration Difficulties. The changes in platelet MAO activity and cholesterol level were not associated with alcohol and drug use among the subjects. This longitudinal analysis provides preliminary evidence that changes in platelet MAO activity and cholesterol, which may reflect changes in central serotonergic activity are associated with attention deficit in adolescents.
Research Interests: Psychology, Cognitive Science, Risk assessment, Adolescent, Comorbidity, and 21 moreDrug Use, Serotonin, Humans, Smoking, Longitudinal Analysis, Estonia, Cholesterol, Female, Alcohol Drinking, Male, Incidence, Risk factors, Drug abuse, Prevalence, Longitudinal Studies, Illicit Drugs, Risk Factors, Risk Assessment, Attention Deficit, Neurosciences, and Monoamine oxidase
To reveal brain regions most significantly related to individual differences in exploratory behaviour, oxidative metabolism was measured by cytochrome c oxidase histochemistry in 2 months old Wistar rats with persistently high (HE) or low... more
To reveal brain regions most significantly related to individual differences in exploratory behaviour, oxidative metabolism was measured by cytochrome c oxidase histochemistry in 2 months old Wistar rats with persistently high (HE) or low (LE) exploratory activity in a novel environment. LE-rats had significantly higher levels of oxidative metabolism in dorsal raphe and inferior colliculi. In contrast, HE-rats had higher metabolic activity in entorhinal cortex. In conclusion, rats with different exploratory styles differ in underlying cerebral activity as measured via oxidative metabolism in regions implicated in defensive behaviours and cognitive processing of sensory stimuli.
Research Interests: Psychology, Cognitive Science, Perception, Animal Behavior, Fear, and 16 moreCognition, Energy Metabolism, Cerebral Cortex, Animals, Male, Cytochrome c oxidase, Cognitive Process, Entorhinal Cortex, Rats, Oxidative phosphorylation, Wistar Rats, Exploratory Behavior, Dorsal raphe, Individual Difference, Oxygen Consumption, and Neurosciences
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Research Interests: Immunohistochemistry, Neural Network, Gene expression, Energy Metabolism, Information Processing, and 16 moreAffect, Serotonin, Brain Mapping, Brain, Humans, Animals, Animal Model, Depressive Disorder, Cytochrome oxidase, Mood Disorders, Positive Affect, Adverse Event, Brain Chemistry, Oxidation-Reduction, Affective Disorder, and LIFE EVENT
The 50 kHz ultrasonic vocalizations (USVs) in rats have been associated with positive affect and rewarding experience. We have previously reported that stable inter-individual differences exist in the expression of these USVs (chirps). We... more
The 50 kHz ultrasonic vocalizations (USVs) in rats have been associated with positive affect and rewarding experience. We have previously reported that stable inter-individual differences exist in the expression of these USVs (chirps). We have examined the effect of four weeks of chronic variable stress on cerebral oxidative metabolism, and depression and anxiety related behavior in male and female high (HC) and low (LC) chirping rats. Significant differences in regional oxidative metabolic activity as measured by cytochrome c oxidase (COX) histochemistry were found between male and female rats: Females had lower oxidative metabolism in several brainstem areas such as dorsal and median raphe and pontine nucleus, some cortical areas, and reward-related forebrain regions such as striatum and nucleus accumbens, but higher oxidative metabolism in amygdala and related limbic regions. Chronic stress increased oxidative metabolism in several depression-related brain regions in male but not female LC-rats such as amygdala, hippocampus and anterior thalamus. No systematic behavioral effect of stress was evident in females. In LC males, stress elicited increased levels of 22-kHz USVs, earlier and more stable reduction of weight gain, persistently lower sucrose intake and preference, and higher levels of immobility in the forced swimming test. These behavioral changes, accompanied by increased oxidative metabolism in limbic brain regions, indicate greater vulnerability to stress of male LC-rats, and suggest that in males low inherent positive affectivity predisposes to anxiety and affective disorders.
Research Interests: Neuroscience, Psychology, Anxiety Disorders, Animal Behavior, Energy Metabolism, and 24 moreNucleus Accumbens, Brain Mapping, Appetite, Brain, Chronic Disease, Female, Animals, Male, Ultrasonics, Cytochrome c oxidase, Behavior change, Depressive Disorder, Mood Disorders, Positive Affect, Rats, Oxidative phosphorylation, Forced Swim Test, Chronic Stress, Body Weight, Wistar Rats, Individual Difference, Weight Gain, Neurosciences, and Affective Disorder
Effects of caerulein, a cholecystokinin octapeptide (CCK-8) receptor agonist, on exploratory activity of mice were investigated. Exploratory and locomotor activity of animals were measured using elevated plus-maze and open field tests.... more
Effects of caerulein, a cholecystokinin octapeptide (CCK-8) receptor agonist, on exploratory activity of mice were investigated. Exploratory and locomotor activity of animals were measured using elevated plus-maze and open field tests. The systemic administration of caerulein at non-sedative doses (100 ng/kg-1 micrograms/kg i.p.) resulted in a significant decrease in the exploratory activity of mice. This effect was completely blocked by proglumide, a CCK-8 receptor. Acute treatment with low doses (0.1-0.75 mg/kg i.p.) of diazepam did not attenuate the anxiogenic-like effect of caerulein, but at more high doses of diazepam the coadministration depressed locomotor activity in mice. After subchronic diazepam treatment (2.5 mg/kg once a day, 10 days, i.p.) tolerance was developed toward the sedative effect of diazepam, and 72 h after withdrawal of the drug the animals showed increased anxiety in the plus-maze test. 30 min after the last injection procedure the anxiogenic-like effect of caerulein (500 ng/kg i.p.) on exploration was absent in both diazepam or vehicle groups. However, 72 h after the last pretreatment injection caerulein (500 ng/kg i.p.) reduced significantly the exploratory activity in control group, whereas it was inactive after diazepam withdrawal. The results obtained in this study support the hypothesis that endogenous CCK-8 an CCK-8 receptors are involved in the neurochemistry of anxiety and the anxiolytic action of benzodiazepine tranquillizers.
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The changes in the extracellular concentration of endogenous noradrenaline and dopamine in the frontal cortex following pretreatment with noradrenergic neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] were studied by in... more
The changes in the extracellular concentration of endogenous noradrenaline and dopamine in the frontal cortex following pretreatment with noradrenergic neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] were studied by in vivo microdialysis in rats anaesthetized with chloral hydrate. Noradrenaline and dopamine levels in frontal cortex were detected only when the uptake inhibitor, nomifensine (10 microM) was present in dialysis fluid. Under those conditions, the Na+ channel agonist veratridine and a depolarising concentration of potassium chloride (60 mM), applied locally through the microdialysis probe, increased the overflow of noradrenaline. Tetrodotoxin had an opposite effect. These results indicate that most of the noradrenaline probably arose from exocytotic release. Noradrenaline efflux in the frontal cortex of DSP-4 pretreated rats (52 +/- 6.1 fmol/sample) did not differ significantly from that of the control animals (69 +/- 4.9 fmol/sample). Dopamine efflux was not changed either (64 +/- 9.6 and 62 +/- 3.9 fmol/sample, respectively). The alpha 2-adrenoceptor antagonist, atipamezole (3 mg/kg i.p.), increased the overflow of noradrenaline in the frontal cortex of saline-treated rats by 100%, whereas in DSP-4 treated rats the increase was only around 30%. The overflow of dopamine was not changed under the conditions described. The effect of atipamezole in DSP-4 treated rats may be of smaller magnitude due to the diminished pool of releasable noradrenaline or due to a downregulation of presynaptic alpha 2-adrenoceptors in the frontal cortex. The perfusion of 60 mM KCl at the end of the experiment unexpectedly produced equivalent increases in noradrenaline and dopamine content in dialysates of both vehicle and DSP-4 treated rats. We conclude that the uptake inhibitor, nomifensine, and atipamezole, which had a stronger effect in vehicle-treated animals, reduced the effect of KCl-stimulation and masked the true difference in changes of noradrenaline efflux. Post-mortem tissue concentrations of noradrenaline 7 days after DSP-4 administration (50 mg/kg) were significantly reduced in the frontal cortex (54%), hippocampus (62.5%) and to lesser extent in the hypothalamus (27%) as compared to vehicle-treated rats. Dopamine and 3,4-dihydroxyphenylacetic acid concentrations were not changed confirming the efficacy and selectivity of the DSP-4 lesion. These results demonstrate that one week after DSP-4 treatment the extracellular levels of noradrenaline and dopamine as assessed by in vivo microdialysis are not changed in the frontal cortex, but atipamezole-stimulated release of noradrenaline is decreased in DSP-4 treated rats.