Does the transcription factor AP-2beta have an impact on the genetic and early environmental influence on ethanol consumption?

Genes involved in alcoholism have consensus sites for the transcription factor activator protein (TFAP) 2beta. In the present study, we investigated TFAP-2beta protein levels in the ethanol-preferring alko, alcohol (AA) and the ethanol-avoiding alko, non-alcohol (ANA) rat lines. Furthermore, basal and ethanol-induced TFAP-2beta levels were examined in Wistar rats exposed to different early postnatal environments that are known to affect later ethanol consumption. Taken together, we found differences in brainstem TFAP-2beta protein between the AA and ANA rats.

Monoamine oxidases: activities, genotypes and the shaping of behaviour.

The importance of an interaction between environment and biological factors for the expression for a particular behaviour is illustrated by results from a series of adolescents in which effects of platelet MAO activity and psychosocial environment on criminality was investigated. In a favourable environment platelet MAO-B activity was not associated with criminality, while a very strong association was found in adolescents from a bad psychosocial environment. Essentially similar findings were obtained when a MAO-A promoter polymorphism was analysed instead of platelet MAO-B activity. In boys, presence of the low functioning allele seemed to be protective against criminal activity in combination with a good environment, while it predisposed for criminality in a bad psycho-social environment. In girls, instead, homozygosity for the high activity MAO-A allele interacted with environment to predict criminality. Possible mechanisms underlying the role of monoamine oxidases for behaviour are discussed.

Transcription factor AP-2 and monoaminergic functions in the central nervous system.

In the central nervous system, transcription factor AP-2 family is one of the critical regulatory factors for neural gene expression and neuronal development. Several genes in the monoaminergic systems display AP-2 binding sites in regulatory regions. In addition, brainstem levels of transcription factor AP-2alpha and AP-2beta are positively correlated to monoamine measures in rat forebrain, suggesting a regulatory role of AP-2 also in the adult brain. Great changes in psychiatric phenotypes due to genetic factors are seldom the result of a single gene polymorphism. Recently, identification of combinations of candidate genes that are all linked to one disease or psychiatric phenotype has been discussed. The expression of these candidate genes might be regulated by the same transcription factors, e.g. AP-2. Recent data on transcription factor AP-2 family in relation to monoaminergic functions are described in this paper. Transcription factor AP-2beta genotype has been studied in relation to personality, platelet monoamine oxidase (MAO) activity, CSF-levels of monoamine metabolites, binge-eating disorder, premenstrual dysphoric disorder, and schizophrenia. Furthermore, the involvement of AP-2 in the molecular mechanism of antidepressant drugs is discussed. Altogether, this paper discusses data supporting a notion that the transcription factor AP-2 family is involved in the regulation of the monoaminergic systems both pre- and postnatally, and, therefore, might be involved in the pathophysiology of neuropsychiatric disorders.

Platelet MAO and personality--function and dysfunction.

Research on the association between platelet monoamine oxidase (MAO) activity and personality traits, such as sensation seeking and impulsiveness, is reviewed with an emphasis on early history and current situation. The effects of MAO-inhibiting compounds in cigarette smoke for the interpretation of this association are discussed and recent results confirming a true association between platelet MAO activity and personality and vulnerability, for e.g. type 2 alcoholism are presented. From a clinical point of view, the link between platelet MAO activity, which is highly genetically regulated and is stable in the individual, and personality traits, has had its greatest impact on the understanding of the nature of constitutional factors making individuals vulnerable, for e.g. substance abuse and other forms of sociopathic behaviour. The molecular mechanisms underlying the association between platelet MAO and behaviour are discussed and evidence that common transcriptional factors, e.g. within the AP-2 family, regulating both the expression of platelet MAO and components of the central monoaminergic systems, such as synthesising enzymes, receptors and transporters, are presented. A hypothesis is put forward, that such common transcription factors may not directly regulate platelet MAO expression, but rather mitochondrial density, or outer mitochondrial membrane surface.

Transcription factor AP-2beta genotype, striatal dopamine D2 receptor density and cerebrospinal fluid monoamine metabolite concentrations in humans.

Transcription factor AP-2beta has been suggested to influence brain monoaminergic systems by regulating target genes. In order to explore a possible functional role, AP-2beta genotype was analysed in relation to striatal dopamine D2 receptor density determined in vivo by positron emission tomography in human subjects (n = 52). The AP-2beta genotype was also analysed in relation to cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxy-phenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in healthy human subjects (n = 90). There was no association between the AP-2beta genotype and measures of dopamine receptor density, or CSF 5-HIAA concentrations. However, AP-2beta genotype was associated with CSF-levels of HVA (in women) and MHPG. These data may suggest a functional involvement of AP-2beta in the dopaminergic system, but should be interpreted with caution until replicated.

Chronic citalopram treatment induces time-dependent changes in the expression and DNA-binding activity of transcription factor AP-2 in rat brain.

Imbalances in the midbrain monoaminergic systems have been implicated to play a role in neuropsychiatric conditions. Several genes in these systems have binding sites for transcription factor activating protein-2 (AP-2) in their regulatory regions. Thus, AP-2 may be a factor controlling the expression of genes in the monoaminergic systems important for maintaining normal psychiatric functions. The present study indicates that subchronic treatment with the antidepressant citalopram induces time-dependent changes in DNA-binding activity and levels of transcription factor AP-2 in rat whole brain. Rats were treated with citalopram (10 mg/kg) for 1, 3, 7 and 21 days. Animals treated for 7 days had significantly decreased DNA-binding activity and levels of AP-2 alpha and AP-2 beta isoforms when compared to saline-treated animals. There was no observed difference between citalopram- and saline-treated animals after 21 days. Elucidation of the molecular mechanisms underlying mental disorders is important for future drug development, where transcription factors might be important drug targets.

Smoking only explains part of the associations between platelet monoamine oxidase activity and personality.

Platelet monoamine oxidase (MAO) activity has been shown to be inversely associated with personality traits such as sensation seeking, impulsiveness and extraversion. Those personality traits have also been linked to vulnerability for substance abuse, e.g. tobacco smoking and early onset or "type 2" alcoholism. Compounds in cigarette smoke have been shown to be inhibitors of MAO, which has led several authors to claim that there is no association between alcoholism, which is the most studied psychiatric condition, and platelet MAO if the effect of smoking is removed. With regard to the association between personality and platelet MAO, authors have in general been cautious. In the present paper we describe a number of results which show that there is such an association, both in clinical series if the effect of smoking is removed and in series where smoking have never taken place. A cornerstone in this regard is the significant association between platelet MAO activity and both behaviour/personality, voluntary alcohol intake and biochemical measures of CNS serotonergic activity in non-human primates. Strong evidence that the regulation of platelet MAO activity takes place on a transcriptional level with an involvement of transcription factors, likely to also regulate central monoaminergic activity, are presented.

Levels of transcription factors AP-2alpha and AP-2beta in the brainstem are correlated to monoamine turnover in the rat forebrain.

The transcription factors AP-2alpha and AP-2beta are implicated to play an important role during embryonic development of different parts of the brain, and in targeted regulation of gene expression in the adult brain. Several monoaminergic genes have binding sites for AP-2 in regulatory regions. We have in the present study, analysed the association between AP-2 levels in the brainstem of rats (n=9) and monoamine levels in the frontal cortex, septum and hippocampus. Several regionally specific correlations were found between AP-2alpha and AP-2beta and specific monoamines in the rat forebrain. The data support our notion that the transcription factor AP-2 family is involved in the regulation of the monoaminergic systems and, therefore, might be involved in the pathophysiology of neuropsychiatric disorders.

Genetic mechanisms of behavior--don't forget about the transcription factors.

Major changes in psychiatric phenotypes due to genetic factors are seldom the result of single gene polymorphisms, but more often the result of several genetic mechanisms. In this millennium article we discuss the notion that the expression of numerous candidate genes could be regulated by the same transcription factors, and that polymorphisms in transcription factor genes might explain some phenotypes. We describe recent results of studies on the biological marker thrombocyte monoamine oxidase (trbc MAO) and the transcription factor AP-2beta. Low levels of trbc MAO is associated with temperamental characteristics such as sensation seeking and impulsiveness, and the enzyme is genetically regulated by specific transcriptional mechanisms. Transcription factor AP-2beta is important for the development of midbrain structures and AP-2beta has several binding sites in the regulatory regions of genes encoding key proteins in the monoamine transmitter systems. We have recently shown AP-2beta to be linked to personality, binge-eating disorder, treatment with antidepressant drugs, and also to trbc MAO. Regardless of whether transcriptions factors, such as AP-2beta, regulate the expression of eg, the number of monoamine neurons or a variety of candidate genes within the monoamine systems, or both, we would like to emphasize the role of transcription factors, besides polymorphisms in monoaminergic candidate genes, when explaining inter-individual differences in temperament and psychiatric vulnerability.

The genotype of human transcription factor AP-2beta is associated with platelet monoamine oxidase B activity.

Platelet monoamine oxidase B (MAO; EC 1.4.3.4.) activity is stable in the individual and is mainly genetically regulated. Levels of MAO-B in platelets have repeatedly been shown to be associated with personality traits. We have recently also demonstrated an association between the genotype of AP-2beta to a variety of personality traits as well as binge-eating disorder. In the present study we have analysed blood samples from 158 males and 64 females with regard to platelet MAO activity and genotype of transcription factor AP-2beta. In both sexes homozygotes for the long allele [CAAA](5) were significantly associated with low platelet MAO activity P<0.0001 (males) and P=0.0158 (females). This study represents a novel approach to increase the understanding about the molecular mechanisms for how the MAOB gene is regulated in blood cells and how this regulation is linked to personality traits.

A polymorphic region in the human transcription factor AP-2beta gene is associated with specific personality traits.

Transcription factor AP-2beta is implicated in playing an important role during embryonic development of different parts of the brain, eg, midbrain, hindbrain, spinal cord, dorsal and cranial root ganglia.1,2 The gene encoding AP-2beta contains a polymorphic region which includes a tetranucleotide repeat of [CAAA] four or five times, located in intron 2 between nucleotides 12593 and 12612.3 Since the midbrain contains structures important for variables such as mood and personality, we have investigated if the AP-2beta genotype is associated with personality traits estimated by the Karolinska Scales of Personality (KSP). Identification of transcription factor genes as candidate genes in psychiatric disorders is a novel approach to further elucidate the genetic factors that, together with environmental factors, are involved in the expression of specific psychiatric phenotypes. The AP-2beta genotype and KSP scores were determined for 137 Caucasian volunteers (73 females and 64 males). The personality traits muscular tension, guilt, somatic anxiety, psychastenia and indirect aggression were significantly associated with the specific AP-2beta genotype, albeit with significant difference between genders. Based on this result the human AP-2beta gene seems to be an important candidate gene for personality disorders. Moreover, the present results suggest that the structure of the intron 2 region of the AP-2beta gene is one factor that contributes to development of the constitutional component of specific personality traits.

Chronic pharmacological treatment with certain antidepressants alters the expression and DNA-binding activity of transcription factor AP-2.

Several of the genes in the serotonergic and the dopaminergic systems have consensus binding sites for the AP-2 transcription factor family in their regulatory regions. Imbalances in these systems have been implicated in many psychiatric disorders, including depression and bipolar affective disorder. We have made an effort to further elucidate the molecular mechanisms of drugs used for affective disorders. Recently, we analyzed the effects of chronic treatment with certain antidepressants on AP-2 in rat brain. The present study demonstrates that chronic administration of three different classes of antidepressants modulates the DNA-binding activity of AP-2 in the rat brain. Chronic administration of citalopram (10 mg/kg), imipramin (10 mg/kg) and lithium-chloride (40 mg/kg) significantly decreased DNA-binding activity of AP-2. Furthermore, citalopram (10 mg/kg) and imipramin (10 mg/kg) significantly decreased the amount of AP-2alpha protein as determined by ELISA. In addition, citalopram (10 mg/kg) significantly decreased the amount of AP-2beta protein. In contrast, chronic administration of lithium-chloride (40 mg/kg) did not affect the amount of the two AP-2 isoforms. An increased understanding of the function of transcription factors and their involvement in human disease, such as depression, could make it possible in the future to selectively modulate relevant target genes directly.

Transcription factor binding to the core promoter of the human monoamine oxidase B gene in the cerebral cortex and in blood cells.

Many studies show that monoamine oxidase B in blood cells is a biological marker for personality characteristics such as sensation seeking. The mechanism underlying this association is so far not explored. In the present study we have performed electrophoretic mobility-shift assays to investigate the pattern of protein binding to a 150 bp fragment of the proximal 5'-flanking region of the human monoamine oxidase B gene. We compared the pattern using nuclear extracts from human brain and lymphocytes. Interestingly, a correlation was observed between monoamine oxidase B enzyme activity in blood cells (platelets) and the binding pattern of two uncharacterized transcription factors. These data are well in line with the long-standing notion that interindividual differences in platelet monoamine oxidase may represent differences in expression of the enzyme rather than genotypic variation.

Isolation and structural elucidation of naphthomycins B and C.

Two new ansamycin antibiotics, the naphthomycins B and C, were isolated from two different strains of Streptomyces. The structures were determined by comparison of the spectra (UV, 1H NMR, 13C NMR) with those of the known naphthomycin A, by spin decoupling experiments (300 MHz) and in one case by a two dimensional NMR analysis. Naphthomycin B (II) is 30-chloronaphthomycin C. Strikingly, naphthomycin A (I) differs from B and C not only by the presence of an additional methyl group at C (2), but also in the configuration of some of the double bonds. A fourth ansamycin antibiotic of the naphthomycin subgroup, actamycin, is 30-hydroxynaphthomycin C.