Investigation of transcription factor AP-2 beta genotype in women with premenstrual dysphoric disorder.

It has repeatedly been shown that the serotonergic system is involved in the symptomatology of premenstrual dysphoric disorder (PMDD). Women with PMDD are reported to differ from symptom-free controls with regard to serotonin-related biological markers. Evidence from family and twin studies suggests a genetic contribution to the aetiology of PMDD. The expression of human transcription factor AP-2beta in neural crest cell lineages and neuroectodermal cells suggests that this protein may be of importance for functional characteristics of neurons by regulating the expression of target genes. Within the monoaminergic systems, several genes have binding sites for AP-2beta in regulatory regions, suggesting an involvement of AP-2beta in these systems. The gene encoding AP-2beta is located on chromosome 6p12-p21.1 and includes a polymorphic region consisting of a variable number of [CAAA] repeats located in the second intron. We have earlier shown that AP-2beta genotype is associated with serotonergic phenotypes and that brainstem levels of AP-2beta correlate positively to serotonin metabolism in rat frontal cortex. The aim of this study was to investigate the relationship between PMDD and transcription factor AP-2beta genotype. The participants included 176 women with PMDD and 91 healthy controls. Genotyping was performed by polymerase chain reactions. We did not observe any differences in AP-2beta genotype frequencies between PMDD subjects and controls. Our results suggest that AP-2beta genotype is not a risk factor for PMDD. To our knowledge, this is the first study investigating transcription factor AP-2beta genotype in women with PMDD. Hence, these results should be considered preliminary until replicated.

Brainstem levels of transcription factor AP-2 in rat are changed after treatment with phenelzine, but not with citalopram.

BACKGROUND: Before therapeutic effect is obtained after treatment with antidepressant drugs, like serotonin selective reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAO-Is) there is an initial lag-period of a few weeks. Neuronal adaptations on a molecular level are supposed to be involved in the initiation of the antidepressant effect. Transcription factor AP-2 is essential for neuronal development and many genes involved in the brainstem monoaminergic systems have binding sites for AP-2 in their regulatory regions. The genotype of the AP-2beta isoform has been associated with e.g. anxiety-related personality traits and with platelet MAO activity. In addition, previous studies have shown that the levels of AP-2alpha and AP-2beta in rat whole brain were decreased after 10 days of treatment with citalopram (SSRI) and imipramine (TCA), and were increased with phenelzine (MAO-I). RESULTS: In the present study, we report that treatment with citalopram for 1, 7 or 21 days did not have effect on the AP-2 levels in rat brainstem. However, after treatment with phenelzine for 1, 7 or 21 days the levels of AP-2alpha and AP-2beta had increased after 7 days, but had returned to control levels at day 21. CONCLUSION: The decrease in AP-2 levels in rat whole brain previously seen after treatment with citalopram does not seem to be localised to the brainstem, it may rather occur in the monoaminergic terminal projection areas. The present data suggest that the increase in AP-2 levels previously seen in rat whole brain after subchronic treatment with phenelzine is located in the brainstem. It cannot, however, be excluded that other brain regions are involved.

Effect of long-term blockade of CRF(1) receptors on exploratory behaviour, monoamines and transcription factor AP-2.

Corticotropin-releasing factor (CRF) holds a central role in reactions to various environmental stimuli. In the present study, the administration of a selective nonpeptide CRF(1) receptor antagonist, CP-154,526, for 6 days, exerted an anxiolytic effect in the elevated zero-maze (EZM) test. CP-154,526 did not affect behaviour in the exploration box when administered acutely, but increased exploration when administered for 5 days, contingently with daily behavioural testing. This effect, although of lesser magnitude, was also present in animals with neurotoxin DSP-4-induced selective denervation of locus coeruleus (LC) projections. When drug administration and behavioural testing were noncontingent in a 2-week administration schedule, CP-154,526 blocked the habituation-induced increase in exploration. This suggests that drug-environment interaction is an important component in the manifestation of the anxiolytic-like effects of CRF(1) receptor blockade. Long-term administration of CP-154,526 had a decreasing effect on noradrenaline (NA) metabolism in the frontal cortex. No manipulation influenced the levels of the transcription factor AP-2 isoforms in the LC area. AP-2 levels correlated positively with 3-methoxy-4-hydroxyphenylglycol (MHPG) in the frontal cortex of vehicle-treated animals. There was a negative correlation between the NA levels in the hippocampus and AP-2 isoforms in the LC area of naive animals. In contrast, in vehicle-treated animals, this correlation was positive. Treatment with CP-154,526, however, made the associations between LC AP-2 levels and hippocampal NA content negative, as was the case in the naive animals. This suggests that CRF(1) receptor blockade counteracts certain mechanisms of habituation, possibly by reducing the LC activity.

Transcription factor AP-2beta genotype associated with anxiety-related personality traits in women. A replication study.

Attempts to link transmitter system genes to certain aspects of personality have been performed. Several monoamine-related gene variants have been investigated. We previously reported an association between a transcription factor activating protein-2beta (AP-2beta) variant and anxiety-related personality traits as estimated by Karolinska Scales of Personality (KSP). To confirm this reported association, we have, in the present study, analysed an enlarged group of healthy volunteers (n = 370) with regard to AP-2beta genotype and personality traits. For estimation of personality traits, individuals completed 5 different personality questionnaires, i.e. Swedish Universities Scales of Personality (SSP), Health-Relevant 5- Factor Personality Inventory (HP5i), Temperament and Character Inventory, the Revised NEO Personality Inventory and KSP. In contrast to men, women having two long AP-2beta alleles displayed lower scores for muscular tension (KSP; F = 10.65, p = 0.0013), somatic trait anxiety (SSP; F = 7.18, p = 0.0081), trait irritability (SSP; F = 4.51, p = 0.032), mistrust (SSP; F = 4.01, p = 0.0468) and negative affectivity (HP5i; F = 10.20, p = 0.0017) than women with at least one short allele. The data presented in this study, together with our previously published data, suggest that AP-2beta intron 2 genotype is associated with low levels of anxiety-related personality traits in women. Hence, these data further suggest the human AP-2beta gene as a novel candidate gene in personality.

Phenelzine treatment increases transcription factor AP-2 levels in rat brain.

BACKGROUND: The elevations of noradrenaline (NA) and serotonin (5-HT) levels in response to acute serotonin reuptake inhibitor (SSRI) or tricyclic antidepressant (TCA) exposure are not consistent with the time course for the therapeutic action of these antidepressants. Thus, neuronal adaptations are needed for the therapeutic effect to arise. Transcription factor Activating Protein -2 (AP-2) is critical for mammalian neural gene expression. Several genes involved in brainstem CNS transmitter systems, especially the monoamines, have AP-2 binding sites in their regulatory regions. We have previously shown that treatment with citalopram and imipramin resulted in a decrease in AP-2alpha and AP-2beta levels in rat brain. We have also reported an association between a specific genotype of AP-2beta to personality traits, binge-eating disorder and platelet monoamine oxidase (MAO) activity. RESULTS: Subchronic administration (10 days) of phenelzine (PLZ) increased the levels of AP-2alpha, AP-2beta and the DNA binding activity of AP-2 in nuclear extracts prepared from rat whole brain when compared with sham treated animals. CONCLUSION: These data suggest that AP-2 is not involved in the therapeutic effect of antidepressants. Rather, the effects of antidepressants seen on the levels of AP-2 might be involved in the expression of side-effects during the lag-period.

The serotonin 2A -1438 G/A receptor polymorphism in a group of Swedish male criminals.

Studies have shown that genetic components to some extent underlie behavioral disorders such as impulsive aggression and violence, and that central serotonergic mechanisms are involved in the development of such behavior. In the present study, we analyzed a polymorphism in the gene encoding the serotonin 2A receptor (5-HT2A -1438 G/A) in a group of Swedish criminals (n=97) and in a group of healthy Swedish blood donors (n=202). The 5-HT2A -1438 GG genotype was lower in the criminal group than in the control group (P=0.034). In accordance with previous results, no associations were found between the 5-HT2A -1438 G/A polymorphism and personality as measured by Karolinska Scales of Personality. Neither were there any associations between the studied polymorphism and the type of crime committed.

Risk factors for the neurohumoral alterations underlying personality disturbances.

Numerous studies have shown that MAO-B activity in platelets correlates with specific personality characteristics such as sensation seeking and impulsiveness. Low levels of platelet MAO as well as the personality traits associated with these low levels have been associated with type 2 alcoholism, recurrent criminality and antisocial violent behavior. Platelet MAO has a high degree of heritability and regulation of MAOB gene expression seems to explain most of the inter-individual differences in activity. The transcription factor family AP-2 is an important regulatory factor for neural gene expression and neural development, especially in midbrain structures, including the monoaminergic nuclei. In man, the gene encoding AP-2beta contains a polymorphic region in the second intron, consisting of a variable number of tandem repeats [CAAA](4-5). The long AP-2beta allele has previously been associated with specific personality traits as well as with binge-eating disorder characterized by an impulsive temperament. We have shown that males and females homozygous for the long AP-2beta allele display significantly lower platelet MAO activity compared to subjects with one or two short alleles. Thus, we find it likely that the personality disturbances previously linked to low platelet MAO activity could be associated with the presence of two long alleles of the AP-2beta gene. We suggest that the molecular mechanisms underlying the association between platelet MAO and vulnerability, e.g. substance abuse, may involve specific transcription factors that regulate the expression of midbrain monoamine structures as well as that of platelet MAO.