Mothers' prenatal stress and their children's antisocial outcomes--a moderating role for the dopamine D4 receptor (DRD4) gene.

BACKGROUND: Maternal distress during pregnancy has been linked to aggressive behavior in offspring. This effect has been interpreted in terms of 'fetal programming'. The 7-repeat (7r) allele of a VNTR polymorphism in exon III of the human dopamine receptor D4 (DRD4) has consistently been associated with externalizing behavior problems, especially in the presence of adverse environmental factors. So far, it is not known whether the DRD4 genotype moderates the effect of prenatal maternal stress on the development of childhood antisocial behavior. METHODS: As part of an ongoing epidemiological cohort study, prenatal maternal stress was assessed using self-report 3 months following child birth. When children were 8, 11, and 15 years old, mothers rated their children's externalizing behavior, and diagnoses of conduct disorder and/or oppositional defiant disorder (CD/ODD) according to DSM-IV were obtained. In a sample of N = 308 participants, the effects of the DRD4 genotype, prenatal maternal stress, and the interaction thereof on antisocial outcome were tested. RESULTS: Under conditions of elevated prenatal maternal stress, children carrying one or two DRD4 7r alleles were at increased risk of a diagnosis of CD/ODD. Moreover, homozygous carriers of the DRD4 7r allele displayed more externalizing behavior following exposure to higher levels of prenatal maternal stress, while homozygous carriers of the DRD4 4r allele turned out to be insensitive to the effects of prenatal stress. CONCLUSIONS: This study is the first to report a gene-environment interaction related to DRD4 and prenatal maternal stress using data from a prospective study, which extends earlier findings on the impact of prenatal maternal stress with respect to childhood antisocial behavior.

Variation in neighbouring genes of the dopaminergic and serotonergic systems affects feather pecking behaviour of laying hens.

Feather pecking is a behavioural disorder of laying hens and has serious animal welfare and economic implications. One of the several aetiological hypotheses proposes that the disorder results from redirected exploratory behaviour. Variation in the gene encoding the dopamine D4 receptor (DRD4) has been shown to be associated with exploratory behaviour in several species, including in a passerine bird species. We therefore considered DRD4 as a candidate gene for feather pecking. We have annotated DRD4 in the chicken genome and have re-sequenced it in 140 animals belonging to: experimental layer lines divergently selected for high and low propensity to feather pecking; the unselected founder population; and two commercial lines with low and high propensity to feather pecking. We have identified two sub-haplotypes of DRD4 that are highly significantly associated with feather pecking behaviour in the experimental (P = 7.30 x 10(-7)) as well as in the commercial lines (P = 2.78 x 10(-6)). Linkage disequilibrium (LD) extends into a neighbouring gene encoding deformed epidermal autoregulatory factor 1 (DEAF1). The product of DEAF1 regulates the transcription of the gene encoding the serotonin (5-hydroxytryptamine) 1A receptor. Thus, DEAF1 represents another candidate gene for feather pecking. Re-sequencing of five animals homozygous for the 'low-pecking' sub-haplotype and of six animals homozygous for the 'high-pecking' sub-haplotype delineated an LD block of 14 833 bases spanning the two genes. None of the variants in the LD block is obviously functional. However, the haplotype information will be useful to select against the propensity to feather pecking in chicken and to elucidate the functional implications of the variants.

Recent progress in medicinal chemistry of D4 agonists.

In the last decades, the physiological and pharmacological properties of dopamine receptors were controversial principally because of the lack of selective ligand for some receptor subtypes. Since 1997, some specific D4 agonists have been described and have allowed a therapeutic approach. We report here, compounds described as D4 agonist and when available the SAR. The major studies for physiological implications and their potential biological applications are also reported and principally their interest in erectile dysfunction.

Characterization of the desensitization properties of five dopamine receptor subtypes and alternatively spliced variants of dopamine D2 and D4 receptors.

Proper regulation of brain dopaminergic activity is essential for maintaining normal mental functions. In this study, the regulatory properties of five different dopamine receptor subtypes and alternative splicing variants of dopamine D2 and D4 were examined. The stimulation of D1R, D2R, D5R but not D3R, D4R caused the robust translocation of beta-arrestin to the plasma membrane. When D1R or D3R were co-expressed with D2R, D1R significantly inhibited the sequestration of D2R, suggesting that the inhibitory effects of D1R on the D2R sequestration could explain the synergistic activity between two receptors. The sequestration of alternatively spliced isoforms of D2R was differently regulated by GRKs and beta-arrestins. Three alternative splicing variants of D4R produced a similar level of beta-arrestin translocation, and the studies with the deletion mutants of D4R within the third cytoplasmic loop revealed that the regions containing the SH3-binding domains are responsible for the beta-arrestin translocation.