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PubMed1996

The biological, social and clinical bases of drug addiction: commentary and debate.

This article summarizes the main discussions at a meeting on the biological, social and clinical bases of drug addiction focused on contemporary topics in drug dependence. Four main domains are surveyed, reflecting the structure of the meeting: psychological and pharmacological factors; neurobiological substrates; risk factors (including a consideration of vulnerability from an environmental and genetic perspective); and clinical treatment. Among the topics discussed were tolerance, sensitization, withdrawal, craving and relapse; mechanisms of reinforcing actions of drugs at the behavioural, cognitive and neural levels; the role of subjective factors in drug dependence; approaches to the behavioural and molecular genetics of drug dependence; the use of functional neuroimaging; pharmaceutical and psychosocial strategies for treatment; epidemiological and sociological aspects of drug dependence. The survey takes into account the considerable disagreements and controversies arising from the discussions, but also reaches a degree of consensus in certain areas.

Brain↗
PubMed1976

Phylogenetic adaptations and the genetics of psychosis.

There is evidence that many social skills and responses which are of adaptive value are under a significant degree of genetic control. It is suggested that in states of hyper-arousal these skills are displayed in inappropriate and incomplete forms and that such behaviour constitutes psychosis. Genetic variation in these skills, under polygenic control, appears to be a determinant of the adaptiveness of the personality, with individuals at the extremes of the distribution tending to be maladjusted, chronically overaroused, and vulnerable to psychotic breakdown. Since the individual subjects's psychotic symptomatology will relflect the make-up of his genotype, the hypothesis is consistent with observed familial occurence of the different froms of functional psychosis. The hypothesis explains many of the characteristic manifestations of psychosis, including those in symptomatic psychosis, and also the genetic association with personality disorder. Evidence for the hypothesis and some predictions it generates are briefly reviewed.

Adult↗
PubMed1995

Sexual dimorphism in the developmental regulation of brain aromatase.

Steroid sex hormones have an organizational role in gender-specific brain development. Aromatase (cytochrome P450AR), converting testosterone (T) to estradiol-17 beta (E2) is a key enzyme in brain development and the regulation of aromatase determines the availability of E2 effective for neural differentiation. Gender differences in brain development and behaviour are likely to be influenced by E2 acting during sensitive periods. This differentiating action has been demonstrated in rodent and avian species, but also probably occurs in primates including humans. In rodents, E2 is formed in various hypothalamic areas of the brain during fetal and postnatal development. The question considered here is whether hypothalamic aromatase activity is gender-specific during sensitive phases of behavioural and brain development, and when these sensitive phases occur. In vitro preoptic and limbic aromatase activity has been measured in two strains of wild mice, genetically selected for behavioural aggression based on attack latency, and in the BALB/c mouse. Short attack latency males show a different developmental pattern of aromatase activity in hypothalamus and amygdala to long attack latency males. Using primary brain cell cultures of the BALB/c mouse, sex differences in hypothalamic aromatase activity during both early embryonic and later perinatal development can be demonstrated, with higher E2 formation in males. The sex dimorphism are brain region specific, since no differences between male and female are detectable in cultured cortical cells. Immunoreactive staining with a polyclonal aromatase antibody identifies a neuronal rather than an astroglial localization of the enzyme. T increases fetal brain aromatase activity and numbers of aromatase-immunoreactive hypothalamic neuronal cell bodies. T appears to influence the growth of hypothalamic neurons containing aromatase. Differentiation of sexually dimorphic brain mechanisms may involve maturation of a gender-specific network of estrogen-forming neurons which are steroid-sensitive in early development.

Age Factors↗
PubMed2006

[Genetic influences on the outcome of the progeny tests for behaviour traits in Hovawart dogs].

The objective of the present study was to evaluate the importance of genetic and environmental sources of variation for results of behaviour tests in young dogs being used for progeny evaluations in the Hovawart dog. In total, 4,113 dogs born in 1995 to 2000 have been available for these analyses. Traits used were appearance, hunting affinity, group of people, acoustical and optical influences and temperament. Variance components were estimated using multivariat linear animal models and Restricted Maximum Likelihood (REML). The models included test-year-season, sex, litter size, age and inbreeding coefficient of the animal as fixed effects. Additive genetic effects of the animal, permanent environmental effect of the litter and the effect of the kennel were considered as random factors. The sex of the dog was significant for all traits. The age of the dog at the test significantly influenced the traits temperament and appearance. Test-year-season was significant for all traits except for appearance, whereas the inbreeding coefficient of the animal was significant for acoustical influences and temperament. Litter size did not influence any of the traits significantly. The estimated heritabilities of the behaviour traits analysed here ranged from h2 = 0.03 to h2 = 0.11 with standard errors of up to 0.03. The additive genetic correlations between most of the traits were moderately to highly positive (rg = 0.16 to rg = 0.91). The traits hunting affinity and appearance showed an additive genetic correlation close to zero (rg = 0.03). Negative additive genetic correlations were found between temperament and appearance as well as acoustical and optical influences (rg = -0.14 to rg = -0.4).

Age Factors↗
PubMed1999

Knockout Corner.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in a number of physiological functions including sleep, appetite, pain perception, and sexual activity. Several pathological states such as migraine, depression, and anxiety have been linked to the serotonergic system, and serotonergic drugs have been used to treat these disorders. To date, there are 14 known serotonin receptor subtypes through which serotonin exerts its multiple actions. The classic pharmacological approach to study how these individual receptor subtypes contribute to various behaviours has been to use selective drugs that either block or activate certain receptor subtypes, and then study the effects of these compounds on physiology and behaviour. A complementary genetic approach is the technique of gene targeting. Using this technology, we and others have begun to examine the contribution of several serotonin receptor subtypes to complex behaviours through the generation of knockout mice that lack the genes encoding these receptors. In this review, we will describe what we have learned about the serotonergic system and the function of the 5-HT(1B) receptor by the analysis of 5-HT(1B) receptor knockout mice. Furthermore, we will discuss the implications of these findings and our plans for future studies.

Journal Article↗
PubMed2005

Association between monoamine oxidase gene polymorphisms and smoking behaviour in Chinese males.

Monoamine oxidase (MAO) is a critical metabolic enzyme of dopamine, which is a key neurotransmitter of the mesolimbic reward pathway in the human brain. Consequently, the gene encoding MAO is an important candidate gene in the genetics of smoking behaviour. We investigated the association between MAOA polymorphisms (a VNTR polymorphism and an EcoRV polymorphism) and smoking status. A community-based cross-sectional study was conducted with 203 current smoking subjects and 168 non-current smoking subjects in Beijing, China. Genotyping for these polymorphisms was performed using PCR and restriction fragment length polymorphism. Multiple logistic regression models were used to analyse the association of MAOA gene polymorphisms with smoking status. We found that individuals with the 1460T/O genotype had a significantly increased the risk of smoking compared to those with 1460C/O. The adjusted odds ratios (aORs) were 3.2 (95% CI 2.0-5.2) in current vs. non-current smokers group, 1.7 (95% CI 1.1-2.8) in ever vs. never smokers group, 2.5 (95% CI 1.4-4.3) in current vs. never smokers group, and 5.3 (95% CI 2.5-11.2) in current vs. former smokers group respectively. We also found that individuals with the 3-repeat genotype of the VNTR polymorphism had a significantly increased risk of smoking significantly compared to those with the 4-repeat genotype. The aORs were 2.0 (95% CI 1.0-4.1) in the current vs. former smokers group, and 1.9 (95% CI 1.0-3.6) in the nicotine dependent vs. non-nicotine dependent group respectively. Moreover, MAOA gene haplotypes were associated significantly with nicotine dependence in every group. In conclusion, there is an important association between MAOA polymorphisms and smoking status, suggesting a possible role of MAOA gene variants in nicotine dependence.

Adult↗
PubMed1998

Statistical methods in genetic research on smoking.

A growing body of evidence suggests that genetic factors have an important influence on the onset and course of smoking. Here we review some of the statistical methods that have been used to test for genetic influences on smoking behaviour, with a particular focus on studies of large national twin samples. We show how many of the hypotheses that have been tested using a genetic model-fitting approach have also been reformulated using logistic regression models that will be more familiar to epidemiologists. Such an approach is more easily extended to allow for sociocultural, as well as genetic, influences on smoking behaviour. Using either approach, data are consistent in indicating that certainly in men, and possibly in women, genetic factors play an important role in predicting which individuals who become cigarette smokers progress to being long-term persistent smokers.

Epidemiologic Methods↗
PubMed1995

The circadian clock: from molecules to behaviour.

Circadian rhythms are a cardinal feature of living organisms. The stereotypical organization of homeostatic, endocrine and behavioural variables around the 24-hour cycle constitutes one of the most conserved attributes among species. It is now well established that circadian rhythmicity is not a learned behaviour, but is genetically transmitted and therefore subject to genetic manipulations. Recent advances in the circadian field have demonstrated that circadian oscillations are cell autonomous, that the circadian mechanism operates through a negative feedback loop and that a growing number of genes is under circadian control. Furthermore, single-gene mutations have been isolated in mammals that have profound effects on circadian behaviour. The production and mapping of one of these mutations in the mouse, an organism about which there exists a wealth of genetic information, should accelerate the elucidation of the molecular events involved in the generation of circadian rhythms in mammals.

Animals↗
PubMed1996

Involvement of the 5-HT1A subtype receptor in the neonatal organization of agonistic behaviour in the rat.

5-hydroxytryptamine (5-HT) interacts with testosterone (T) in the development of a number of neuronal systems controlling sexually dimorphic adult behaviours. In this report, we investigated this interaction on the organization of agonistic behaviour in males, females, androgenized females (250 micrograms/pup of T proprionate on the day of birth), and males castrated on the day of birth. We have shown previously that manipulating 5-HT2 activity over the 2nd week of life modulates adult agonistic behaviour, depending on genetic sex and the presence of T. In this report, we investigated the effects seen in adulthood of a 5-HT1A agonist [8-OH-DPAT, 0.25 mg/kg, intraperitoneally (i.p.)] and antagonist (WAY100135, 0.25 mg/kg, i.p.) given over days 8-16 postpartum. The test for agonistic behaviour was carried out in a neutral territory against a matched conspecific, and introductory, offensive and defensive activities were note. Results show that neonatal administration of the 5-HT1A antagonist WAY100135 increases introductory activity and defense in the presence of neonatal T, independent of genetic sex, because these effects were seen in sham-castrated males and androgenized females. Offence followed a similar pattern, in that it was increased by WAY100135, but only in males. In the case of defence, the effects of the antagonist were reinforced by the action of the agonist (8-OH-DPAT) in both males and females, indicating an inhibitory role of 5-HT1A perinatal activity on defence in the presence of malelike levels of circulating T and a facilitatory role when levels of T are low or negligible. These findings indicate that 5-HT1A activity is involved in the development of agonistic behaviour and the effects are influenced by T. The results also show that the offensive and defensive facets of agonistic activity are controlled differently.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2004

Genetic analysis of noroviruses taken from gastroenteritis patients, river water and oysters.

As oysters are eaten raw in Japan, their contamination with the non-bacterial agent of gastroenteritis has become a serious health problem. As it is well known that oysters tend to concentrate noroviruses (NV) in their digestive diverticula, NV may be linked with the acute gastroenteritis. However, since NV cannot be cultivated in cell cultures, and they have genetic diversity, the behaviour of NV in the aquatic environment is little known. In this study, NV samples were taken from gastroenteritis patients; from the river flowing into the oyster-farming area; and from oysters harvested from that river. Genetic identities of NV samples were analysed in capsid and RNA-dependent RNA polymerase (RdRp) regions respectively. In both regions, strains taken from patients were >96% identical with those from river and oyster samples. This proved that oysters were contaminated with NV excreted from patients with gastroenteritis.

Animals↗
PubMed2000

Genetic identification of neurons controlling a sexually dimorphic behaviour.

In the fruit fly Drosophila melanogaster, locomotor activity is sexually dimorphic: female flies constantly modulate their activity pattern whereas males show a steadier, stereotyped walking pace [1]. Here, we mapped the area of the brain controlling this behavioural dimorphism. Adult male Drosophila expressing a dominant feminising transgene in a small cluster of neurons in the pars intercerebralis exhibited a female-like pattern of locomotor activity. Genetic ablation of these neurons prevented the feminisation of the locomotor activity of transgenic males. The results suggest that this cluster of neurons modulates sex-specific activity, but is not involved in initiating fly locomotion. Nor does it control male courtship behaviour, because feminisation of courtship was not correlated with the feminisation of locomotor activity.

Animals↗
PubMed2001

Comparison of multiple measures of ADHD symptomatology: a multivariate genetic analysis.

The phenotypic and genetic interrelationships underlying ADHD symptomatology assessed by various instruments were examined on a sample of 735 male and 819 female same-sex twin pairs, aged 8 to 16 years, participating in the first phase of the Virginia Twin Study of Adolescent Behavioral Development (VTSABD). Multivariate analyses were applied to parental and teacher ratings from an investigator-based interview, the CAPA, and three questionnaires (the CBCL and the Rutter Parent and Teacher Scales). Results from patterns of intercorrelations and factor analyses of maternal measures suggested that at the phenotypic level, these assessed the same underlying behavioural construct, which differed from other emotional and behavioural constructs. However, genetic analyses showed that in addition to a common factor underlying the expression of ADHD as assessed across the range of measures, additional genetic factors were identified that were method- and rater-specific. The findings suggest that although the investigator-based interview and the behavioural checklists tap similar aspects of ADHD behaviour, there is additional rater-specific variance.

Adolescent↗
PubMed1983

[Demonstration of prenatal maternal influences by embryo transplantation in mice].

A comparison between inbred C57BL/6 Mice either transferred at an early developmental stage into the uterus of a hybrid female and then nursed by this mother, or only fostered to such a mother at birth, is performed in order to differentiate between uterine and postnatal maternal effects. At 21 days of age, animals from embryo transfer are heavier and display a greater amount of locomotor activity during a 48 hr period in a seminatural environment than crossfostered subjects. On the other hand, the L.D. distribution of this activity is not affected by the differences in development environments. The interest of such a methodology for the genetic analysis of behavioural differences related to differences in the environment during ontogeny is discussed.

Animals↗
PubMed2004

Vasopressin, oxytocin and social behaviour.

Understanding the neurobiology of social behaviour in mammals has been considerably advanced by the findings from two species of vole, one of which is monogamous and pair bonds whereas the other species is promiscuous and fails to form any long-lasting social relationships. The combination of neurobehavioural studies and molecular genetics has determined behavioural differences between the two species linked to the neural distribution of vasopressin 1A receptor in the male brain. More importantly, vasopressin 1A receptor gene transfer including the upstream regulatory sequence has enhanced male social affiliation in a non-monogamous species. Male affiliative bonding depends upon release of both vasopressin and dopamine in the ventral striatum enhancing the reward value of odour cues that signal identity.

Animals↗
PubMed2000

Features of nuclear architecture that influence gene expression in higher eukaryotes: confronting the enigma of epigenetics.

Complex mechanisms that influence gene expression in mammalian cells have been studied intensively over recent years. Genetic elements that control both the tissue specific patterns and levels of gene expression together with the proteins they bind have been characterised in detail and are clearly pivotal in activating pathways of gene expression. But it is also clear that the behaviour of these genetic elements is complicated by epigenetic factors, so that their introduction into cells with the necessary developmental history-and hence appropriate global concentrations of essential transcription factors-will not guarantee the desired levels of transcription. Recent experiments have reinforced this view and confirmed that apparently critical functions performed by defined genetic elements at certain chromosomal sites are not inevitably recapitulated at other chromosomal locations. Hence, a re-evaluation of the function of critical control elements is required using experimental systems that simplify the range of factors arising from local chromatin organisation. In this way, it should be possible to reveal the intricacies of gene expression that might eventually allow us to reproduce natural levels of expression from artificial gene constructs in human cells. J. Cell. Biochem. Suppl. 35:69-77, 2000.

Animals↗
PubMed2003

Transpositional behaviour of an Ac/Ds system for reverse genetics in rice.

A collection of transposon Ac/ Ds enhancer trap lines is being developed in rice that will contribute to the development of a rice mutation machine for the functional analysis of rice genes. Molecular analyses revealed high transpositional activity in early generations, with 62% of the T0 primary transformants and more than 90% of their T1 progeny lines showing ongoing active transposition. About 10% of the lines displayed amplification of the Ds copy number. However, inactivation of Ds seemed to occur in about 70% of the T2 families and in the T3 generation. Southern blot analyses revealed a high frequency of germinal insertions inherited in the T1 progeny plants, and transmitted preferentially over the many other somatic inserts to later generations. The sequencing of Ds flanking sites in subsets of T1 plants indicated the independence of insertions in different T1 families originating from the same T0 line. Almost 80% of the insertion sites isolated showing homology to the sequenced genome, resided in genes or within a range at which neighbouring genes could be revealed by enhancer trapping. A strategy involving the propagation of a large number of T0 and T1 independent lines is being pursued to ensure the recovery of a maximum number of independent insertions in later generations. The inactive T2 and T3 lines produced will then provide a collection of stable insertions to be used in reverse genetics experiments. The preferential insertion of Ds in gene-rich regions and the use of lines containing multiple Ds transposons will enable the production of a large population of inserts in a smaller number of plants. Additional features provided by the presence of lox sites for site-specific recombination, or the use of different transposase sources and selectable markers, are discussed.

Blotting, Southern↗
PubMed1994

The Emanuel Miller Memorial Lecture 1993. Genetic research and identification of environmental influences.

As the importance of genetic influence in developmental psychopathology becomes widely accepted, we should not lose sight of the importance of genetic research for the investigation and identification of environmental influences. First, genetic research provides the best available evidence for the importance of nongenetic factors in behavioural development. Rarely does genetic influence account for more than half of the variance. Second, genetic research indicates that environmental effects on behavioural development largely involve nonshared environmental processes that make children in the same family different from one another. New research on this topic is presented and implications for research are discussed.

Adoption↗