Personality traits as predictors of early alcohol inebriation among young adolescents: Mediating effects by mental health and gender-specific patterns

The aim of this study was to predict alcohol inebriation and mental health (internalizing and externalizing problems plus well-being), and potential gender-specific patterns among young adolescents, by a biopsychosocial model of personality traits. Self-reported data from 853 adolescents (479 girls) in Sweden, aged 13–15 years, from the Longitudinal Research on Development In Adolescence (LoRDIA) program were used. Predictions from personality to inebriation and mediating effects of mental health were estimated by means of logistic regression and generalized structural equation modelling. Separated gender analyses were performed throughout the study to reveal potential gender-specific patterns. Externalizing problems, Novelty Seeking and Cooperativeness had independent effects on alcohol inebriation for both genders as well as Harm Avoidance among girls and Internalizing problems among boys. Novelty Seeking and Self-Directedness had indirect effects through externalizing problems and Harm Avoidance and Self-Directedness had indirect effects through internalizing problems for boys. Self-directedness showed an indirect effect through externalizing problems for girls. The combination of an immature character (low Self-directedness and Cooperativeness) with an extreme temperament profile (high Novelty Seeking and low Harm Avoidance) was a predictor of inebriation across gender, both directly and indirectly through mental health. This study contributes with valuable information about gender-specific considerations when developing and conducting preventative interventions targeting psychological risk and resilience factors for early alcohol inebriation among young adolescents.     

Hispanic and Anglo college women's risk factors for substance use and eating disorders

This study investigated the role of temperament style (Novelty Seeking and Harm Avoidance) of Hispanic American and Anglo college women in moderating and mediating the relationship between family addiction/family functioning and offspring problem behaviors. The sample was comprised of 67 Hispanic American and 770 Anglo undergraduate women. Findings of this study indicate that the processes of risk that lead to substance use and eating disorders follow different routes for Hispanic American and Anglo women. Novelty Seeking and Harm Avoidance were found to be important factors in both moderating and mediating the effects of parental drinking and family dysfunction for both Hispanic and Anglo college women.     

Associations between Cloninger's temperament dimensions and acute tobacco withdrawal

This study examined associations between three temperament dimensions measured by the Temperament and Character Inventory-125 [Cloninger, C.R. (1992). The Temperament and Character Inventory-125 (TCI-125; Version 1.)] and tobacco abstinence effects. Smokers (N=203, >/= 15 cigarettes/day) attended two laboratory sessions, one following 12 h of abstinence and the other following ad libitum smoking (order counterbalanced). Participants completed measures of withdrawal symptoms, cigarette urges, and affect. Smokers high in Novelty Seeking reported greater abstinence-induced increases in several nicotine withdrawal symptoms, negative affect, and cigarette craving. Smokers high in Harm Avoidance reported greater abstinence-induced increases in negative affect and urges to smoke to relieve distress. Reward Dependence was not associated with abstinence effects. Novelty Seeking and Harm Avoidance showed independent predictive associations with negative affect and urges, and their associations with abstinence effects persisted when controlling for FTND scores. Smokers with different temperaments display different patterns of acute tobacco withdrawal, and may benefit from treatments matched to their particular abstinence profile.     

Serotonin transporter promoter gene polymorphic region (5-HTTLPR) and personality in female patients with seasonal affective disorder and in healthy controls.

Serotonergic pathways have been related to altered personality patterns in seasonal affective disorder (SAD). The short allele (s) of a polymorphism in the serotonin transporter promoter gene (5-HTTLPR) has been associated with neuroticism and anxiety-related personality traits in healthy volunteers. We investigated personality and 5-HTTLPR in female SAD patients using the Temperament and Character Inventory (TCI). TCI was completed by 56 female patients and 76 age-matched female controls. DNA was genotyped using polymerase chain reaction methods. Subjects homozygous for the long allele (l) were compared to s carriers. Females with SAD had higher scores in Harm Avoidance and lower scores in Novelty Seeking, Self-Directedness and Cooperativeness when compared to controls. Patients carrying the s allele had lower Self-Directedness scores. Our data indicate that females with SAD show altered personality traits. The s allele was associated with lower Self-Directedness scores in SAD patients, whereas there were no significant differences in TCI dimensions between patients and controls in carriers of the long allele.     

Relationship of family history, antisocial personality disorder and personality traits in young men at risk for alcoholism.

Studies examining possible risk factors for the development of alcoholism have focused recently on a variety of personality factors, including those associated with risk-taking behaviors. Alcohol-seeking behavior leading to the abuse of alcohol may be associated with a variety of risk-taking behaviors that derive from certain personality traits. Further, there is evidence that personality traits are transmitted across generations. This study examined the relationship of a family history of alcoholism, antisocial personality disorder (ASP) and alcohol use to several personality traits including the Tri-dimensional Personality Questionnaire (TPQ) in a sample (N = 91) of nonalcoholic, young male volunteers. The men with ASP scored higher than the non-ASP men on the Novelty Seeking Scale of the TPQ, but not on the Harm Avoidance or Reward Dependence subscales. In addition, ASP men scored higher than non-ASP men on a measure of impulsivity and tended to score higher on measures of sensation seeking, psychopathy and monotony avoidance. A family history of alcoholism did not differentiate the young men on any of the childhood behavior problems, personality measures or alcohol-related variables.     

Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits.

The involvement in neural plasticity and the mediation of effects of repeated stress exposure and long-term antidepressant treatment on hippocampal neurogenesis supports a critical role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of affective and other stress-related disorders. A previously reported valine to methionine substitution at amino-acid position 66 (BDNF Val66Met) seems to account for memory disturbance and hippocampal dysfunction. In the present study, we evaluated the impact of the BDNF Val66Met polymorphism on individual differences in personality traits in a sample of healthy volunteers in relation to other common gene variants thought to be involved in the pathophysiology of affective disorders, such as the serotonin transporter promoter polymorphism (5-HTTLPR) and a variable number of tandem repeat polymorphism of the dopamine transporter gene (DAT VNTR). Personality traits were assessed using the NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant DAT VNTR-dependent association between NEO-PI-R Neuroticism and the BDNF Val66Met polymorphism. Among individuals with at least one copy of the DAT 9-repeat allele, carriers of the BDNF Met allele exhibited significantly lower Neuroticism scores than noncarriers. This interaction was also observed for TPQ Harm Avoidance, a personality dimension related to Neuroticism. Our results support the notion that allelic variation at the BDNF locus--in interaction with other gene variants--influences anxiety- and depression-related personality traits.     

Do anorectic men share personality traits with opiate dependent men? A case-control study

BACKGROUND: Eating disorders (ED) and substance use disorders (SUD) display clinical and psychodynamic analogies. The co-diagnosis of a substance use disorder in male ED patients is frequent. Nevertheless, knowledge about the mutual predisposing factors or personality analogies is currently scarce and hypotheses are controversial. METHODS: The Temperament and Character Inventory (TCI) was used to assess 21 anorectic men, 79 heroin-dependent men, and 75 control men matched for age and education. RESULTS: Anorectic and opiate-addicted patients displayed higher Harm Avoidance and lower Self-directedness and Cooperativeness. Anorectic men displayed lower Reward Dependence and higher Persistence. Opiate addicts had higher Novelty Seeking and Self-transcendence. DISCUSSION: Anorectic and heroine-dependent subjects share personality traits related to anxiety, fearfulness and antisocial features. Nevertheless, the personality profile does not completely overlap and this could influence the choice of the "substance" of abuse and the related clinical differences between anorexia and heroin dependence.     

Cloninger's temperament and character dimensions in young adulthood and their relation to characteristics of parental alcohol use and smoking

OBJECTIVE: We examined the relationship of parental alcohol use (i.e., the frequency of alcohol intake and getting drunk) and smoking to Cloninger's temperament dimensions (Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence) and character dimensions (Self-Directedness, Cooperativeness and Self-Transcendence) in young adulthood. METHOD: We used a 14-year longitudinal study of 1,849 (1,101 female) randomly selected healthy adolescents and young adults, and their parents. Alcohol consumption and smoking were self-reported by the parents. Offspring temperament and character were measured by the Temperament and Character Inventory (TCI) 14 years later. RESULTS: Maternal and paternal frequency of alcohol intake, getting drunk and smoking were associated with offspring temperament and character dimensions, particularly Novelty Seeking, in young adulthood for both men and women. CONCLUSIONS: The results support the relevance of Cloninger's concepts and the TCI in identifying subjects with unique characteristics related to their family histories. Possible mediating mechanisms are discussed.     

The BDNF Val66Met Polymorphism Modulates the Generalization of Cued Fear Responses to a Novel Context

Brain-derived neurotrophic factor (BDNF) has a crucial role in activity-dependent synaptic plasticity and learning and memory. The human functional single-nucleotide BDNF rs6265 (Val66Met) polymorphism has been found to be associated with alteration in neural BDNF release and function correlating with altered emotional behavior. Here, we investigated for the first time the hypothesis that this polymorphism in humans modulates the context dependency of conditioned fear responses. Applying a new paradigm examining generalization of cued fear across contexts, 70 participants stratified for BDNF Val66Met polymorphism were guided through two virtual offices (context) in which briefly illuminated blue and yellow lights served as cues. In the fear context, one light (conditioned stimulus, CS+) but not the other light (CS−) was associated with an electric shock (unconditioned stimulus, US). In the safety context, both lights were presented too, but no US was delivered. During the test phase, lights were presented again both in learning contexts and in a novel generalization context without any US. All participants showed clear fear conditioning to the CS+ in the fear context as indicated by potentiation of startle responses and reports of fear. No fear reactions were found for the CS+ in the safety context. Importantly, generalization of fear responses indicated by the potentiation of startle response to the CS+ compared with the CS− in the novel context was evident only in the Met-carrying group. These are the first results to provide evidence in humans that BDNF modulates the generalization of fear responses. Such context-dependent generalization processes might predispose Met carriers for affective and anxiety disorders.     

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF^Val/Val) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF^Met/Met). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF^Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF^Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.     

Involvement of protein kinase C in reduced relaxant responses to the NO/cyclic GMP pathway in piglet pulmonary arteries contracted by the thromboxane A2-mimetic U46619

1. Impairment of nitric oxide (NO)/cyclic GMP production and/or increased activities of thromboxane A₂ (TXA₂) and endothelin-1 (ET-1) have been associated with pulmonary hypertension. We have analysed the interactions of noradrenaline (NA), the TXA₂-mimetic U46619 and ET-1 with the relaxation induced via cyclic GMP in isolated piglet intrapulmonary arteries.
2. The contractions induced by NA were augmented by endothelium removal or by methylene blue and pre-contracted rings were fully relaxed by acetylcholine, sodium nitroprusside (SNP), atrial natriuretic peptide and 8-bromo-cyclic GMP. In contrast, U46619- and ET-1 induced contractions were endothelium-independent and only partially relaxed by the latter vasodilators. Whereas the reduced responses to SNP in arteries contracted by U46619 were independent of the U46619-induced tone, a higher concentration of ET-1 (tone higher than that induced by NA) was required to reduce the vasodilator responses to SNP. NA, U46619 and ET-1 had no effect on the SNP-induced increases in cyclic GMP.
3. The reduced relaxant responses to SNP in arteries pre-contracted by U46619 were specific for piglet pulmonary arteries since they were not observed in piglet mesenteric or coronary arteries or in rat pulmonary arteries. Furthermore, there were no differences in the relaxant response to the adenylate cyclase activator forskolin in piglet pulmonary arteries pre-contracted by either NA, U46619 or ET-1.
4. SNP-induced relaxation was inhibited by thapsigargin (but not by inhibition of the membrane Na⁺/K⁺ ATPase nor K⁺ channels) indicating a role for Ca²⁺ sequestration by the Ca²⁺ ATPase in the effects of SNP.
5. The phorbol ester 12-myristate, 13-acetate inhibited the relaxant response to SNP. The inhibitory effect of U46619 on SNP-induced relaxation was abolished by the protein kinase C inhibitor (PKC) staurosporine suggesting that PKC may be a part of the signal transduction mechanism.
6. In summary, piglet pulmonary arteries when activated by a TXA₂-mimetic show abnormally reduced relaxant responses to the NO/cyclicGMP pathway. This effect appears to be mediated by activation of PKC.

     

Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor

BACKGROUND AND PURPOSE

Caffeic acid phenethyl ester (CAPE) is a component of honey bee propolis that can induce expression of haem oxygenase-1 (HO-1). Because HO-1 induction has been suggested to protect dopaminergic neurons in the substantia nigra, we examined the effect of CAPE in experimental models of dopaminergic neurodegeneration.

EXPERIMENTAL APPROACH

Neuroprotective effect of CAPE was investigated in rat organotypic midbrain slice cultures and in vivo, using a mouse model of dopaminergic neurodegeneration induced by intranigral injection of LPS and intrastriatal injection of 6-hydroxydopamine.

KEY RESULTS

CAPE protected dopaminergic neurons in slice cultures from IFN-γ/LPS-induced injury. The effect of CAPE was inhibited by zinc protoporphyrin IX, an HO-1 inhibitor, and by neutralizing antibody against brain-derived neurotrophic factor (BDNF). A p38 MAPK inhibitor SB203580 prevented activation of NF-E2-related factor 2, attenuated increased expression of HO-1 and BDNF, and blocked the neuroprotective actions of CAPE. In the LPS-injected mouse model, daily intraperitoneal administration of CAPE protected dopaminergic neurons, up-regulated HO-1 and BDNF, and reduced the increase of activated microglia/macrophages. Neuroprotective effects of CAPE against LPS-induced injury was prevented by zinc protoporphyrin IX or anti-BDNF antibody. CAPE protected dopaminergic neurons and alleviated methamphetamine-induced rotational behaviour also in 6-hydroxydopamine hemiparkinsonian mice.

CONCLUSION AND IMPLICATIONS

CAPE is a novel type of neuroprotective agent whose actions are mediated by both HO-1 and BDNF. These findings may provide novel clues to develop neuroprotective agents for treatment of neurodegenerative disorders.     

DRD2/ANKK1 Polymorphism Modulates the Effect of Ventral Striatal Activation on Working Memory Performance

Motivation is important for learning and cognition. Although dopaminergic (D2) transmission in the ventral striatum (VS) is associated with motivation, learning, and cognition are more strongly associated with function of the dorsal striatum, including activation in the caudate nucleus. A recent study found an interaction between intrinsic motivation and the DRD2/ANKK1 polymorphism (rs1800497), suggesting that A-carriers of rs1800497 are significantly more sensitive to motivation in order to improve during working memory (WM) training. Using data from the two large-scale imaging genetic data sets, IMAGEN (n=1080, age 13–15 years) and BrainChild (n∼300, age 6–27), we investigated whether rs1800497 is associated with WM. In the IMAGEN data set, we tested whether VS/caudate activation during reward anticipation was associated with WM performance and whether rs1800497 and VS/caudate activation interact to affect WM performance. We found that rs1800497 was associated with WM performance in IMAGEN and BrainChild. Higher VS and caudate activation during reward processing were significantly associated with higher WM performance (p<0.0001). An interaction was found between the DRD2/ANKK1 polymorphism rs1800497 and VS activation during reward anticipation on WM (p<0.01), such that carriers of the minor allele (A) showed a significant correlation between VS activation and WM, whereas the GG-homozygotes did not, suggesting that the effect of VS BOLD on WM is modified by inter-individual genetic differences related to D2 dopaminergic transmission.     

Complicated interaction between psychostimulants and morphine in expression of phenotype of behavior in the dopaminergic system of BALB/c mice

It is believed that BALB/c mice appear to be less sensitive to the locomotor effects of abused drugs compared to other strains, and several behaviors induced by abused drugs depend on genetic factors. The present study was designed to investigate the effects of the interaction between psychostimulants and morphine on behavior in BALB/c mice. Morphine and cocaine induced hyperlocomotion and hypolocomotion, respectively, while methamphetamine did not affect locomotor activity and high doses of methamphetamine significantly increased self-injurious behavior. Cocaine or methamphetamine increased the effects of morphine on locomotor behavior. Haloperidol (a dopamine-receptor antagonist) attenuated the hyperlocomotion induced by the combination of cocaine or methamphetamine plus morphine. These results indicate that the synergistic effects of methamphetamine or cocaine and morphine on locomotor activity are mediated through enhancement of the dopaminergic system and that combinations of psychostimulants and morphine enhance the locomotor activity in BALB/c mice. On the other hand, morphine completely attenuated methamphetamine-induced self-injurious behavior. Furthermore, a low dose (0.01 mg/kg) of haloperidol significantly increased the effects of methamphetamine and morphine on the locomotor activity. Hyperlocomotion induced by psychostimulants is mediated by the mesolimbic dopaminergic system, whereas stereotyped behaviors is mediated by the nigrostriatal dopaminergic system. Our findings suggest that balances of the activation of dopaminergic neurons (between mesolimbic and nigrostriatal systems) may play an important role to engender corresponding behavioral outcomes in BALB/c mice.     

Differential Roles of α6β2* and α4β2* Neuronal Nicotinic Receptors in Nicotine- and Cocaine-Conditioned Reward in Mice

Mesolimbic α6* nicotinic acetylcholine receptors (nAChRs) are thought to have an important role in nicotine behavioral effects. However, little is known about the role of the various α6*-nAChRs subtypes in the rewarding effects of nicotine. In this report, we investigated and compared the role of α6*-nAChRs subtypes and their neuro-anatomical locus in nicotine and cocaine reward-like effects in the conditioned place preference (CPP) paradigm, using pharmacological antagonism of α6β2* nAChRs and genetic deletion of the α6 or α4 subunits in mice. We found that α6 KO mice exhibited a rightward shift in the nicotine dose–response curve compared with WT littermates but that α4 KO failed to show nicotine preference, suggesting that α6α4β2*-nAChRs are involved. Furthermore, α6β2* nAChRs in nucleus accumbens were found to have an important role in nicotine-conditioned reward as the intra-accumbal injection of the selective α6β2* α-conotoxin MII [H9A; L15A], blocked nicotine CPP. In contrast to nicotine, α6 KO failed to condition to cocaine, but cocaine CPP in the α4 KO was preserved. Intriguingly, α-conotoxin MII [H9A; L15A], blocked cocaine conditioning in α4 KO mice, implicating α6β2* nAChRs in cocaine reward. Importantly, these effects did not generalize as α6 KO showed both a conditioned place aversion to lithium chloride as well as CPP to palatable food. Finally, dopamine uptake was not different between the α6 KO or WT mice. These data illustrate that the subjective rewarding effects of both nicotine and cocaine may be mediated by mesolimbic α6β2* nAChRs and that antagonists of these receptor subtypes may exhibit therapeutic potential.     

Val66Met functional polymorphism and serum protein level of brain-derived neurotrophic factor (BDNF) in acute episode of schizophrenia and depression

Background

Brain-derived neurotrophic factor (BDNF) influences neuron differentiation during development as well as the synaptic plasticity and neuron survival in adulthood. BDNF has been implicated in the pathogenesis of schizophrenia and depression. Val66Met polymorphism and BDNF serum level are potential biomarkers in neuropsychiatric disorders. The aim of this study was to determine the effect of BDNF gene Val66Met functional polymorphism on serum BDNF concentration in patients with schizophrenia, during depression episode and in healthy control group.

Influence of BDNF and COMT polymorphisms on emotional decision making

Decision making is an important brain function. Although little is known about the genetic basis of decision making, it has been suggested that it is mediated by the modulation of neurotransmitter systems. We investigated how the BDNF Val66Met and COMT Val158Met polymorphisms affect emotional decision making using the Iowa Gambling Task (IGT). One hundred sixty-eight healthy Korean college students (93 males, 75 females) with a complete dataset were included in the data analysis. The IGT and genotyping for the polymorphisms of BDNF Val66Met and COMT Val158Met were performed. Both Met/Met and Val/Met of the BDNF Val66Met polymorphism were significantly associated with a lower mean score of blocks 3-5 of the IGT and with less improvement from block 1 to block 3-5 than the Val/Val. However, the BDNF was not significantly associated with the score of block 1, and the COMT Val158Met polymorphism produced no significant effect on IGT performance. No interaction effect was observed between the BDNF and the COMT for the IGT. These findings suggest the BDNF Val66Met may affect the emotional decision making performance.     

BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.