LRRK2 Gene Variants Associated With a Higher Risk for Alcohol Dependence in Multiethnic Populations.

Background: Genetics influence the vulnerability to alcohol use disorders, and among the implicated genes, three previous studies have provided evidences for the involvement of LRRK2 in alcohol dependence (AD). LRRK2 expression is broadly dysregulated in postmortem brain from AD humans, as well as in the brain of mice with alcohol dependent-like behaviors and in a zebrafish model of alcohol preference. The aim of the present study was to evaluate the association of variants in the LRRK2 gene with AD in multiethnic populations from South and North America. Methods: Alcohol-screening questionnaires [such as CAGE and Alcohol Use Disorders Identification Test (AUDIT)] were used to determine individual risk of AD. Multivariate logistic regression analyses were done in three independent populations (898 individuals from Bambuí, Brazil; 3,015 individuals from Pelotas, Brazil; and 1,316 from the United States). Linkage disequilibrium and conditional analyses, as well as in silico functional analyses, were also conducted. Results: Four LRRK2 variants were significantly associated with AD in our discovery cohort (Bambuí): rs4768231, rs4767971, rs7307310, and rs1465527. Two of these variants (rs4768231 and rs4767971) were replicated in both Pelotas and US cohorts. The consistent association signal (at the LRRK2 locus) found in populations with different genetic backgrounds reinforces the relevance of our findings. Conclusion: Taken together, these results support the notion that genetic variants in the LRRK2 locus are risk factors for AD in humans.

Early postnatal l-Dopa treatment causes behavioral alterations in female vs. male young adult Swiss mice.

Dopaminergic signaling and neurodevelopment alterations are associated with several neuropsychiatric disorders. Knockout mice for dopamine transporters (DAT) as well as site-specific knockout mice lacking dopaminergic D2 autoreceptors in dopaminergic neurons (DA-D2RKO) display behavioral alterations such as hyperlocomotion and abnormal prepulse inhibition. However, it is possible that dopaminergic imbalances may have different effects during varied neurodevelopmental windows. In our previous study, we observed that elevated levels of dopamine during the perinatal developmental window increased exploratory behavior of juvenile (4-week-old) Swiss female mice and impaired hedonic behavior in males. In this study, we investigated whether these behavioral alterations persist through young adulthood. In order to do so, we administered daily doses of l-Dopa to mice pups beginning from postnatal day 1 (PD1) to PD5. At the age of 8 weeks, we submitted the young adult males and females to the open field test, elevated plus maze, forced swimming test, and sucrose preference test. We observed that augmentation of dopamine levels during the perinatal developmental window increased locomotor behavior in females, but not males. We also observed an increase in anxiety-behavior in females and anxiolytic-like behavior in males. In addition, we observed stress-coping behavior in males and an increase of hedonic behavior in females. Our results show that dopamine signaling is important for behavioral development and that transient imbalances of dopamine levels can cause permanent behavioral alterations - alterations which are different in males than in females. These data may help in better understanding the spectrum of symptoms associated with different neuropsychiatric disorders.

l-Dopa treatment during perinatal development leads to different behavioral alterations in female vs. male juvenile Swiss mice.

Alterations in dopaminergic signaling and neurodevelopment are associated with many neuropsychiatric disorders, such as attention deficit and hyperactivity disorder (ADHD), autism, and schizophrenia. Imbalances in dopamine levels during prenatal development are associated with behavioral alterations later in life, like hyperactivity and addiction, and it is possible that dopaminergic imbalances may have diverse effects during different neurodevelopmental windows. In this study, we investigate whether an increase in dopamine levels during the perinatal developmental window affects behavior of juvenile male and female Swiss mice. In order to do so, we intraperitoneally administered daily doses of l-Dopa to mice pups beginning from postnatal day 1 (PD1) to PD5, which increased the levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the striatum of the pups. At the age of 4 weeks, we submitted the juvenile males and females to the open field test, elevated plus maze, forced swimming test, and sucrose preference test. We observed that increase of dopamine levels during the perinatal developmental window increased exploratory behavior in juvenile females, but not males. We observed no changes in anxiety- and depressive-like behaviors. In contrast, we observed that increased dopamine levels during the perinatal period lead to hedonic alterations in juvenile males, but not females. Our results show that dopamine signaling is important for behavioral development and that transient imbalance of dopamine levels causes juvenile behavioral alterations, which are different in males than in females. These data may help in better understanding the spectrum of symptoms associated with different neuropsychiatric disorders.

Is the serotonin transporter polymorphism (5-HTTLPR) a potential marker for suicidal behavior in bipolar disorder patients?

BACKGROUND: Suicide prediction is a huge challenge for mental health workers. Structured interviews based on epidemiological and clinical factors don't show effectiveness for suicide prevention. Biological markers, such as 5-HTTLPR, could help for identification of potential suicide attempters. METHODS: We evaluated 198 bipolar patients and 103 health controls, using a structured interview according to DSM-IV criteria. Genotyping, blind of clinical assessment for identification of S carriers and structured interviews were performed in order to describe clinical and epidemiological factors which could be associated with suicide behavior. Statistical analyses were calculated by the x(2) test and logistic regression model. RESULTS: We found that 26.77% and 16.67% had a lifetime history of non violent suicide attempt and violent suicide attempt, respectively. The clinical factors associated with violent and non violent suicide attempt had several differences. Violent suicide attempters had an earlier illness onset and had a higher number of psychiatric comorbidities (borderline personality disorder, panic disorder and alcoholism). The frequency of S allele carriers was higher only in those patients who had made a violent suicide attempt in their lifetime (x(2)=16.969; p=0.0001). In a logistic regression model including these factors, S allele carrier (5-HTTLPR) was the only factor associated with violent suicide attempt. LIMITATIONS: Sample size and retrospective assessment of suicide behavior history are the limitations of this study. CONCLUSIONS: Our study showed that serotonin polymorphism (5-HTTLPR) is strongly associated with violent suicidal behavior in BD patients. If confirmed, our results could be an important step to create a genetic tool for long-term suicide prediction.