CACNA1C Risk Variant and Amygdala Activity in Bipolar Disorder, Schizophrenia and Healthy Controls.

CACNA1C Risk Variant and Amygdala Activity in Bipolar Disorder, Schizophrenia and Healthy Controls.

PLoS One. 2013; 8(2): e56970
Tesli M, Skatun KC, Ousdal OT, Brown AA, Thoresen C, Agartz I, Melle I, Djurovic S, Jensen J, Andreassen OA

Several genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups.Rs1006737 was genotyped in 250 individuals (N?=?66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group.In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups.These results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ. HubMed – addiction


MicroRNA let-7d regulates the TLX/microRNA-9 cascade to control neural cell fate and neurogenesis.

Sci Rep. 2013 Feb 25; 3: 1329
Zhao C, Sun G, Ye P, Li S, Shi Y

MicroRNAs have important functions in the nervous system through post-transcriptional regulation of neurogenesis genes. Here we show that microRNA let-7d, which has been implicated in cocaine addiction and other neurological disorders, targets the neural stem cell regulator TLX. Overexpression of let-7d in vivo reduced neural stem cell proliferation and promoted premature neuronal differentiation and migration, a phenotype similar to those induced by TLX knockdown or overexpression of its negatively-regulated target, microRNA-9. We found a let-7d binding sequence in the tlx 3′ UTR and demonstrated that let-7d reduced TLX expression levels in neural stem cells, which in turn, up-regulated miR-9 expression. Moreover, co-expression of let-7d and TLX lacking its 3′ UTR in vivo restored neural stem cell proliferation and reversed the premature neuronal differentiation and migration. Therefore, manipulating let-7d and its downstream targets could be a novel strategy to unravel neurogenic signaling pathways and identify potential interventions for relevant neurological disorders. HubMed – addiction


Alcohol- or drug-use disorders and motor vehicle accident mortality: A retrospective cohort study.

Accid Anal Prev. 2013 Feb 1; 53C: 149-155
Callaghan RC, Gatley JM, Veldhuizen S, Lev-Ran S, Mann R, Asbridge M

A large body of research has linked alcohol consumption and motor vehicle accidents (MVAs), but far fewer studies have estimated the risk of MVA fatality among drug users. Our study addresses this gap. We identified cohorts of individuals hospitalized in California from 1990 to 2005 with ICD-9 diagnoses of methamphetamine- (n=74,170), alcohol- (n=592,406), opioids- (n=68,066), cannabis- (n=47,048), cocaine- (n=48,949), or polydrug-related disorders (n=411,175), and these groups were followed for up to 16 years. Age-, sex-, and race-adjusted standardized mortality rates (SMRs) for deaths due to MVAs were generated in relation to the California general population. Standardized MVA mortality ratios were elevated across all drug cohorts: alcohol (4.5, 95% CI, 4.1-4.9), cocaine (3.8, 95% CI, 2.3-5.3), opioids (2.8, 95% CI, 2.1-3.5), methamphetamine (2.6, 95% CI, 2-3.1), cannabis (2.3, 95% CI, 1.5-3.2) and polydrug (2.6, 95% CI, 2.4-2.9). Males and females had similar MVA SMRs. Our large, population-based study found elevated risk of MVA mortality across all cohorts of individuals with alcohol- or drug-use disorders. Given that illicit drug users are often unaware of or misperceive the impacts of drug use on safe driving, it may be important for health-service or public-health interventions to address such biases and improve road safety. HubMed – addiction


Deep Brain Stimulation of the Subthalamic Nucleus Increases Premature Responding in a Rat Gambling Task.

Behav Brain Res. 2013 Feb 19;
Aleksandrova LR, Creed MC, Fletcher PJ, Lobo DS, Hamani C, Nobrega JN

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option for the motor symptoms of Parkinson’s disease (PD). However, several recent studies have found an association between STN-DBS and increased impulsivity. Currently, it is not clear whether the observed increase in impulsivity results from STN-DBS per se, or whether it involves an interaction with the underlying PD neuropathology and/or intake of dopaminergic drugs. We investigated the effects of STN-DBS on performance of intact rats on two tasks measuring impulsive responding: a novel rat gambling task (rGT) and a differential reinforcement of low rate responding (DRL20s) schedule. Following initial behavioural training, animals received electrode implantation into the STN (n=24) or sham surgery (n=24), and were re-tested on their assigned behavioural task, with or without STN-DBS. Bilateral STN-DBS administered for two hours immediately prior to testing, had no effects on rGT choice behaviour or on DRL response inhibition (p> 0.05). However, STN-DBS significantly increased premature responding in the rGT task (p= 0.0004), an effect that took several sessions to develop and persisted in subsequent trials when no stimulation was given. Consistent with the notion of distinct facets of impulsivity with unique neurochemical underpinnings, we observed differential effects of STN-DBS in the two tasks employed. These results suggest that STN-DBS in the absence of parkinsonism may not lead to a general loss of inhibitory control, but may instead affect impulsivity under specific conditions. HubMed – addiction