Ada Man Choi Ho

Impulsivity in Hong Kong-Chinese club-drug users

To investigate the relationship between personality, club-drug use and high-risk drug-related behaviour, 360 club-drug users and 303 non-drug users in Hong Kong were assessed on measures of two impulsivity dimensions, reward drive and rash impulsivity, and a related trait of punishment sensitivity. The most frequently used drugs were ketamine, ecstasy, and cannabis, with the majority of participants using two or more drugs on any one occasion. Club-drug users were more rash-impulsive and reward-driven, and less punishment-sensitive than non-drug users (p<0.001). Rash impulsivity, but not reward drive or punishment sensitivity, was significantly (p<0.001) associated with risky drug-related behaviour. There was no association between any personality traits and preferred drug. These findings suggest that, while those who use club drugs are generally more impulsive and less punishment-sensitive, some discrete facets of impulsivity are associated with differing patterns of drug-use behaviour.

The expression of NMDA receptor subunit mRNA in human chronic alcoholics.

Ethanol is a modulator at the N‐methyl‐d‐aspartate class of glutamate receptors in the brain. In animal studies the receptor adapts to sustained ethanol exposure through altered expression of the subunits that make up the receptor complex. We used real‐time RT‐PCR normalized to GAPDH to assay NR1, NR2A, and NR2B subunit mRNA in superior frontal and primary motor cortex tissue obtained at autopsy from chronic alcoholics with and without co‐morbid cirrhosis of the liver, and from matched controls. The expression of all three subunits was significantly lower in both areas of cirrhotic alcoholics than in the corresponding areas in both controls and alcoholics without co‐morbid disease, who did not differ significantly from each other. The decrease was area‐dependent when cases were partitioned by the 5‐HTTLPR allele. Thus, polymorphisms in one gene can have a significant effect on the expression of a second, unrelated, gene. The expression of the N‐methyl‐d‐aspartate glutamate receptor complex is under multifactorial control.

Dopamine Receptor D4 Gene −521C/T Polymorphism Is Associated with Opioid Dependence through Cold‐Pain Responses

Heroin users exhibit abnormal pain sensitivity called opioid‐induced hyperalgesia that may weaken their determination to abstain. The dopamine receptor D4 gene (DRD4) is associated with heroin dependence; one of its polymorphisms is a C/T variation 521 bp upstream to the gene (−521C/T). We investigated whether this polymorphism was related to opioid dependence through modulation of cold‐pain responses. We recruited 84 heroin‐dependent Chinese male subjects and 168 healthy male Chinese controls. Genotyping was performed by PCR‐RFLP. A significantly higher T allele frequency was observed in the heroin group (P= 0.041). Of the cohort recruited, 43 current heroin users and 66 controls were further subjected to a cold‐pressor test (CPT) to determine their pain threshold and tolerance. TT controls demonstrated a significantly lower pain threshold than did their CC/CT counterparts (P= 0.022) and TT opioid users (P= 0.006). Moreover, CC/CT controls had a significantly higher pain tolerance than TT controls (P= 0.042) and CC/CT opioid users (P= 0.010). The data suggest that DRD4−521C/T plays an important role in opioid dependence through modulating cold‐pain responses. TT individuals might have a higher tendency to use opioids because they experience pain less strongly after chronic opioid use.

Association of polymorphisms in RGS4 and expression of RGS transcripts in the brains of human alcoholics

Chronic alcoholism leads to neurotoxic effects in the central nervous system. Neuroadaptive changes in the brain may lead to tolerance to, and dependence on, alcohol as a result of alterations in synaptic complexity. G-proteins are negatively regulated by RGS proteins, which are integral to many neural pathways that include neurotransmission, hormonal responses, and chemotactic signals. These considerations, together with findings from microarray analyses of human autopsy brain, suggest that proteins involved in G-protein signalling, specifically the RGS protein family, may play an important role in the functioning of neural systems that are affected by chronic alcohol abuse. We used Real Time PCR to measure the expression of two members of the RGS family, RGS4 and RGS7, in the superior frontal gyrus and primary motor cortex from alcoholic and non-alcoholic cases. Overall, cirrhotic alcoholics had lower expression levels of RGS4 mRNA than controls and non-cirrhotic alcoholics. We also report that the four RGS4 SNPs (SNP1, 4, 7 and 18) may be associated with alcoholism in European Caucasians at the haplotype level. The haplotype T-C-G (SNP1-4-18) may exert a protective effect against alcoholism.

Pain response in heroin users: Personality, abstinence, and modulation by benzodiazepines

We compared cold-pain responses among male current opioid users with and without concurrent benzodiazepine use, long-term ex-users, and healthy controls. Forty-eight current opioid users (14 concurrently using benzodiazepines), 34 ex-users (abstinent for ≥1 y) and 63 controls received cold-pressor tests. Pain threshold (first reporting pain) and pain tolerance (total immersion time) were recorded. Pain thresholds were similar in ex-users and current users; pain tolerance was similar in ex-users and controls. Net pain tolerance (endurance) in ex-users was intermediate between the other two groups. Current users showed higher pain threshold and shorter pain tolerance than controls (p<0.05). Current users not co-using benzodiazepines showed the lowest pain tolerance and net pain tolerance, and differed significantly from controls, ex-users, and current users co-using benzodiazepines (p<0.05). Neuroticism was higher in current users than in the other two groups (p<0.001), extraversion marginally lower (p<0.05); net pain tolerance differences remained significant after controlling for these. Benzodiazepine use modulates pain tolerance in opioid users. Pain responses altered by opioid use may partially recover with abstinence.

Crfr1 gene polymorphism is associated with heavy drinking onset in alcohol-dependent subjects

35th Annual Scientific Meeting of the Research Society on Alcoholism, June 23-27. San Francisco, California

Gene polymorphisms, personality traits and alcohol craving in alcohol-dependent subjects

Myelin, the membrane extension of a specialized cell called oligodendrocyte, has recently gained tremendous interest, due to its involvement in a wide variety of neurological and psychiatric disorders, ranging from neonatal ventricular leukomalacia to metabolic syndromes of genetic origin, from schizophrenia to inflammatory demyelination, such as Multiple Sclerosis. Our laboratory has been working towards an understanding of the molecular mechanisms underlying the acquisition of oligodendrocyte identity, which is necessary for myelin formation in the developing and adult brain. Early ultra-structural studies in the brain of developing animals had reported that the progression of oligodendrocyte progenitors towards myelinating cells was characterized by increased chromatin compaction. We have reproduced these changes in vitro, in primary cultures of oligodendrocyte progenitors from the developing rodent brain, thereby validating this culture system as an important model for the study of chromatin during oligodendrocyte differentiation. The basic unit of chromatin is the nucleosome, which is composed of an octamer of four core histones and 146 base pairs of DNA wrapped around it. The structural and functional state of chromatin is modulated by posttranslational modifications of residues at the tails of histones. We shall review evidence that histone modifications and other epigenetic events are essential for the acquisition of a myelinating phenotype. The implications for disease states will be discussed. (Supported by grants RO1-NS024295 and NS52738.)

N-Methyl-D-Aspartate receptor expression in the cortex of human chronic alcoholics : The influence of the Taqia Polymorphism of Ankk1

MicroRNAs (miRNAs) represent a large class of small single-stranded non-coding RNAs that are thought to regulate diverse functions by post-transcriptional gene silencing. Recently, miRNAs are have been shown to be crucial regulators of gene expression, affecting a wide variety of cellular functions. In brain, miRNAs have been shown to play an important role during development and in regulation of synaptic plasticity, and have been implicated in human brain diseases. In previous studies, we and others have used cDNA and oligonucleotide microarrays to identify and classify genes with altered expression following long-term alcohol consumption; however, the potential role of miRNA regulation of these genes has not been investigated. In the present study, we used miRNA arrays (Ambion+Invitrogen human, mouse, and rat probes) to classify miRNAs with altered expression in postmortem prefrontal cortex following long-term alcohol consumption. miRNAs profiles were obtained from the identical samples (14 well characterized alcoholics and 13 matched controls) that were used in a previous cDNA microarray study (Neuropsychopharm 31, 1574-82, 2006). We found that ~20 miRNAs were significantly up-regulated (p<0.002; 20-45%) in the alcoholic group compared to controls. Interestingly, miRNA down-regulation was not observed at this level of significance. Functional classification of the predicted target genes of the regulated miRNAs demonstrated a large degree of overlap with published mRNA data. For example, genes involved in ubiquitination, apoptosis, cell adhesion, neurogenesis, and neural disease are predicted targets of the regulated miRNAs. In addition, approximately one third of the significantly regulated mRNAs from the previous microarray study were identified as potential targets of the significantly changed miRNAs. miRNAs are key regulators of gene expression but the functions of many human miRNAs are yet to be discovered. This study provides the first analysis of miRNA levels in human alcoholism and raise the possibility that the reduced of expression of brain genes seen in human alcoholism may be due, at least in part, to increased levels of miRNAs. Supported by NIH AA12404.