G. Ponce

The role of behavioral impulsivity in the development of alcohol dependence: a 4-year follow-up study.

BACKGROUND Although many studies have established a close relation between impulsivity and alcohol use disorders, little is known about the role of behavioral impulsivity in the development of these disorders. OBJECTIVES To determine the role of 2 laboratory paradigms of impulsivity in the development of alcohol use disorders. METHODS Follow-up study carried out with 471 participants diagnosed as heavy drinkers (HD) and followed-up for 4 years. Initially, they were compared with a healthy control group. Assessment of behavioral impulsivity was carried out with the Continuous Performance Test (CPT), and the Stop-Signal Task (SST) assessed behavioral inhibitory control. Differential reinforcement for low-rate responding (DRLR) was used to evaluate the delay reward dimension. The Structured Clinical Interview (SCID-DSM-IV) was used to diagnose alcohol dependence. RESULTS The HD performed worse than the control group in all the behavioral tests of impulsivity. Performance in DRLR was the only behavioral impulsivity test that classified the HD correctly compared to controls. Logistic regression analysis indicated that performance on SST was a significant predictor [odds = 1.52(CI = 1.08-2.31)] of developing alcohol dependence. CONCLUSIONS Our results support the relation between behavioral impulsivity and alcohol use disorders. The paradigm related to delay of reward may be a factor associated with the use of alcohol and the incapacity to control inhibition as dependence develops.

Long-Acting Injectable Risperidone Compared with Zuclopenthixol in the Treatment of Schizophrenia with Substance Abuse Comorbidity

Objective: This study aimed to compare the efficacy of long-acting risperidone and zuclopenthixol in subjects with schizophrenia and substance abuse. Method: A total of 115 subjects with schizophrenia and substance use disorders were enrolled for an open, randomized, controlled, 6-month follow-up study. Fifty-seven subjects were selected for treatment with long-acting injectable risperidone, while another 58 were treated with zuclopenthixol-depot. Results: Long-acting risperidone patients presented fewer positive urine tests (8.67 compared with 10.36, P = 0.005), showed improved scores on the Positive and Negative Syndrome Scale, and showed better compliance with the Substance Abuse Management program. The use of long-acting risperidone and less severe dependence explained the outcome at the end of the follow-up. Conclusions: Long-acting injectable risperidone was more effective than zuclopenthixol-depot in improving substance abuse and schizophrenia symptoms in subjects with dual diagnosis.

The ANKK1 Kinase Gene and Psychiatric Disorders

The TaqIA single nucleotide polymorphism (SNP, rs1800497), which is located in the gene that codes for the putative kinase ANKK1 (ANKK1) near the termination codon of the D2 dopamine receptor gene (DRD2; chromosome 11q22–q23), is the most studied genetic variation in a broad range of psychiatric disorders and personality traits. A large number of individual genetic association studies have found that the TaqIA SNP is linked to alcoholism and antisocial traits. In addition, it has also been related to other conditions such as schizophrenia, eating disorders, and some behavioral childhood disorders. The TaqIA A1 allele is mainly associated with addictions, antisocial disorders, eating disorders, and attention-deficit/hyperactivity disorders, while the A2 allele occurs more frequently in schizophrenic and obsessive-compulsive patients. Current data show that the TaqIA polymorphism may be a marker of both DRD2 and ANKK1 genetic variants. ANKK1 would belong to a family of kinases involved in signal transduction. This raises the question of whether signaling players intervene in the pathophysiology of psychiatric disorders. Basic research on the ANKK1 protein and its putative interaction with the D2 dopamine receptor could shed light on this issue.

The ANKK1 gene associated with addictions is expressed in astroglial cells and upregulated by apomorphine.

BACKGROUND TaqIA, the most widely analyzed genetic polymorphism in addictions, has traditionally been considered a gene marker for association with D2 dopamine receptor gene (DRD2). TaqIA is located in the coding region of the ANKK1 gene that overlaps DRD2 and encodes a predicted kinase ANKK1. The ANKK1 protein nonetheless had yet to be identified. This study examined the ANKK1 expression pattern as a first step to uncover the biological bases of TaqIA-associated phenotypes. METHODS Northern blot and quantitative reverse-transcriptase polymerase chain reaction analyses were performed to analyze the ANKK1 mRNA. To study ANKK1 protein expression, we developed two polyclonal antibodies to a synthetic peptides contained in the putative Ser/Thr kinase domain. RESULTS We demonstrate that ANKK1 mRNA and protein were expressed in the adult central nervous system (CNS) in human and rodents, exclusively in astrocytes. Ankk1 mRNA level in mouse astrocyte cultures was upregulated by apomorphine, suggesting a potential relationship with the dopaminergic system. Developmental studies in mice showed that ANKK1 protein was ubiquitously located in radial glia in the CNS, with an mRNA expression pick around embryonic Day 15. This time expression pattern coincided with that of the Drd2 mRNA. On induction of differentiation by retinoic acid, a sequential expression was found in human neuroblastoma, where ANKK1 was expressed first, followed by that of DRD2. An opposite time expression pattern was found in rat glioma. CONCLUSIONS Spatial and temporal regulation of the expression of ANKK1 suggest an involvement of astroglial cells in TaqIA-related neuropsychiatric phenotypes both during development and adult life.

Gender-specific COMT Val158Met polymorphism association in Spanish schizophrenic patients.

The functional Val158Met polymorphism (rs4680) located at the gene that codes for the catechol‐O‐methyltransferase (COMT) has been extensively investigated in schizophrenia although current data are still controversial. Since COMT activity is sexually dimorphic, we carried out two independent studies in homogeneous samples of male and female Spanish schizophrenic patients. In males, we found an association between the homozygous Val genotype and the disorder, which resembled a recessive model (P = 0.022; odds ratio [OR] = 1.67). This Val homozygotes overrepresentation is produced at the expense of the heterozygous individuals decrease, whilst the Met homozygotes showed no differences when compared controls and patients. As a consequence, the heterozygous genotype in this sample had a protective effect (P = 0.03; OR = 0.65) and a strong deviation from Hardy–Weinberg equilibrium in male cases was observed (P = 0.006). In addition, a 2‐SNP haplotype analysis (rs4818‐Val158Met) confirmed there is an overrepresentation of the different homozygous Val genotypes in the male schizophrenic sample. Regarding females, we did not find any statistically significant association between COMT SNP and schizophrenia. In the light of this we suggest that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population.

Association in alcoholic patients between Psychopathic Traits and the additive effect of allelic forms of theCNR1 andFAAH endocannabinoid genes, and the 3′ Region of theDRD2 Gene

Little is known about the genetic factors that underlie the comorbidity between alcohol use disorder and antisocial personality disorder. Previous studies have associated both, dopaminergic and endocannabinoid systems to severe alcoholism with non-adaptive disrupted behaviours. In this work we have examined some gene variants involved in such systems in a sample of alcoholic patients to test whether there is a relationship with antisocial traits. The genetic analysis involved the genotyping of the single nucleotide polymorphism (SNP) TaqIA located nearby theDRD2 gene, the 10-repeat allele of a variable number tandem repeats (VNTR) of theSLC6A3 gene, the C385AFAAH SNP and the 3′-UTR microsatellite ofCNR1 gene. The clinical study was performed in 137 Spanish alcohol dependent males. Antisocial Personality Disorder (DSM-IV) diagnosis was made by applying the International Personality Disorder Examination, and psychopathic traits were evaluated by the Hare’s Psychopathy Checklist Revised (PCL-R). The genotype distribution indicates there is a relationship between the TaqIA SNP,CNR1 andFAAH genes and PCL-R’s Factor 1 in alcoholic patients. This relationship seems to be additive and independent and might be responsible for 11.4% of the variance in this PCL-R subscale. Our results suggest the implication of the dopaminergic and endocannabinoid systems in those processes leading to the comorbidity of alcoholism and antisocial behaviour.

C957T DRD2 polymorphism is associated with schizophrenia in Spanish patients

Objective:  The objective was to confirm whether a homozygous genotype for the C957 allele of the C957T DRD2 gene single nucleotide polymorphism (SNP) is associated with schizophrenia in an independent study population.

Naltrexone improves outcome of a controlled drinking program

Naltrexone is widely used in therapeutic programs with abstinence as a goal. However, it has been used in only a few studies aimed at reducing alcohol consumption. The purpose of this study was to evaluate the efficacy of naltrexone as an adjunct in controlled drinking programs. This was an open randomized study of 12 weeks duration that compared two therapeutic strategies: use of naltrexone in a controlled drinking program (NTX+CD) and the controlled drinking program alone (CD), without NTX. Each group comprised 30 male patients with mild alcohol dependence. During treatment, there were no differences between groups in drinking behavior, though the NTX+CD group showed significantly less craving. In the 12-month follow-up period, the NTX+CD group showed significantly fewer drinking days and heavy drinking days and less craving than the CD group. The results of this study suggest a role for naltrexone in controlled drinking programs.

The ANKK1 Protein Associated with Addictions has Nuclear and Cytoplasmic Localization and Shows a Differential Response of Ala239Thr to Apomorphine

The TaqIA single-nucleotide polymorphism (SNP), which is the most widely studied genetic polymorphism in addictions, is located at the gene that encodes the RIP kinase ANKK1 near the gene for dopamine receptor D2. The TaqIA SNP is in strong linkage disequilibrium with the SNP rs7118900, which changes the alanine at position 239 to threonine in the ANKK1 protein (Ala239/A2; Thr239/A1). In silico analysis has predicted that this polymorphic substitution creates an additional phosphorylation site in the kinase domain of ANKK1. To investigate the contribution of ANKK1 to the pathophysiology of TaqIA-associated phenotypes, we analyzed transfected HEK293T cells with the human ANKK1-kinaseAla239 and ANKK1-kinaseThr239 variants tagged with GFP. We observed that the ANKK1-kinase is located in both the nucleus and the cytoplasm, suggesting that there is nucleocytoplasmic shuttling of this putative signal transducer. In addition, we found that the Ala239Thr ANKK1-kinase polymorphism exhibited strong expression differences in both the nucleus and the cytoplasm at basal level and when stimulated with the dopamine agonist apomorphine. Specifically, the ANKK1-kinaseThr239 variant showed the highest level of basal protein expression, while ANKK1-kinaseAla239 was 0.64-fold lower. After treatment with apomorphine, ANKK1-kinaseAla239 showed a 2.4-fold increment in protein levels, whereas a 0.67-fold reduction was observed in ANKK1-kinaseThr239. Thus, here we provide the first evidence of functional ANKK1 differences that are marked by TaqIA and could be associated with vulnerability to addiction.

Differential dorsolateral prefrontal cortex activation during a verbal n-back task according to sensory modality

Functional neuroimaging studies carried out on healthy volunteers while performing different n-back tasks have shown a common pattern of bilateral frontoparietal activation, especially of the dorsolateral prefrontal cortex (DLPFC). Our objective was to use functional magnetic resonance imaging (fMRI) to compare the pattern of brain activation while performing two similar n-back tasks which differed in their presentation modality. Thirteen healthy volunteers completed a verbal 2-back task presenting auditory stimuli, and a similar 2-back task presenting visual stimuli. A conjunction analysis showed bilateral activation of frontoparietal areas including the DLPFC. The left DLPFC and the superior temporal gyrus showed a greater activation in the auditory than in the visual condition, whereas posterior brain regions and the anterior cingulate showed a greater activation during the visual than during the auditory task. Thus, brain areas involved in the visual and auditory versions of the n-back task showed an important overlap between them, reflecting the supramodal characteristics of working memory. However, the differences found between the two modalities should be considered in order to select the most appropriate task for future clinical studies.