Ankyrin Repeat and Kinase Domain Containing 1 Gene, and Addiction Vulnerability.

The TaqIA single nucleotide variant (SNV) has been tested for association with addictions in a huge number of studies. TaqIA is located in the ankyrin repeat and kinase domain containing 1 gene (ANKK1) that codes for a receptor interacting protein kinase. ANKK1 maps on the NTAD cluster along with the dopamine receptor D2 (DRD2), the tetratricopeptide repeat domain 12 (TTC12) and the neural cell adhesion molecule 1 (NCAM1) genes. The four genes have been associated with addictions, although TTC12 and ANKK1 showed the strongest associations. In silico and in vitro studies revealed that ANKK1 is functionally related to the dopaminergic system, in particular with DRD2. In antisocial alcoholism, epistasis between ANKK1 TaqIA and DRD2 C957T SNVs has been described. This clinical finding has been supported by the study of ANKK1 expression in peripheral blood mononuclear cells of alcoholic patients and controls. Regarding the ANKK1 protein, there is direct evidence of its location in adult and developing central nervous system. Together, these findings of the ANKK1 gene and its protein suggest that the TaqIA SNV is a marker of brain differences, both in structure and in dopaminergic function, that increase individual risk to addiction development.

The ANKK1/DRD2 locus is a genomic substrate for affective priming and recognition of angry faces.

INTRODUCTION: Ankyrin repeat and kinase domain containing I (ANKK1) and dopamine D2 receptor (DRD2) genes have been associated with psychopathic traits in clinical samples. On the other hand, individuals high in psychopathy show reduced affective priming and deficits in facial expression recognition. We have hypothesized that these emotion-related cognitive phenomena are associated with Taq IA (rs18000497) SNP (single nucleotide polymorphism) of the ANKK1 gene and with C957T (rs6277) SNP of the DRD2 gene. METHODS: We performed a genetic association analysis in 94 self-reported Caucasian healthy volunteers. The participants completed 144 trials of an affective priming task, in which primes and targets were emotional words. They also had to recognize 64 facial expressions of happiness, sadness, anger, and fear in an expression recognition task. Regarding the genetic analyses, Taq IA and C957T SNPs were genotyped. RESULTS: We found that the C957T SNP TT genotype was associated with a stronger priming effect and a better recognition of angry expressions. No associations were found for the Taq IA SNP. In addition, in silico analysis demonstrated that C957T SNP is a marker of a regulatory sequence at the 5' UTR of ANKK1 gene, thus suggesting the involvement of the whole ANKK1/DRD2 locus in cognitive-emotional processing. CONCLUSIONS: These results suggest that affective priming and recognition of angry facial expressions are endophenotypes that lie on the pathway between the ANKK1/DRD2 locus and some deviant phenotypes.

Startle-response based tasks and laboratory measures of impulsivity in abstinent alcoholic patients.

AIMS: It is well known that impulsivity is a risk factor for the development of Addictive Disorders, and more specifically Alcohol Use Disorders (AUD). Recently, the Startle-Response Based Tasks (SRBT) and its different forms of plasticity have been found to be impaired in the alcoholic population. This is the first study to explore the correlation between impulsivity laboratory tasks and the SRBT test, in order to determine whether impulsivity and startle response (SR) could be related and in turn, explain their association with Alcohol Dependence (AD). SUBJECTS: 40 men, who met DSM-IV criteria for AD and had been abstinent for at least one month. Impulsivity was assessed using three laboratory tests: Continuous Performance Test (CPT), Stop-Signal Task (SST) and Differential Reinforcement for Low-Rate Responding (DRL6). Patients also underwent the SR test. They were compared to 40 matched controls. RESULTS: Impulsivity laboratory measures tasks (SST and commissions of the CPT) correlated positively with the magnitude of SR (P < 0.05) and with habituation (P < 0.05). Scores on DRL6 correlated negatively with the magnitude of SR (P < 0.05). This was not found in the control group. CONCLUSIONS: The fact that impulsivity laboratory measures and the SR are correlated in patients but not in controls, could imply the existence of a common link for these two measures in alcoholic patients. Our findings support the hypothesis of the existence of two different vulnerability pathways for the development of AUD: anxiety and disinhibitory behaviour.

Impairments of prepulse inhibition of the startle response in abstinent alcoholic male patients.

AIMS: Prepulse inhibition (PPI) of the startle reflex, which refers to the ability of innocuous sensory events to reduce the startle reflex, has been described as an operational measure of sensorimotor gating that is reduced in several neuropsychiatric disorders, such as schizophrenia, but experience is lacking in addictions and alcoholism. The aim of this study was to examine the existence of impairments in the startle response and PPI in abstinent alcoholic men. METHODS: Testing for PPI was conducted on 60 abstinent alcoholic men aged 18-65 years (mean 46.37) who met DSM-IV criteria for alcohol dependence and had been abstinent for more than a month at the time of testing. The comparison group were compared with 37 sex- age- and education-matched controls without alcohol dependence. RESULTS: Magnitudes of the startle reflex were lower in patients than in controls. The differences were statistically significant (P < 0.05) in trials with prepulses presented 30 and 120 ms before the onset of the startle stimulus. There was also a statistically significant (P < 0.05) reduced percentage of PPI when the prepulse was presented 30 ms before the startle stimulus. CONCLUSIONS: These data suggest that sensory information processing mechanisms could be damaged in abstinent alcoholic patients. The fact that these findings are common to other psychiatric disorders could indicate the existence of a common vulnerability marker and explain the high degree of comorbidity between alcoholism and other mental illnesses.