The effects of single nucleotide polymorphisms in glutamatergic neurotransmission genes on neural response to alcohol cues and craving.
The aim of the current study was to determine genotype effects of four single nucleotide polymorphisms (SNPs) in the genes of the N-Methyl-d-aspartate receptor (GRIN1, GRIN2A, GRIN2C) and kainate receptor (GRIK1), which have been previously associated with alcoholism, on behavior, neural cue-reactivity and drinking outcome. Eighty-six abstinent alcohol dependent patients were recruited from an in-patient setting. Neuropsychological tests, genotyping and functional magnetic resonance imaging (fMRI) were used to study genotype effects. GRIN2C risk allele carriers displayed increased alcohol cue-induced activation in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (dlPFC). Neural activation in the ACC positively correlated with craving for alcohol (r = 0.201, P = 0.032), whereas activation in the dlPFC showed a negative association (r = -0.215, P = 0.023). In addition, dlPFC activation predicted time to first relapse (HR = 2.701, 95%CI 1.244-5.864, P = 0.012). GRIK1 risk allele carriers showed increased cue-induced activation in the medial prefrontal (PFC) and orbitofrontal cortex (OFC) and in the lateral PFC and OFC. Activation in both clusters positively correlated with alcohol craving (rmedOFC, medPFC  = 0.403, P = 0.001, rlatOFC, latPFC  = 0.282, P = 0.008), and activation in the cluster that encompassed the medial OFC predicted time to first relapse (HR = 1.911, 95%CI 1.030-3.545, P = 0.040). Findings indicate that SNPs in the GRIN2C and GRIK1 genes are associated with altered cue-induced brain activation that is related to craving for alcohol and relapse risk.
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Patrick
P
Bach
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Martina
M
Kirsch
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Sabine
S
Hoffmann
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Anne
A
Jorde
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Karl
K
Mann
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Josef
J
Frank
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin, Germany.
Katrin
K
Charlet
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin, Germany.
Anne
A
Beck
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin, Germany.
Andreas
A
Heinz
Division of Mind and Brain Research, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Germany.
Henrik
H
Walter
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Marcella
M
Rietschel
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Falk
F
Kiefer
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
Sabine
S
Vollstädt-Klein
D000293:Adolescent; D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000235:genetics* / Q000503:physiopathology; D066249:Craving / Q000187:drug effects; D003463:Cues; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D009778:Occipital Lobe / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018092:Kainic Acid Receptors / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012008:Recurrence; D009435:Synaptic Transmission / Q000235:genetics*; D013702:Temporal Lobe / Q000187:drug effects; D055815:Young Adult
D009419:Nerve Tissue Proteins; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C485668:GRIN1 protein, human; C432823:NR2C NMDA receptor
Alcoholism; cue-reactivity; fMRI; glutamate receptors; relapse; single nucleotide polymorphisms