Genetic modulation and treatment response
Chronic intake of ethanol is associated with a compensatory up-regulation of glutamatergic neurotransmission. Several lines of evidence indicate a direct interaction of glutamate and dopamine systems for normal and addictive behavior (Kalivas and Volkow, 2005). Recent models propose that motivating drives mediated by dopaminergic neurotransmission are integrated with goal-directed behavior and willed acts processed in the prefrontal cortex driven by glutamatergic neurotransmission. This circuit is seen to form and control long-term behavior relevant for addiction (Lisman and Grace, 2005). Recent studies suggest that polymorphisms within the glutamate-associated genes modulate the risk of alcohol intake, dependence, craving and relapse. With a candidate gene based case-control study in a sample of an extensively phenotyped high-risk population (160 alcohol dependent patients and 50 high-risk subjects – MARC sample) and 160 healthy controls, the genetic contribution of specific candidate loci to glutamate phenotypes and withdrawal will be analysed. Our overall goal is to investigate the association of genetic variants 1) with cerebral glutamate concentrations measured with magnetic resonance spectroscopy (MRS) and 2) with severity and duration of alcohol withdrawal.
Furthermore, it will be studied whether increased glutamate brain levels are 3) predictive for treatment response with the glutamate modulator acamprosate and 4) if glutamate concentrations are related to alcohol use habits and risk factors for alcohol use in non-dependent probands. In cooperation with SP11 (Rietschel, Nöthen) we will elucidate if genes which modulate the glutamate system (transport, biosynthesis and metabolism) control also (endo)phenotypes of alcohol use and dependence. In addition, the association between increased glutamate levels, response to acamprosate and variants in those genes which are most likely involved in enhancing glutamatergic activity will be examined. The project cooperates closely with SP15 (Sartorius, Spanagel) on glutamate spectroscopy and microdialysis in rodents and will allow the translation of animal data into clinical evidence.
Projektleiter: K. Mann, G. Ende, J. Gallinat
Förderer: Nationales Genomforschungsnetz (NGFN II/NGFN plus)
Genomweite Assoziationsstudie zur Alkoholabhängigkeit in einer Fall-Kontrollstichprobe. |
