Gene-environment interaction and intermediate phenotypes in alcohol dependence.

D ysfunction o f brain dopam ine system s is involved in various neuropsychiatric disorders. C hallenge studies w ith dopam ine receptor agonists have been perform ed to assess dopam ine receptor function ing, c lassically u sing the release o f grow th horm one (GH) from the h indbrain as p rim ary outcom e m easure. The objective o f the current study was to assess dopam ine receptor fun ction in g at the level o f the forebrain. Fifteen healthy, m ale volunteers received apom orphine su b lin gu ally (2mg), subcutaneously (0.005mg/kg), and placebo in a balanced, double blind cross-over design. Outcome m easures were p lasm a GH levels, perform ance on an AX continuous perform ance test and prepulse inh ibition o f the acoustic startle. The relation betw een central outcom e m easures and apom orphine levels observed in p lasm a and calcu lated in the brain , was m odelled u sing a tw o-com partm ental pharm acokinetic-pharm acodynam ic analysis. After adm in istration o f apom orphine p lasm a GH increased, perform ance on the AX continuous perform ance test deteriorated, p articu larly in participan ts w ith low baselin e perform ance. Apom orphine disrupted PPI on h igh intensity (85dB) prepulse tria ls and im proved PPI on low intensity (75dB) prepulse trials, p articu larly in p articipan ts w ith low baselin e PPI. High cognitive perform ance at base lin e was associated w ith reduced baselin e sensorim otor gating. N europhysiological m easures correlated best w ith calcu lated brain apom orphine levels, after subcutaneous adm in istration . M odulation o f the effect o f apom orphine by baselin e perform ance levels provides evidence for an inverted U-shape relation betw een prefrontal dopam ine fun ction in g and cognitive perform ance, and m esolim bic dopam ine fun ction in g and sensorim otor gating. Future apom orphine ch allenge tests preferen tially use m ultip le outcom e m easures, after subcutaneous adm in istration o f apom orphine.