Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers

Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent D-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to D-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean +/- s.d. = 22.1 +/- 3.4 years) [C-11]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated D-amphetamine (3 x 0.3 mg kg(-1), by mouth; n = 8) or placebo (3 x lactose, by mouth; n = 9). Mood and physiological measurements were recorded throughout each session. Before the D-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P <= 0.05). Following the D-amphetamine regimen, the stress-induced cortisol responses were augmented (P < 0.04), and voxel-based analyses showed larger stress-induced decreases in [11C] raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [C-11]raclopride binding, primarily in the sensorimotor striatum (P < 0.05). Together, this study provides evidence for drug x stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.