Cross-Sensitization Between Stimulants and Stress in Humans: Behavioral and Neurochemical Correlates

Abstract

Dysregulation of the stress response is a potential etiologic factor in the development/relapse of dopamine (DA) related disorders including drug-dependency and psychosis. We previously demonstrated increased DA release in healthy volunteers who underwent a subchronic regimen of d-Amphetamine, an observation interpreted as evidence of neurochemical sensitization (Boileau et al., 2006). The aim of the present study was to use the PET/[11C]Raclopride method, in a comparable design, to test the hypothesis that repeated exposure to d-amphetamine in the laboratory cross-sensitizes with stress. Seventeen healthy male volunteers (21.9 ± 1.7y) underwent 3 PET sessions. [11C]Raclopride binding to D2/3 receptors was measured during an unstressful version of the Trier Mental Challenge Task (day 0), and during two stressful versions: prior to (day 1) and 14 days after (day 21) the last dose of a sub-chronic d-Amphetamine (3 x 0.3 mg/kg p.o) (n=8) or a placebo regimen (3x lactose p.o) (n=9). Mood and physiological measurements were recorded regularly throughout each session. Exposure to the mental challenge stress elicited the expected behavioral and physiological responses in both groups (p≤0.001), but failed to demonstrate a measurable change in [11C]Raclopride receptor occupancy. Relative to the non-stressful version, greater increases in DA release were detected upon re-exposure to stress 14 days after the last dose of stimulants in the right ventral striatum, anterior left caudate (p≤0.01), anterior left putamen and anterior right caudate (p≤0.10), than after the placebo regimen. Though preliminary, these data suggests that stress and stimulants may cross-react to elicit DA sensitization in young adult males.