Decreased brain dopaminergic responses in active cocaine dependent subjects

Objectives Cocaine addiction is associated with lost of control and compulsive drug use. We (Volkow et al., 1997) and others (Martinez et al, 2007) using PET and [C-11]raclopride (dopamine - DA D2/3 receptor radioligand) have shown markedly blunted DA increases after intravenous stimulant administration in detoxified cocaine dependent subjects. Here we assessed striatal DA responses in active cocaine dependent subjects.

Methods Nineteen active cocaine dependent subjects (CD, 45±3 y/o) and 24 age- and gender-matched normal control subjects (NC) were evaluated with PET and [C-11] raclopride with placebo (PL) and the stimulant drug methylphenidate (MPH) (0.5 mg/kg, i.v.). Self-report ratings (1-low to 10-high) of MPH effect were recorded. D2/3 receptor (D2R) availability (Binding PotentialND) was analyzed with the ROI method.

Results CD had lower D2R with PL administration in caudate (CD, 2.4±0.32), putamen (PU, 2.87±0.32) and ventral striatum (VS, 2.43±0.43) than NC (CD: 2.65±0.38, PU: 3.26±0.49, VS: 2.86±0.37). MPH administration induced greater decrements in D2R in NC (PU: -14.8±12.7%, p < 0.004; VS: -18.6±17%, p < 0.0002) than in CD where changes in striatal specific binding were not significant (PU: -2.8±12.5%; VS: +1.8±15.9%). NC reported greater ratings of high (+5.5±2.1, p <0.0001) and restless (+3.8±2.8, p < 0.00001) than CD (+2.6±2.1, +0.4±1.4) after MPH. The correlations of self-report ratings with D2R showed changes in high, which were inversely correlated with D2R decrement in VS (r = 0.37, p< 0.01) and changes in restlessness, which were inversely correlated with D2R decrement in PU (r = 0.4, p < 0.009).

Conclusions These results in active CD expanded prior findings of decreased striatal DA responses in detoxified CD. They also showed that abnormal striatal DA responses were associated with the effects of MPH on subjective self-reports.

Research Support NIDA/NIAAA/GCRC, DOE/OBER (infrastructure support)