Fast uptake and long-lasting binding of methamphetamine in the human brain: comparison with cocaine

Abstract

Methamphetamine is one of the most addictive and neurotoxic drugs of abuse. It produces large elevations in extracellular dopamine in the striatum through vesicular release and inhibition of the dopamine transporter. In the U.S. abuse prevalence varies by ethnicity with very low abuse among African Americans relative to Caucasians, differentiating it from cocaine where abuse rates are similar for the two groups. Here we report the first comparison of methamphetamine and cocaine pharmacokinetics in brain between Caucasians and African Americans along with the measurement of dopamine transporter availability in striatum. Methamphetamine's uptake in brain was fast (peak uptake at 9 min) with accumulation in cortical and subcortical brain regions and in white matter. Its clearance from brain was slow (except for white matter which did not clear over the 90 min) and there was no difference in pharmacokinetics between Caucasians and African Americans. In contrast cocaine's brain uptake and clearance were both fast, distribution was predominantly in striatum and uptake was higher in African Americans. Among individuals, those with the highest striatal (but not cerebellar) methamphetamine accumulation also had the highest dopamine transporter availability suggesting a relationship between METH exposure and DAT availability. Methamphetamine's fast brain uptake is consistent with its highly reinforcing effects, its slow clearance with its long-lasting behavioral effects and its widespread distribution with its neurotoxic effects that affect not only striatal but also cortical and white matter regions. The absence of significant differences between Caucasians and African Americans suggests that variables other than methamphetamine pharmacokinetics and bioavailability account for the lower abuse prevalence in African Americans.

Fig. 1

(A) Images for [¹¹C]d-methamphetamine showing transaxial planes from the top to the head to the base of the skull; (B) images for [¹¹C]cocaine showing transaxial planes from the top to the head to the base of the skull. Distribution volume images were constructed for each subject (n=19) and all of the images were normalized to the SPM 99 atlas (http://www.fil.ion.ucl.ac.uk/spm/) and averaged. We use a rainbow color bar where red corresponds to a DV of 16 cc mL^-1 for the [¹¹C]d-methamphetamine images and 6 cc mL^-1 for the [¹¹C]cocaine images.

Fig. 2

(A) Average distribution volumes ± sdm for [¹¹C]d-methamphetamine for Caucasians (n=9) and African Americans (n=10). Unpaired t-test revealed no difference between the two groups. We note that for both groups the DV’s in the caudate, putamen and the thalamus were significantly greater than those in the cerebellum (p=0.0001). (B) average distribution volumes ± sdm for [¹¹C]cocaine for Caucasians and African Americans. Unpaired t tests revealed significantly higher DV for the caudate and cerebellum (p<0.05) with a trend for the putamen and thalamus (p=0.09) (left panel) for the African Americans. (cdt=caudate; put=putamen, thal=thalamus; cb=cerebellum).

Fig. 3

Average time-activity curves ±sdm for [¹¹C]d-methamphetamine and [¹¹C]cocaine in putamen, thalamus, cerebellum and white matter. Time-activity curves were generated for each subject and an average value ± sdm was obtained for each time point combining data from all subjects (n=19).

Fig. 4

(A) Averaged images of [¹¹C]d-methamphetamine (n=19) at the level of the striatum at different time frames over a 90 minute imaging session; (B) averaged images of [¹¹C]cocaine (n=19) (bottom row) at the level of the putamen over a 54 minute imaging session. Note that [¹¹C]cocaine peaks earlier and clears faster than [¹¹C]d-methamphetamine. The time (minutes) for each frame is indicated below the image. We use a rainbow color bar where red represents the highest uptake and purple the lowest. The [¹¹C]d-methamphetamine images, red corresponds to 0.006% injected dose/cc whereas for the [¹¹C]cocaine images, red corresponds to 0.008% of the injected dose/cc. The dynamic images from both the [¹¹C]d-methamphetamine and [¹¹C]cocaine studies were normalized to the SPM 99 atlas (http://www.fil.ion.ucl. ac.uk/spm/) so that individual time frames could be averaged across subjects. The average time frame data was obtained by weighting each image by the factor f=avg dose/dose subj, summing over subjects and dividing by the number of subjects.

Fig. 5

(A) Averaged time-activity curves for [¹¹C]d-methamphetamine uptake in the ventral striatum (n=19) along with the time course of the ‘high’ (Newton et al., 2006); (B) Averaged time-activity curves for [¹¹C]cocaine uptake in the putamen (n=19) along with the time course of the ‘high’ (Volkow et al. 1997). Both the time-activity curves and the time course for the ‘high’ were normalized to the highest value for presentation.

Fig. 6

Correlation plot between the AUC (*normalized for the plasma AUC) for the [¹¹C]dmethamphetamine time-activity curve in the putamen and DAT availability in putamen (R=0.59; p=0.008).