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Decreased vesicular monoamine transporter type 2 availability in the striatum following chronic cocaine self-administration in nonhuman primates
Narendran R, Jedema HP, Lopresti BJ, Mason NS, Himes ML and Bradberry CW
Biological Psychiatry, 77:488-492, 2015

In a recent positron emission tomography study, Drs. Rajesh Narendran, Charles Bradberry and their colleagues demonstrated less [(11)C]-(+)-dihydrotetrabenazine ([(11)C]DTBZ) binding to striatal vesicular monoamine transporter type 2 (VMAT2) in cocaine abusers compared with control subjects.  They found that a significant limitation of these between-group comparison human studies is their inability to establish a causal relationship between cocaine abuse and lower VMAT2. Additionally, studies of rodents that evaluated VMAT2 binding before and after cocaine self-administration do not support a reduction in VMAT2. 

To clarify these discrepant VMAT2 findings and attribute VMAT2 reduction to cocaine abuse, the investigators imaged four rhesus monkeys with [(11)C]DTBZ positron emission tomography before and after 16 months of cocaine self-administration. They derived the [(11)C]DTBZ binding potential in the striatum by using the simplified reference tissue method with the occipital cortex time activity curve as an input function.

Findings from this study indicate that chronic cocaine self-administration led to a significant (25.8 ± 7.8%) reduction in [(11)C]DTBZ binding potential.  In contrast to the cocaine rodent investigations that do not support alterations in VMAT2, these results in nonhuman primates clearly demonstrated a reduction in VMAT2 binding following prolonged exposure to cocaine.  Drs. Narendran, Bradberry and colleagues also found that lower VMAT2 implies that fewer dopamine storage vesicles are available in the presynaptic terminals for release, a likely factor contributing to decreased impact of cocaine on dopamine transmission in cocaine users, an observation that contrasts with predictions from rodent studies. This project may serve as the basis for future studies designed to clarify the clinical significance of lower VMAT2 in cocaine abusers, including its relationship to relapse and vulnerability to mood disorders.

Contributors:
Rajesh Narendran, MD, Brian J. Lopresti, MSNE and Neale Scott Mason, PhD (Department of Radiology, University of Pittsburgh)

Hank Jedema, PhD, Michael L. Himes and Charles W. Bradberry, PhD (Department of Psychiatry, University of Pittsburgh)

This article appeared in the journal Biological Psychiatry.  Click here to view the abstract.