Dopamine transporter levels in cocaine dependent subjects

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Abstract

Cocaine use is a significant problem in the US and it is well established that cocaine binds to the dopamine transporter (DAT) in the brain. This study was designed to determine if the DAT levels measured by 99mTc TRODAT SPECT (single photon emission computed tomography) brain scans are altered in cocaine dependent subjects and to explore clinical correlates of such alterations. SPECT brain scans were acquired on 21 cocaine dependent subjects and 21 healthy matched controls. There were significantly higher DAT levels in cocaine dependent subjects compared to controls for the anterior putamen (p = 0.003; Cohen's d effect size = 0.98), posterior putamen (p < 0.001; effect size = 1.32), and caudate (p = 0.003; effect size = 0.97). DAT levels in these regions were 10%, 17%, and 8% higher in the cocaine dependent subjects compared to controls. DAT levels were unrelated to craving, severity of cocaine use, or duration of cocaine use, but DAT levels in the caudate and anterior putamen were significantly (p < 0.05) negatively correlated with days since last use of cocaine.

Introduction

Cocaine binds to the dopamine transporter (DAT) in the brain (Ritz et al., 1987), thereby blocking uptake resulting in increases in synaptic dopamine in the striatum and the nucleus accumbens (Di Chiara and Imperato, 1988, Egilmez et al., 1995). The magnitude of the blockage of the DAT in humans correlates with the degree of self-reported “high” from cocaine (Volkow et al., 1997). Aspects of the mechanism of cocaine binding to the dopamine transporter have been studied at the cellular level (Chen and Reith, 2000). Studies have revealed that cocaine induces increases in the plasma membrane DAT immunoreactivity (Little et al., 2002) and results in the movement of DAT to the cell surface (Daws et al., 2002).

In vitro autoradiographic studies of cocaine binding in brain sections from nonhuman primates have found the highest density of binding sites for cocaine in the basal ganglia, the brain region with the highest density of dopamine terminals (Madras and Kaufman, 1994). In humans, autoradiographic studies of post-mortem striatal specimens from cocaine users have revealed significant increases in DAT binding sites (Little et al., 1993), and specific increases in the density of high affinity sites on the DAT (Staley et al., 1994), compared with control subjects. Additionally, in nonhuman primates, exposure to cocaine over an 18-month period, compared to animals not exposed to cocaine, has been found to lead to a higher density of DAT binding sites, specifically in the ventral striatum where the shell of the nucleus accumbens is found (Letchworth et al., 2001). Though most studies support the claim that cocaine use causes an increase in DAT levels, there are some investigations yielding different findings in animals including lower uptake in the nucleus accumbens, or no changes in the striatum, when measured 24 h after the last of 3 daily administrations of cocaine in rats (Izenwasser and Cox, 1990). Similarly, normal levels of DAT have been reported in the autopsied brains of chronic cocaine users (Wilson et al., 1996). It has been speculated that differences across studies in brain regions examined, time elapsed since last cocaine use, and type of radioligand used for quantifying DAT may explain the inconsistency of the findings (Volkow et al., 1996).

The long-term behavioral effects of cocaine may be related to alterations in dopamine transmission that follow from DAT blockade. As a consequence of high levels of synaptic dopamine, chronic cocaine use is associated with reduction in availability of dopamine D2 receptors that persists 3–4 months after detoxification (Volkow et al., 1993). Imaging studies have documented higher DAT levels for recently (about 4 days) abstinent cocaine-using subjects compared to control (Malison et al., 1998, Jacobsen et al., 2000). No studies, however, have examined DAT levels as a function of clinical characteristics of cocaine use among active cocaine dependent subjects. Based on primate data on duration and dosage of cocaine exposure in relation to DAT (Letchworth et al., 2001), it would be expected that duration of cocaine use and severity of cocaine usage (amount of use in past month) might be associated with higher DAT levels. Because withdrawal symptoms appear related to a depletion in dopamine (Dackis and Gold, 1985), abstinence would be expected to be associated with a recovery of DAT levels, although the time period for recovery to relatively normal levels is uncertain. Craving is another clinical characteristic of sustained cocaine use that might be associated with alterations in DAT. Studies have found that increased mu-opioid receptor binding, another neurotransmitter system that affects dopamine systems in the brain, is positively corrected with craving (Zubieta et al., 1996, Gorelick et al., 2005).

In this study, 99mTc TRODAT-1 was used to image DAT levels using single photon emission computed tomography (SPECT) in 21 cocaine dependent patients who were recently abstaining and 21 healthy controls. The following hypotheses were tested: (a) there is significantly greater 99mTc TRODAT-1 uptake for cocaine patients compared to controls, and (b) the pattern of 99mTc TRODAT-1 uptake will co-vary with clinical characteristics of cocaine use: negatively for time since last use, positively for amount of cocaine being used, positively for duration of cocaine addiction, and positively for craving.

Section snippets

Subjects

Cocaine dependent subjects were currently seeking outpatient counseling for their cocaine use. The control sample contained 21 age-matched healthy volunteers. All healthy volunteers included in the study had no significant medical, neurological or psychiatric diseases. All subjects gave written informed consent and all procedures for this study were approved by the Institutional Review Board and Radiation Safety Committee of the University of Pennsylvania and by the Food and Drug Administration.

Results

For the cocaine dependent patients, 1 identified himself as White, 18 as African American, and 2 as Other (Table 1). Seventy-six percent (n = 16) of the sample were men. The average age of patients was 42.8 (S.D. = 6.2) years. More than half (12 patients; 57%) were employed and 16 patients (76%) lived alone. Most (67%) used crack cocaine, and the average days of use in the month prior to treatment was 12.1 days. At the time of the scans, patients had last used cocaine on average 7.5 days (S.D. = 9.7;

Discussion

The results support the first hypothesis, that there are group differences in 99mTc TRODAT-1 uptake and hence DAT levels between cocaine patients and controls. All three specific subregions of the basal ganglia (anterior putamen, posterior putamen, caudate) were significantly different in cocaine patients compared to controls, although the effects were strongest for the putamen regions.

It is possible that confounds between the cocaine dependent and control samples may explain the between-group

Conflict of interest

The authors have no conflicts of interest.

Acknowledgements

We wish to thank Bojun Hu, Bridget Hearon, and Julia Narducci who assisted with the collection of the data, and Christina Temes, who assisted with the production of the final manuscript.

Role of funding: Funding for this study was provided by NIA grant R01 AG-17524 and NIH grant R21 DA-016002. NIDA and NIA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors:

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