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Deficits in dopaminergically modulated striato-thalamo-prefrontal circuits contribute to compromises in self-control and motivation in cocaine addiction (Goldstein and Volkow, 2002). Methylphenidate (MPH), a dopaminergic agonist, has been successfully used to enhance inhibitory control and salience attribution in attention-deficit hyperactivity disorder and other prefrontal psychopathologies (eg, frontotemporal dementia); indeed MPH has been suggested to improve signal-to-noise ratio (SNR) and optimize activity (eg, processing efficiency) in brain regions that modulate executive functions (Mehta et al, 2000; Volkow et al, 2008). However, in clinical trials on cocaine addiction, MPH did not reduce cocaine consumption (Volkow et al, 2004). We hypothesized that oral MPH would improve executive function in individuals with cocaine use disorders (CUDs), an effect that, when coupled with cognitive or behavioral interventions, may improve the clinical outcome.
In the current functional magnetic resonance imaging (fMRI) study, 13 CUDs (12 male subjects, mean age=46.2 years, mean duration of cocaine use, predominantly smoked=17.9 years, all meeting the current cocaine dependence criteria) matched on education and intellectual functioning with 14 healthy controls (all male, mean age=38.8, group differences statistically controlled) received 20mg oral MPH or placebo in a randomized and counterbalanced order over two consecutive MRI sessions (separated by a mean of 14 days, MRI performed on a 4-T whole-body Varian/Siemens scanner). During peak MPH effects (60–90min post administration), subjects performed an emotional variant of the color-word Stroop task: subjects were monetary remunerated for correct pressing for color of drug-related and matched neutral words. This task engages the prefrontal cortex in CUD (Goldstein et al, 2007). Importantly, despite lack of group differences in task engagement or performance, compared with healthy controls, CUD showed robust anterior cingulate cortex (ACC) hypoactivations, encompassing the rostroventral ACC (rvACC) (extending to the medial orbitofrontal cortex (mOFC)) and the caudal–dorsal ACC (cdACC) (Goldstein et al, 2009).
Results showed that MPH did not increase task-related cocaine craving in CUD. Importantly, the current results demonstrated that compared with placebo, MPH during a salient cognitive task (1) enhanced the cdACC (Brodmann area (BA) 24, 32) and rvACC/mOFC (BA 10, 32) task response in the CUD; (2) the larger the signal increases in rvACC/mOFC (BA 10, 32), the greater the improvement in task accuracy; and (3) MPH decreased response impulsivity (errors of commission) in all subjects (see Figure 1).
These fMRI results are the first to show that oral MPH improved the response of the ACC and associated task performance in CUD consistent with the cognitive benefits of MPH in other psychopathologies. In CUD, we speculate that these effects reflect MPH-induced increases in dopamine neurotransmission in these dopamine-deficient individuals. Specifically, we postulate (based on preclinical electrophysiological studies) that MPH increased SNR by enhancing dopamine (perhaps also noradrenergic) neurotransmission, thereby enhancing the activation of regions involved in the task (ACC). Although clinical trials with MPH have not been effective in decreasing cocaine use in CUD, these results suggest that MPH may have therapeutic benefits in facilitating behavioral modification (eg, impulse control) when combined with specific cognitive interventions.
This study was supported by grants from the National Institute on Drug Abuse (to RZG: R01DA023579) and the General Clinical Research Center (5-MO1-RR-10710) and the Department of Energy, Office of Biological and Environmental Research (for infrastructure support). We also acknowledge the contributions of Patricia A Woicik, PhD, Thomas Maloney, PhD, Dardo Tomasi, PhD, Nelly Alia-Klein, PhD, Juntian Shan, BSc, Jean Honorio, MSc, Dimitris Samaras, PhD, Ruiliang Wang, PhD, Frank Telang, MD, and Gene-Jack Wang, MD to this study.
Goldstein received consultation fee from Medical Directions for design of education material, and honoraria fee from the Federal Judicial Center and the Gruter Institute for Law and Behavioral Research for lectures, both about neuroimaging in drug addiction. There are no other conflict of interest to declare.