Brain DA D2 Receptors Predict Reinforcing Effects of Stimulants in Humans: Replication Study NORA D. VOLKOW, 1,2 * GENE-JACK WANG, 1 JOANNA S. FOWLER, 3 PETHER THANOS, 1 JEAN LOGAN, 3 SAMUEL J. GATLEY, 1 ANDREW GIFFORD, 1 YU-SHIN DING, 3 CHRIS WONG, 1 AND NAOMI PAPPAS 1 1 Medical Department, Brookhaven National Laboratory, Upton, New York 11973 2 Department of Psychiatry State University of New York at Stony Brook, Stony Brook, New York 11794 3 Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973 KEY WORDS raclopride; addiction; vulnerability; PET; methylphenidate; reinforce- ment; striatum ABSTRACT We had shown that striatal DA D2 receptors levels predicted the rein- forcing responses to the psychostimulant drug methylphenidate in nondrug-abusing subjects. Here, we assessed the replicability of this finding. We measured D2 receptors with PET and [ 11 C]raclopride (twice to determine stability) in seven nondrug-abusing subjects to assess if they predicted the self-reports of “drug-liking” to intravenous methylphenidate (0.5 mg/kg). DA D2 measures were significantly correlated with “drug- liking” in both evaluations ( r 5 0.82 and r 5 0.78); subjects with the lowest levels reported the higher ratings of “drug-liking” and vice versa. These results replicate our previous findings and provide further evidence that striatal DA D2 receptors modulate reinforcing responses to stimulants in humans and may underlie predisposition for drug self-administration. Synapse 46:79 – 82, 2002. © 2002 Wiley-Liss, Inc. INTRODUCTION One of the most challenging problems in the neuro- biology of drug addiction is to understand why some individuals abuse drugs while others do not. Studies in laboratory animals have provided evidence that dopa- mine (DA), a neurotransmitter involved with move- ment, cognition, and reward, modulates predisposition to drug abuse (Piazza et al., 1991). For example, in laboratory animals high DA activity in the striatum has been associated with decreased rates of cocaine self-administration (Glick et al., 1994). In humans, it has been hypothesized that low levels of D2 receptors lead to a “reward deficiency syndrome” that predis- poses subjects to use drugs as a means to compensate for the decrease in activation of reward circuits by physiological reinforcers (Noble et al., 1991). However, the potential role that DA D2 receptors have in the predisposition to drug addiction is still controversial (Goldman et al., 1998). We recently showed that in nondrug-abusing human subjects the levels of DA D2 receptors in striatum predicted the reinforcing re- sponses to the psychostimulant drug methylphenidate; subjects with low levels reported MP as pleasant, whereas those with high levels reported it as unpleas- ant (Volkow et al., 1999). In that study we postulated that high DA D2 receptor levels may protect against drug self-administration. Here we assessed the repli- cability of our previous finding of a relationship be- tween striatal DA D2 receptors and self-reports of “drug-liking.” We used [ 11 C]raclopride, a DA D2 receptor radioli- gand, and positron emission tomography (PET) to de- termine if there was a relationship between the DA D2 receptor levels in striatum (brain region where the nucleus accumbens, which is the structure associated with drug reinforcement, is located) and the reinforcing responses to methylphenidate (MP) (psychostimulant drug that like cocaine increases DA by blocking the DA transporters; Ritz et al., 1987). Since the measures of DA D2 receptors as assessed with [ 11 C]raclopride have been shown to be sensitive to changes in extracellular Contract grant sponsor: the U.S. Department of Energy; Contract grant num- ber: DE-ACO2-798CH10886, Contract grant sponsor: the National Institutes of Drug Abuse; Contract grant numbers: DA06891, DA09490. We thank David Schlyer and Robert Carciello for Cyclotron operations; Payton King, Alejandro Levy, Donald Warner, and Christopher Wong for PET operations; Colleen Shea, Richard Ferrieri for radiotracer preparation; and Noelwah Netusil for patient care. *Correspondence to: Nora D. Volkow, Medical Department, Brookhaven Na- tional Laboratory, Upton, NY 11973. E-mail: volkow@bnl.gov Received 5 April 2002; Accepted 2 May 2002 DOI 10.1002/syn.10137 Published online 00 Month 0000 in Wiley InterScience (www.interscience. wiley.com). SYNAPSE 46:79 – 82 (2002) © 2002 WILEY-LISS, INC.