Striatal Dopamine Responses to Intranasal Cocaine Self-Administration in Humans Sylvia M.L. Cox, Chawki Benkelfat, Alain Dagher, J. Scott Delaney, France Durand, Samuel A. McKenzie, Theodore Kolivakis, Kevin F. Casey, and Marco Leyton Background: The effect of self-administered cocaine on extracellular dopamine (DA) levels has not been measured in humans. Methods: Ten nondependent cocaine users underwent positron emission tomography [ 11 C]raclopride scans following intranasal self- administration of cocaine hydrochloride (1.0 mg/kg) and placebo powder. Results: Compared with placebo, intranasal cocaine self-administration decreased [ 11 C]raclopride binding values in the ventral limbic striatum and putamen. Individual differences in the magnitude of the [ 11 C]raclopride response in the ventral striatum were predicted by lifetime histories of stimulant drug use. Conclusions: The results suggest that 1) intranasal cocaine self-administration increases synaptic DA levels in human striatum and 2) prior use of stimulant drugs on the street is associated with progressively greater cocaine-induced DA responses. These dopaminergic effects might influence susceptibility to drug–seeking behavior and the progression to substance abuse. Key Words: Cocaine, cortisol, dopamine, reward, sensitization, vulnerability I n laboratory animals, psychostimulant drugs such as cocaine increase activity within the ascending midbrain dopamine (DA) system. Within the striatum, these effects are larger in ventral than dorsal regions (1) and following active self-admin- istration compared with passive receipt (2,3). It has been pro- posed that the DA responses enhance the incentive salience of the drugs and drug-related cues, thereby increasing susceptibility to subsequent drug-taking behavior (4,5). A growing functional neuroimaging literature suggests that similar drug effects occur in humans (6,7). For example, positron emission tomography (PET) studies indicate that cocaine binds to DA transporters and increases striatal DA responses (8,9). However, these previous studies tested the effects of passively administered cocaine and lacked the anatomical resolution suf- ficient to identify regional differences. In the present study, we tested the effect of intranasal cocaine self-administration on striatal DA responses in nondependent cocaine users. Changes in extracellular DA were measured using PET with the labeled tracer [ 11 C]raclopride and coregistration to each individual’s anatomical magnetic resonance imaging (MRI) scan. We predicted that cocaine would decrease striatal [ 11 C]ra- clopride binding and that these changes would occur preferen- tially within the ventral limbic striatum. Methods and Materials Subjects Ten nondependent cocaine users (aged 23.7  2.8; two women, eight men; see Table 1) were recruited from the community through advertisements in local newspapers. For all subjects, the primary and preferred route of self-administration was intranasal. All were free of current or past substance dependence, as determined by a semistructured clinical inter- view for DSM-IV diagnoses (10). Six of the 10 participants were current light smokers with a score of less than 3 on the Fagerstrom Test for Nicotine Dependence (11). All were free of current substance abuse, but 2 of 10 subjects met criteria for past substance abuse (Subject 1: THC and cocaine abuse; Subject 2: heroin and alcohol abuse). Participants were free of any other current Axis I psychopathology and were physically healthy as determined by a medical exam, an electrocardiogram, and standard laboratory tests. Before each test session, subjects abstained from nicotine for at least 12 hours and from alcohol for at least 24 hours. On the morning of each test day, all tested negative on a urine drug screen sensitive to cocaine, opiates, phencyclidine, barbiturates,  9 -tetrahydrocannabinol, benzodi- azepines, and amphetamines (Triage Panel for Drugs of Abuse, Biosite Diagnostics, San Diego, California). Women were tested during the follicular phase. The study was carried out in accor- dance with the Declaration of Helsinki and was approved by the Research and Ethics Board of the Montreal Neurological Institute. All participants gave written informed consent. Procedure The data presented here are part of a larger study in which subjects underwent PET scans with the labeled tracer [ 11 C]raclo- pride following the ingestion of 1) cocaine (1.0 mg/kg) plus a nutritionally balanced amino acid (AA) mixture (BAL), 2) placebo powder (100 mg lactose) plus BAL, and 3) cocaine hydrochloride (1.0 mg/kg) plus a tryptophan-deficient AA mixture. This article focuses on the effect of cocaine versus placebo powder (Sessions 1 and 2). Cocaine and placebo were self-administered intranasally. To keep the physical amount of powder constant, the active drug was mixed with lactose to yield a total of 100 mg. All test sessions were given double-blind in a randomized, counterbalanced order. On the test day, subjects came to the laboratory at 9 AM, were weighed, and ingested a nutritionally balanced AA mixture, as described previously (12). Four hours following the AA drink, subjects were transported to the PET unit. Upon arrival, a heparin and normal saline-primed catheter was inserted into their ante- cubital vein for bolus injection of tracer and to withdraw blood. From the Departments of Psychiatry (SMLC, CB, FD, SAM, TK, KFC, ML), Neurology and Neurosurgery (CB, AD, ML), and Department of Emer- gency Medicine (JSD), McGill University, Montréal, Québec, Canada. Address reprint requests to Marco Leyton, Ph.D., Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1; E-mail: marco.leyton@mcgill.ca. Received December 2, 2008; revised January 15, 2009; accepted January 18, 2009. BIOL PSYCHIATRY 2009;65:846 – 850 0006-3223/09/$36.00 doi:10.1016/j.biopsych.2009.01.021 © 2009 Society of Biological Psychiatry