539 NEUROIMAGING CLINICS OF NORTH AMERICA Neuroimag Clin N Am 17 (2007) 539–555 Imaging the Neurochemistry of Alcohol and Substance Abuse Diana Martinez, MDa,*, Jong-Hoon Kim, MDa, John Krystal, MDb, Anissa Abi-Dargham, MDa,c - Cocaine dependence Behavioral correlates of low D2/3 receptor Dopamine D2/3 receptors and dopamine binding potential transmission Alcohol dependence and presynaptic Functional significance of low D2/3 dopamine receptor binding in cocaine Alcohol dependence and the dopamine dependence transporter Behavior and dopamine transmission Serotonin and alcohol dependence Imaging cue-induced craving in cocaine Measures of GABA in alcohol dependence dependence Opioids and alcohol dependence Cocaine dependence and the dopamine - Heroin dependence transporter - Methamphetamine abuse Imaging studies of cocaine dependence - Methylenedioxymethamphetamine and other neurotransmitters (Ecstasy) abuse - Alcohol dependence - Hallucinogens - Dopamine D2/3 receptor and alcohol Summary dependence - References Positron emission tomography (PET) and single we briefly overview the concepts that are needed photon emission computed tomography (SPECT) to interpret these studies. The PET radiotracers use radiotracers to image molecular targets in the most frequently used in substance abuse research human brain. These techniques have been applied are those that label the dopamine type 2/3 (D2/3) over the last decade to study addiction and provide receptors of the striatum, such as the antagonists an important body of knowledge about the neuro- 18F-N-methylspiroperidol (labeled with a posi- chemical alterations associated with drug and tron-emitting fluorine) and 11 C-raclopride (labeled alcohol dependence. with a positron emitting carbon). Other radio- Although the techniques of PET and SPECT tracers that are available include those that label molecular imaging have been reviewed elsewhere, the dopamine transporter, serotonin transporter a Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Drive, Box #31, New York, NY 10032, USA b Yale University School of Medicine, VA Connecticut Healthcare System (116-A), 950 Campbell Avenue, West Haven, CT 06516, USA c Department of Radiology, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Drive, Box #31, New York, NY 10032, USA * Corresponding author. E-mail address: [email protected] (D. Martinez). 1052-5149/07/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.nic.2007.07.004 neuroimaging.theclinics.com 540 Martinez et al and receptors, GABA receptor, and opioid receptors. been performed in cocaine-dependent subjects, so The outcome measure in PET studies is termed re- the authors’ review of the literature begins with ceptor availability or binding potential (BP), which this disorder. is equivalent in pharmacologic terms to the product of receptor density and affinity of the radiotracer for Cocaine dependence the receptor. In addition to the BP, PET and the radiotracer Dopamine D2/3 receptors and dopamine 11 C-raclopride can also be used to measure striatal transmission dopamine transmission. 11 C-raclopride binding is As early as 1990, studies with PET have shown that sensitive to the endogenous dopamine in the brain: cocaine addiction is associated with alterations in increases in extracellular dopamine (produced with dopamine receptors. Using PET and 18F-N-methyl- a psychostimulant such as methylphenidate or spiroperidol, Volkow and colleagues [3] demon- amphetamine) decrease 11 C-raclopride binding strated that cocaine dependence was associated (Fig. 1). In the same individual, therefore, a com- with a decrease in D2/3 receptor availability in the parison of baseline (ie, pre-stimulant) and post- striatum compared with healthy control subjects. stimulant BP provides an indirect measure of Subsequent studies performed using similar dopamine transmission. The mechanism underly- methods have consistently shown decreases of ing the decrease in radiotracer binding is believed 11% to 15% in striatal D2/3 receptors in this same to be competition between extracellular dopamine population using 11 C-raclopride [4–6]. In addition, and the radiotracer for the D2/3 receptor, although Volkow and colleagues [4] reported that the de- other mechanisms, such as receptor affinity state, crease in D2/3 receptors persisted in a group of internalization, or polymerization may also play cocaine-dependent subjects rescanned after 3 a critical role [1,2]. months of inpatient rehabilitation. Several PET studies in human drug- and alcohol- Although this decrease in D2/3 receptor BP was dependent subjects have been performed using first measured in cocaine dependence, a similar de- these techniques. Most of these studies have mea- crease has been seen in several other addictions, sured dopamine receptors and dopamine release such as heroin addiction [7], alcohol dependence in the striatum, and thus are the focus of this review. [8,9], methamphetamine abuse [10], and even obe- In addition, most PET studies of addiction have sity [11]. These findings suggest that low D2/3 Fig. 1. Comparison of am- phetamine-induced [11C]ra- clopride displacement in a healthy control (top row) and cocaine dependent subject (bottom row). Panel A shows the healthy control in the pre-amphetamine condition, panel B shows the post-amphetamine [11C]raclopride binding in the control. Panel C shows the cocaine dependent subject in the pre-amphet- amine condition, and panel D shows the post-amphet- amine condition in the same subject. In the pre- amphetamine condition, there is higher D2/3 recep- tor binding in the healthy control compared to the co- caine dependent subject (panel A versus panel B). In the post-amphetamine condition, there is a notable decrease in [11C]raclopride binding in the healthy control, whereas there is little difference in the cocaine dependent subjects. The decrease in radiotracer binding in the healthy control subject correlates with greater dopamine release, whereas the cocaine dependent subject has blunted dopamine transmission. Imaging the Neurochemistry of Addiction 541 receptor availability might be a general risk factor subjects [6]. In the study of dopamine transmis- for addiction, and it has been hypothesized that sion, cocaine dependence was associated with 11 low D2/3 receptor BP is associated with a low sensi- a marked reduction in amphetamine-induced C- tivity to naturally occurring reinforcers and a pro- raclopride displacement in each of the functional pensity to depend on pharmacologic stimulation subregions [18]. These studies thus demonstrate to experience reward [12,13]. that in cocaine dependence the deficits in dopa- In addition to baseline D2/3 receptor BP, PET mine neurotransmission are similar across the ven- studies have been used to investigate dopamine tral and dorsal subdivisions of the striatum. transmission in cocaine dependence. Volkow and colleagues [5] demonstrated that cocaine depen- Functional significance of low D2/3 receptor dence was associated with less displacement of binding in cocaine dependence 11 C-raclopride following methylphenidate (0.5 The observation of decreased D2/3 receptor BP in mg/kg IV) compared with control subjects, suggest- cocaine-dependent subjects raises the question of ing that cocaine dependence is associated with whether this finding may serve as a risk factor for a loss of dopamine transmission. Malison and col- cocaine dependence. In fact, a series of studies leagues [14] reported similar results using SPECT have suggested that a high level of D2/3 BP may 123 and I-IBZM (which also labels the D2/3 receptor) be protective against developing dependence. A using amphetamine (0.3 mg/kg IV) to increase en- recent study reported that nonaddicted siblings of dogenous dopamine. Both studies thus suggest cocaine abusers had a higher D2/3 receptor BP that cocaine dependence is associated with a de- compared with their cocaine-dependent siblings crease in presynaptic dopamine function. This hy- [19]. Because the siblings presumably had similar pothesis is supported by a PET study showing that risk factors for dependence, this finding suggests cocaine-dependent subjects (abstinent 11–30 that elevated D2/3 receptor BP may be a neurobio- days) had lower uptake of the levodopa analog logic marker of resilience. Volkow and colleagues 18 6- F-fluoro-L-DOPA compared with healthy con- [20,21] reported that high striatal D2/3 receptor BP trol subjects, suggesting that cocaine dependence in healthy control subjects was predictive of an un- is associated with a decrease in the dopamine stores pleasant experience following administration of the of the presynaptic neuron [15]. psychostimulant methylphenidate, and conversely, Because of the resolution of PET (and SPECT) lower D2/3 BP was associated with a pleasurable ex- cameras, these studies measured dopamine recep- perience. Insofar as a pleasurable experience with tors and dopamine transmission in the striatum a drug indicates a risk for substance abuse, these re- as a whole. In other words, the resolution did not sults indicate that high D2/3 receptor BP may be allow for differentiation of the signal emitted protective. from the caudate, putamen, and ventral striatum. The authors recently investigated the correlation With a higher-resolution device, the substructures between low D2/3 receptor BP and the choice to of the striatum can be measured separately self-administer