Neuroimaging in drug abuse - Springer Link

Neuroimaging in Drug Abuse Kimberly P. Lindsey, PhD*, S. John Gatley, PhD, and Nora D. Volkow, MD

Address *Medical Department, Brookhaven National Laboratory, Building 490, Upton, NY 11973, USA. E-mail: [email protected] Current Psychiatry Reports 2003, 5:355–361 Current Science Inc. ISSN 1523-3812 Copyright © 2003 by Current Science Inc.

Neuroimaging techniques, including positron emission tomography (PET), are ideally suited for studies of addiction. These minimally invasive modalities yield information about acute and long-term drug-induced structural and functional changes in the brain over time. Changes can be observed in the brains of human and animal subjects during drug self-administration. Neuroimaging with PET allows precise quantification and visualization of the drug and its rates of movement in the body. In addition, imaging reveals recovery of function and reappearance of neuronal markers in abstinent drug users. Evidence that suggests that PET may have use in identifying individuals predisposed to become addicted is emerging. Finally, candidate pharmacotherapies for drug addiction can be critically evaluated. These unique assets clearly point to the use of these strategies for addiction studies.

Although the existence of a final common pathway of reward is hotly debated, it is certain that virtually all sufficiently characterized self-administered drugs enhance dopaminergic signaling in reward-relevant brain circuitry (reviewed in [1]) by means of increasing dopaminergic cell firing, inhibiting dopamine uptake, or enhancing basal dopamine release. Dopaminergic effects are especially relevant in the case of psychostimulants such as cocaine and the amphetamines. Several factors make psychostimulant addiction especially amenable to study with neuroimaging techniques such as positron emission tomography (PET). First, PET, in particular, is designed for measurement of drug action. It is a powerful pharmacologic tool naturally suited for evaluation of drug interactions with living systems. Second, psychostimulants exert their effects through dopaminergic circuitry. Selective radioligands for many aspects of dopamine systems, such as the dopamine transporter and dopamine D1 and D2 receptors, are currently available, simplifying evaluation of these circuits with PET. Third, dopaminergic markers are concentrated in discrete brain regions—striatum and nucleus accumbens and, to a lesser degree, the globus pallidus, cingulate cortex, olfactory tubercle, and amygdala [2]. Finally, the minimally invasive nature of PET imaging makes it suitable for use in studies involving repeated measures in living patients.

Introduction Millions of different chemicals have been characterized; however, the subset of these that are self-administered by humans or animals numbers merely in the tens. Examination of these few self-administered drugs reveals little similarity in structure or in drug effect. Voluntary consumption of this subset of diverse chemicals produces a very wide array of desirable subjective effects in humans, ranging from sedation to stimulation through hallucination and beyond. It is believed by many that the vast majority of humans worldwide engage in daily repeated self-administration of pharmacologic doses of nonprescribed drugs with subjective and behavioral consequences. Despite that nearly all individuals voluntarily use psychoactive drugs at some time during their lives, the fundamental bases of addiction are not fully understood. Examination of the proximal mechanism of action of abused drugs reveals that numerous different immediate substrates mediate their actions. The multiplicity of primary neuronal effectors necessitates the examination of downstream events in a quest for a common pathway mediating the reinforcing properties of drugs of abuse.

Positron Emission Tomography Positron emission tomography is a versatile and minimally invasive imaging technique that can be used in vivo to answer mechanistic questions about biochemistry and physiology in animals and humans. Many of the drugs of abuse can be radiolabeled and detected in the body using PET. Bioavailability can be measured and quantified in any organ of interest. Pharmacokinetics and biodistribution can be directly observed within the context of living organisms. The degree of neuroreceptor occupancy by drugs can be determined, and competition assays can take place in a living subject during a PET scanning protocol, yielding information about specificity of binding in vivo. Positron emission tomography relies on the radiochemical properties of positron emitting isotopes. Radioactive isotopes such as 15O, 11C, and 18F emit positrons on decay, which interact with nearby electrons resulting in the production of two gamma rays, which are emitted in opposite directions. These isotopes can be used to label molecules of interest, such as drugs, water, gases, or analogs of

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nutrients such as glucose. After injection of a miniscule quantity of radiolabeled substance, detection of the gamma rays by the PET camera allows inference of the location of the decayed isotope-labeled molecule within the body. Positron emission tomography is exquisitely sensitive— capable of detecting radiolabeled tracers present at nano- or picomolar concentrations in living systems. Technologic advances are improving the somewhat poor spatial resolution (compared with magnetic resonance imaging) of PET images. Although most molecules can be radiolabeled with positron emitters, and their kinetics and distribution evaluated using PET, practically useful radiotracers must possess certain properties of lipophilicity, specificity, and affinity. The evaluation of a number of neurotransmitter systems awaits the development of suitable ligands. The most widely characterized system thus far is the dopaminergic system.

Imaging dopaminergic systems Several PET radioligands are available for the evaluation of different aspects of dopaminergic circuitry, including dopamine synthesis and metabolism, dopamine transporters, and dopamine receptors (D2 and D1). Inferences about extracellular dopamine can be drawn from PET imaging experiments using suitable tracers. Dopaminergic radioligands have been used to assess several pathologies, including Parkinson’s disease, other movement disorders, schizophrenia, and substance abuse. Brain alterations arising from chronic stimulant use Subtle alterations in brain neurochemistry can be assessed with PET. Changes in the density of neurotransmitter receptors and transporters occur after exposure to drugs. These changes can be compensatory, arising from homeostatic mechanisms, or can arise as the result of damage to neurons or nerve terminals. Chronic use of psychostimulants, such as methamphetamine, has been shown to cause reductions in dopamine nerve terminal markers, such as the dopamine transporter in nonhuman primates [3,4] and in humans [5]. These in vivo neuroimaging results are in good agreement with results obtained ex vivo using postmortem human brain [6]. Reductions in D2 receptor levels have also been documented not only in psychostimulant addicts [7, 8], but also in abusers of opiates [9] and alcohol [10]. Acute alterations of extracellular dopamine Through blockade of the dopamine transporter (and, in the case of the amphetamines, by direct release of dopamine), addictive psychostimulants cause acute increases in extracellular dopamine, which can be measured in vivo using [11C] raclopride. Raclopride is a D2 receptor–specific radiotracer that has sufficiently low affinity that its binding is sensitive to the concentration of extracellular dopamine [11]. Administration of a drug that increases extracellular dopamine, such as cocaine, amphetamine,

or methylphenidate, causes reductions in D2 receptor availability, which is reflected in a decrease in the [ 11C] raclopride signal in dopaminergic brain regions as measured using PET [12]. Drug occupancy at receptor (transporter) sites The relationship between occupancy and drug-induced subjective states is of central importance to basic and clinical addiction research. Dynamic PET can be used to identify interactions of drugs with their target sites. These studies are conducted with standard radiolabeled PET ligands, which share a binding site with the drug of interest. The occupancy of the drug of interest is inferred indirectly from its ability to displace the radioligand from the common binding site of the compounds. Neuroreceptor imaging with PET can also be used to relate molecular events, such as a drug occupying its target site, to organismal events, such as behavior, clinical efficacy, or self-reported drug effects. The relationship between selfreported euphoria and cocaine occupancy of the dopamine transporter (DAT) is fairly well documented [13–16]. At least 40% occupancy has been required for intravenously administered cocaine to be perceivable to a user [15]. The doses commonly used by addicts that produce sensations of “high” result in DAT occupancy levels of about 60% to 77% [15]. Similarly, DAT occupancy by therapeutically relevant doses of methylphenidate, which is a selective DAT blocker clinically prescribed for attention deficit-hyperactivity disorder, has been reported at approximately 50% [17].

Pharmacokinetics of Abused Drugs Although it remains clear that dopaminergic effects are important in mediating reinforcement, these alone are not sufficient to induce subjective reinforcing effects. Recent research has generated increasing amounts of evidence supporting the idea that pharmacokinetic properties of drugs are important determinants of abuse liability for drugs that act directly or indirectly on dopaminergic systems. Drugs that have a rapid onset of action are perceived as more reinforcing than slow-onset drugs [18,19]. Duration of drug effect is also an important parameter. One of the characteristics of an abused drug is that it promotes maladaptive patterns of drug self-administration; shortacting abused drugs promote more frequent use than those with longer durations of actions [19]. Positron emission tomography neuroimaging studies have confirmed the earlier finding that drugs with slow onset and long half-life are less reinforcing than fast onset, short-acting drugs in human [17,20,21], and in animal models [22,23,24•], even when the occupancy produced by the drugs is the same. For instance, pharmacokinetic factors have been invoked to explain the reduced abuse liability of oral methylphenidate compared with cocaine [25]. Methylphenidate and cocaine are stimulant drugs with similar in vivo potencies to

Neuroimaging in Drug Abuse • Lindsey et al.

block dopamine transporters and differ mainly in their pharmacokinetics, but methylphenidate has a slower onset and longer duration of action. Thus, results from PET neuroimaging studies suggest that the rate of change in extracellular dopamine, as well as the absolute amount of dopamine increase from a baseline state, seems important.

Functional studies: glucose metabolism Changes in neuronal activity are accompanied by alterations in metabolism, reflected in altered glucose demand in associated brain areas. [18F] fluorodeoxyglucose (FDG) is a widely used radiolabeled glucose analogue taken up as glucose and accumulated in cells. Use of FDG allows detection of metabolic alterations, which occur in a variety of normal and pathologic states, including drug addiction. Acute drug-induced changes, long-term alterations resulting from chronic drug use, and effects of withdrawal on regional rates of glucose metabolism can all be assessed using this technique. In individuals who abuse cocaine, regional FDG metabolism has been acutely reduced by 40 mg of intravenous cocaine in neocortical areas, basal ganglia, portions of the hippocampal formation, thalamus, and midbrain [26]. In contrast, patients studied within 1 week of cocaine withdrawal had higher levels of global brain metabolism, as well as higher levels of regional brain metabolism, in the basal ganglia and orbitofrontal cortex than normal patients [27]. Because of the ethical problems with administering cocaine to cocaine-naïve individuals, PET studies in nonhuman primates will be extremely valuable in measuring acute metabolic effects of cocaine without the confounding variables present in individuals who abuse cocaine, who, by nature, are also likely to show chronic effects of cocaine use. Reduced rates of frontal metabolism in neurologically intact patients who use cocaine have been shown to persist chronically even after 3 to 4 months of detoxification [28]. As mentioned previously, psychostimulant addicts have been demonstrated to have lower levels of D2 receptors than normal control individuals [7,8]. This reduction in D2 has been associated with reduced glucose metabolism in orbitofrontal cortex and in anterior cingulate gyrus as measured with PET and FDG [29•]. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. Similarly, the anterior cingulate gyrus has been associated with inhibitory control, thus its dysfunction in the patients addicted to cocaine could contribute to addicts’ poor impulse control when exposed to cocaine. Use of PET with two separate radiotracers ([11C] raclopride for evaluation of D2 receptor levels and [18F] FDG for evaluation of glucose metabolism) within the same individual allows this correlation. Brain activity associated with subjective states, such as drug craving, can be evaluated with PET by exposing patients

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to appropriate stimuli (often consisting of handling drug paraphernalia or viewing videos of drug-taking, buying, and so forth) after FDG injection. Areas activated during cocaine craving include the orbitofrontal cortex, which is a brain region involved in salience attribution and in conditioned responses [30,31,32•], the temporal insula [31], which is a brain region involved in autonomic control, the dorsolateral prefrontal cortex [26,32•], which is a region linked to working memory, and the hippocampus, which is a region involved with memory [33]. In addition, after a addict’s exposure to cocaine-related cues, rates of glucose metabolism have been elevated in the amygdala, a brain structure that is thought involved in the emotional aspects of memory, [26,32•]. Using PET, drug craving can be associated with the function of certain brain structures. Perhaps more important than this, craving potentially can be evaluated and even quantified through correlation with brain metabolic changes without reliance on the patient’s own subjective evaluations.

Functional studies: blood flow Changes in neuronal activity are also accompanied by alterations in oxygen demand, which are reflected in redistribution of cerebral blood flow to associated brain areas. Chronic perfusion deficits have been demonstrated in cocaine users using radiolabeled markers of blood flow with PET and the related technique single photon emission computed tomography (SPECT). Areas involved include the frontal cortex [34–36], temporal cortex [35,36], parietal [36] and anterofrontal cortex, and basal ganglia [37]. Acute cocaine-induced alterations in regional cerebral blood flow have been studied thus far only in rhesus monkeys, who showed prominent cocaine-induced activation of dorsolateral prefrontal cortex in response to 1 mg/kg of intravenously administered cocaine [38•]. Changes in cerebral blood flow associated with drug craving have also been characterized and are similar to those reported by the studies measuring glucose metabolism. Increases in limbic flow, including anterior cingulate gyrus [39,40•] amygdala [39,40•], and insula [40•], have been documented in response to cocaine-related cues in individuals who abuse cocaine. Vulnerability to addiction The National Institute on Drug Abuse estimates that about one in 10 people who try cocaine become addicted. Some individuals, thus, seem more likely to abuse drugs than others. PET can be used to glean information about factors that contribute to vulnerability to addiction. Dopamine has been implicated in the individual variance in susceptibility to drug abuse in rats [41–43]. Also in rats, upregulation of D2 gene expression by means of intra-accumbens injection of a viral vector encoding the gene for the D2 receptor has been shown to reduce ethanol consumption compared with injections of noncoding vector into the same brain region [44•]. PET studies evaluating the dopamine D2 receptor with [ 11C] raclopride found an inverse correlation between D2 receptor availability and

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subjective ratings of “drug liking” after intravenous methylphenidate administration in normal humans [45]. Patients with high dopamine D2 receptor availability described the same dose of methylphenidate as unpleasant. Together, these data suggest that there may be ways to identify individuals who are predisposed to addiction.

Neuroimaging and Addiction Treatment As discussed previously, addiction to various drugs has a number of biologic sequelae. In addition to the assessment of drug-induced acute and chronic structural and metabolic changes in brain, neuroimaging is becoming increasingly useful in evaluating the efficacy of abstinence and addiction treatments to normalize brain function.

Pharmacotherapies for addiction Behavioral and psychologic rationales currently dominate the treatment of psychostimulant addiction. As more information about neurobiologic substrates of addiction is generated using human neuroimaging and animal models, additional therapeutic strategies are expected to emerge. A great deal of effort has been made to develop a pharmacotherapy for stimulant users. Given the reasonable success of methadone maintenance therapies for heroin addicts, there has been considerable interest in a similar approach to psychostimulant addiction. A substitute drug that is a member of the broad class of psychostimulants, yet less reinforcing and less toxic than street drugs and has slower kinetics, may be useful in treating psychostimulant addicts. Such a drug could become part of a harm-reduction strategy, reducing or eliminating withdrawal, minimizing chances of overdose, and allowing addicts the chance to return to more productive lives. A suitable addiction pharmacotherapy would normalize altered neurochemistry and block dopaminergic binding sites, which are the targets of illicit psychostimulants. Such a pharmacotherapy has not yet been found. However, imaging techniques are invaluable in the development of psychoactive drugs in general, and especially in the assessment of these types of putative addiction medications. Drug development A number of drugs that show promise as addiction therapies in preclinical studies utilizing animal models of addiction have been discovered. Among these are long-acting psychostimulant analogues of several different chemical classes (reviewed in [46]). Intense research on this topic is ongoing. Questions remain about the mechanism by which these candidate drugs reduce psychostimulant self-administration and also about the subjective effects of these drugs in humans. A number of obstacles must be overcome before these drugs can be used or even tested in human populations. Safety The sensitivity of PET allows detection of radiolabeled drugs injected intravenously in quantities of less than 1 mg

[47]. This has obvious implications for patient safety, because the high sensitivity of PET allows an extremely small quantity of an injected radiolabeled experimental drug. Approvals for use of new drugs in humans are streamlined because doses used in PET are far below those required to yield clinical effects [47]. Additionally, many novel stimulant analogues, which show promising binding profiles in vivo, lack clinical utility because they cannot cross the blood-brain barrier. Brain penetration can be evaluated using PET in humans with minimal doses and maximal patient safety. Specificity Most importantly, evaluation of the specificity of drug interactions with desired target sites within the living brain is possible. Medication development strategies often include synthesis of analogues of known drugs in hopes of enhancing their desirable properties and minimizing undesirable properties, such as side effects. Assessment of these new compounds in vitro and in animal behavioral models is sometimes insufficient to define their mechanisms of action. PET can be used in vivo to evaluate the competition between novel drugs and radiotracers specific for putative receptor sites. Potency and efficacy With the help of PET, correlations can be made between a known drug’s efficacy and its occupancy at its receptor site. Armed with this information, rational dosing regimens can be devised for new drugs that yield a similar level of occupancy, reducing the need to test wide ranges of drug doses in clinical settings. In addition, questions about the degree of occupancy of candidate addiction medications can be compared with occupancy produced by the abused drug in humans and in animals. Preclinical studies have evaluated the DAT occupancy achieved by drugs that reduce cocaine self-administration in rodent and nonhuman primate models. Results of these studies suggest that the occupancy required by doses of DAT blockers to significantly reduce cocaine self-administration is very similar to that produced by self-administered cocaine itself [48•,49•]. As discussed previously, however, occupancy is likely not the sole determinant of a drug’s reinforcing efficacy. This idea is supported further by results from experiments with humans in whom two injections of methylphenidate (a DAT blocker) were given 1 hour apart. In this experiment, self-reports of the subjective effects of the injections of methylphenidate were identical even in the presence of 75% residual occupancy of the DAT from th e fir st in ject ion [ 50]. Th ese a nd ot her studies, although generating even more questions about the use of dopamine transporter blockers as pharmacotherapies for psychostimulant addiction, clearly point to the use of PET neuroimaging in evaluation of putative psychoactive medications.


Kinetics of pharmacotherapeutic agents If short action and fast onset contribute to abuse liability, then long-acting, slow-onset drugs may be more desirable as pharmacotherapeutic agents for addiction. PET allows direct comparisons of the kinetics of different drugs or of different routes of administration of the same drug in the same individual if desired. Work in these areas is in its infancy; however, the proof of concept is well established. Differences in the reinforcing efficacy of doses of cocaine by different routes of administration have been related to DAT occupancy [51••]. Results from this experiment showed that even with equivalent DAT occupancy, cocaine administered via the intravenous route was perceived as more reinforcing than intranasal cocaine.

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studies implicate neural pathways involved in expectancy and reinforcing salience (orbitofrontal cortex), inhibitory control (anterior cingulate and prefrontal cortex), memory (hippocampus), and emotional aspects of memory (amygdala), among others. PET neuroimaging has also demonstrated use in medications development and may play an increasingly important role in evaluating potential pharmacotherapeutic agents for addiction, as well as psychoactive medications in general. Over the next few years, researchers can look forward to extending these strategies and principles to neurotransmitter systems other than dopamine as radioligands for these systems are developed.

References and Recommended Reading Recovery from addiction Positron emission tomography neuroimaging can be used to evaluate normalization of neurotransmitter systems after treatment or abstinence. Loss of dopamine neuron terminal markers in methamphetamine abusers recovers after protracted abstinence [52••]. Although normalization of blood flow after abstinence from abused psychostimulants has not yet been evaluated using PET, other techniques, such as transcranial Doppler ultrasonography, have suggested that chronic cocaine-induced blood flow abnormalities do resolve with abstinence [53]. Cocaine-abusing patients showed normalization of cocaine-induced elevations in global brain metabolism and elevations of regional brain metabolism in the basal ganglia and orbitofrontal cortex after 2 to 4 weeks of abstinence from cocaine [27]. In addition, preclinical studies in conscious rhesus monkeys have shown that acute cocaine-induced brain activation was blocked when cocaine was administered fifteen minutes after 10 mg/kg alaproclate, which is a selective serotonin reuptake inhibitor [38•]. More work in this area is needed.

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Conclusions In summary, PET neuroimaging is a sensitive clinical research tool with special use for imaging dopaminergic systems. Because addictive psychostimulant drugs, such as cocaine and amphetamine, exert their actions within dopaminergic circuitry, PET has been used extensively to measure a variety of parameters associated with psychostimulant drug action and addiction. Subtle changes in brain chemistry, such as alterations in extracellular dopamine, and the density of its transporter and receptors have been evaluated. Results from these studies are in good agreement with previous studies using other methodologies in postmortem samples or animal models. Functional changes have been assessed with PET as well. Acute and chronic changes in blood flow and glucose use have been measured in humans under a variety of experimental conditions, including acute cocaine administration, withdrawal states, and also using paradigms designed to generate sensations of drug craving. Results from these

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48.• Villemagne VL, Rothman RB, Yokoi F, et al.: Doses of GBR12909 that suppress cocaine self-administration in nonhuman primates substantially occupy dopamine transporters as measured by [11C] WIN35,428 PET scans. Synapse 1999, 32:44–50. This paper demonstrates the use of PET to correlate occupancy at drug target sites to drug function in the context of a preclinical cocaine medications development study. 49.• Wilcox KM, Lindsey KP, Votaw JR, et al.: Self-administration of cocaine and the cocaine analog RTI-113: relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys. Synapse 2002, 43:78–85. These results suggest that self-administered doses of experimental long-acting selective DAT blockers produce a similar degree of DAT occupancy as self-administered doses of cocaine in monkeys (approximately 80%). Additionally, although the DAT blockers do attenuate cocaine self-administration when given as pretreatments to the selfadministration session, the occupancy required for this effect is also about 80%.

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