Applications in Substance Abuse Research

Perhaps the greatest advantage of PET and SPECT lies in their tremendous flexibility for studying a variety of brain functions, an attribute based on the virtually unlimited number of biologically relevant compounds that lend themselves to radiola-beling. To date, studies in substance abuse disorders have taken advantage of these techniques to study the in vivo pharmacology of drugs of abuse as well as the effects of abused drugs and/or drug addiction on neuronal activity/metabolism and brain chemistry. A majority of substance abuse studies have focused on cocaine addiction, and this disorder will be emphasized to illustrate the types of applications.

In Vivo Pharmacology

PET and SPECT have been used to understand various aspects of the pharmacology of abused substances, including their pharmacokinetics, their occupancy of molecular targets in the brain (i.e., receptors, transporters), and their competition with pharmacologic antagonists and/or known pharmacotherapies.

Since all drugs of abuse are fundamentally organic (i.e., carbon containing) molecules, [11C] radiochemistry makes PET uniquely suited to the study of their pharmacokinetics (i.e., since insertion of the radiolabel does not alter the native pharmacology of the parent drug). In fact, PET radiotracers currently exist for [11C]cocaine, [11C]heroin, [11C]morphine, and [11C]nicotine (Hartvig et al., 1984; Fowler et al., 1989; Halldin et al., 1992), and tracer doses of these compounds have been used to study the pharmacokinetics of each in vivo. Among the earliest applications is work by Fowler and colleagues (Fowler et al., 1989). Their pioneering work with [11C]cocaine in humans demonstrated extremely high levels of brain uptake (8-10% of the injected dose) into basal ganglia (a brain region containing the highest concentrations of dopamine transporters) that occurred rapidly (peaking within 4-6 min) and cleared quickly (with an initial brain half-life of approx 20 min). These studies were consistent with the known kinetics of cocaine's behavioral euphoria.

In addition to studies of pharmacokinetics, PET and SPECT have been used to assess the degree to which drugs of abuse occupy the molecular targets of their action. Again, studies of cocaine and the dopamine transporter are illustrative. The first such study by Malison and colleagues (Malison et al., 1995) used SPECT and the radioiodinated cocaine analog [123I]P-CIT (also known as [123I]RTI-55). Using sequential cocaine displacements, behaviorally relevant (i.e., euphorigenic) doses of cocaine were shown to occupy measurable (conservatively, >15%) levels of the DAT in vivo. Although differences in the relative kinetics of the radiotracer (i.e., [123I]p-CIT) and displacer (i.e., cocaine) precluded exact occupancy measures (Malison et al., 1986), subsequent studies by Logan and colleagues (Logan et al., 1997) have more definitively established occupancy values in excess of 60-70% for subjects experiencing a drug-induced "high" (Volkow et al., 1997a). Such high levels of occupancy are not necessarily characteristic of all abused drugs as suggested by work with benzodiazepines. Specifically, SPECT displacement studies with [123I]iomazenil indicate that pharmacologically active doses of lorazepam occupy fewer than 5% of benzodiazepine receptors (Sybirska et al., 1993), data consistent with the existence of a large receptor reserve in humans.

Neuronal Activity/Metabolism

Regional changes in neuronal activity are associated with changes in energy utilization that can be assessed with radiotracer techniques in one of two ways: 1) through measures of the regional cerebral rates of glucose metabolism (rCGM), or 2) through measures of regional cerebral blood (rCBF), which under most physiological conditions is positively coupled to glucose metabolism. In the case of PET, techniques involving radiolabeled analogs of glucose (i.e., [18F]fluorodeoxyglucose or [18F]FDG) and radiolabeled water (i.e., [15O]H2O) are used to measure rCGM and rCBF, respectively. Although no comparable SPECT analog of [18F]FDG exists, several tracers exist for measuring rCBF, including 99mTc-HMPAO, 123I-iodoamphetamine, and 133Xe.

Using such techniques, investigations haven fallen broadly into two areas as relates to substance abuse, including both the acute effects of drug administration and the long-term consequences of addiction on neuronal activity (e.g., during states of drug abstinence and/or treatment). Among the first to exploit such techniques for studies of human drug abusers, London and colleagues (London et al., 1990) examined the effects of intravenous cocaine (30 mg) on rCGM using [18F]FDG and PET. Cocaine induced global reductions in brain metabolism that were inversely correlated with ventricular size. These investigators posited that reductions in brain metabolism may be one mechanism whereby drugs are reinforcing/rewarding. In addition, Volkow and colleagues have attempted to understand the metabolic correlates of both acute (i.e., <1 wk) and sustained (i.e., 1-4 mo) drug abstinence in chronic cocaine abusers (Volkow et al., 1991, 1993). The latter studies have indicated patterns of abnormally high metabolic rates in orbitofrontal cortex and striatum upon initial detoxification that change to reductions in metabolic activity in prefrontal cortex, orbitofrontal cortex, temporal cortex and cingulate gyrus as compared to non-drug-dependent controls. These studies suggest a temporally dynamic and regionally complex circuitry of abnormalities in brain function that are associated with cocaine addiction and its clinical manifestations.

Most recently, PET researchers have applied [15O]H2O and [18F]FDG techniques to studies of cognitive activation in an attempt to understand more transient psychological states, including cue-induced drug craving (Grant et al., 1996; Childress et al., 1999). In both instances, investigators have started to highlight the importance of brain structures like the amygdala and medial temporal lobe in mediating the learned/conditioned aspects of addiction. While such activation paradigms are extremely exciting and have tremendous potential, this area of research is likely to give way to functional magnetic resonance imaging (fMRI) techniques given the latter's superior temporal and spatial resolution and lack of radiation exposure (Breiter et al., 1997).

Brain Chemistry

Two major attributes of PET and SPECT, high sensitivity and biochemical selectivity, make these methods the technique of choice for the majority of in vivo neurochemical measurements. Their sensitivity enables measurement of substrates at concentrations 10-12M, several orders of magnitude lower than magnetic resonance spectroscopy capabilities (10-3 to 10-5M). Thus, PET and SPECT are capable of measuring various facets of neurochemical function in the brain, including synthesis and release of transmitters, receptors, transporters, and metabolic enzymes, with active developmental research aimed at probes of second messenger systems and gene expression.

Neurotransmitter Synthesis

Analogous to [18F]FDG techniques for measuring glucose metabolic rates, radiolabeled substrates of specific synthetic enzymes make possible in vivo measurements of neurotransmitter synthesis rates in the living brain. Two examples include 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) (Garnett et al., 1983) and [ 11C]alpha-methyl-tryptophan ([11C]a-Me-TRP) (Diksic and Grdisa, 1995), probes of dopamine (aromatic L-amino acid decarboxylase) and serotonin (tryptophan hydroxylase) synthesis rates, respectively. Using the former tracer, Baxter and colleagues (1988), documented reduced rates of dopamine synthesis in cocaine abusers as compared to controls. In addition, [18F]FDOPA has been successfully used in animal studies as a measure of psychostimulant- (i.e., methamphetamine-) induced neurotoxicity in striatum (Melega et al., 1996).

Receptors and Transporters

Currently, neurotransmitter receptors and transporters are the neurochemical targets receiving greatest attention in PET and SPECT imaging. Focus on these molecules has been based on the notion that alterations in the drug's binding site and/or neurotransmitter system may provide insights into neurochemical lesions and/or adaptations in the addicted brain. In cocaine addiction, initial studies focused on regulation on the D2 receptor. Using [18F]N-methylspiperone and PET, Volkow and colleagues (Volkow et al., 1990) reported reductions in striatal D2 receptors in recently detoxified cocaine abusers. Subsequent work has suggested persistence of these reductions for abstinence intervals up to 3-4 mo (Volkow et al., 1993). Complementing this work of post-synaptic dopamine function have been analogous studies of the presynaptic dopamine transporter. Although an initial study failed to find differences in DAT between cocaine abusers and controls (Volkow et al., 1996), work by Malison and colleagues (Malison et al., 1998a) revealed moderate (~25%) elevations in striatal cocaine binding sites in acutely (i.e., < 96 h) abstinent cocaine abusers as measured by [123I]p-CIT and SPECT. The latter findings were consistent with previous post-mortem reports in cocaine-related deaths (Little et al., 1993; Staley et al., 1994). Although these elevations appeared to persist within the same cohort of subjects after 1 month of cocaine abstinence, subsequent studies in formerly cocaine dependent subjects in residential drug treatment (mean abstinence interval 9 mo) indicates an apparent normalization in DAT (Malison et al., 1996). While definitive studies of the causes of such neurochemical alterations in dopaminergic markers remain to be done, such studies are consistent with enduring (or perhaps premorbid) changes in brain neurochemistry that characterize the addicted brain.

Neurotransmitter Release

Among the early criticisms of in vivo measurements of neuroreceptors were the potentially confounding influences created by competitive binding between the endogenous (i.e., neurotransmitter) and exogenous (i.e., radiotracer) ligands. However, this perceived liability has been exploited in recent studies that aim primarily to measure neurotransmitter release instead of the receptors themselves. Several PET and SPECT dopamine D2 receptor imaging studies in humans and monkeys now provide good evidence that both the resting levels of synaptic dopamine and the levels of stimulant-induced dopamine release may be inferred from corresponding reciprocal changes in the occupancy by the radiotracer (Dewey et al., 1991; Laruelle et al., 1997). For example, psychostimulant administration has been shown to produce displacement in radioligand binding, an effect mediated indirectly through the release of endogenous dopamine. Using such techniques (i.e., methylphenidate administration in conjunction with [11C]raclopride PET imaging), Volkow and colleagues (Volkow et al., 1997b) tested hypotheses of neurochemical sensitization in living cocaine abusers. Contrary to expectations, cocaine abusers were found to have reduced levels of stimulant-induced dopamine release (as reflected by smaller reductions in [11C]raclopride uptake) as compared to controls. A recent abstract by Malison and colleagues using the SPECT D2 receptor imaging agent [123I]IBZM and amphetamine provides preliminary replication of this finding (Malison et al., 1999). These latter studies emphasize the importance of using in vivo neuroimaging techniques to validate preclinical models of addiction, and they illustrate the potential of these techniques for feeding back and informing basic science research into substance abuse.

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