Mg I 100 g min

Fig. 3. Positron emission tomography (PET) scans showing reduction of cerebral glucose metabolism (an index of brain function) by 40 mg intravenous cocaine hydrochloride injection. Human volunteers with histories of drug abuse were subjected to PET scanning with [18F]fluorodeoxyglucose as a tracer for cerebral glucose metabolism. Each volunteer was studied twice, with placebo and cocaine given in pseudorandom order. Rates of cerebral glucose metabolism are indicated on the color bars. At the dose given, cocaine produces euphoria while reducing activity in the cerebral cortex (seen as a shift from light to dark, or, in the color version of this figure, from red to yellow). For more details, see London et al. (1990b). (Courtesy of Dr. E.D. London, National Institute on Drug Abuse, Baltimore, MD.) (See color plate 6 appearing after p. 134.)

Cocaine Binding and Receptor Studies

Much work has focused on characterizing the in vivo distribution and pharmacological properties of central cocaine binding sites. Fowler et al. (1989) used a subpharmacological, or tracer, dose of [11C]cocaine to map cocaine binding sites in the human brain with PET. They found peak binding of [11C]cocaine in the striatum at 4-10 min after iv injection, with clearance to half-peak binding at 25 min, paralleling the documented time course of cocaine's euphoric effects. Concurrent baboon studies employing pretreatment with nomifensine (a dopamine reuptake inhibitor) noted reduced striatal uptake of [11C]cocaine, demonstrating the selectivity of striatal cocaine binding to the presynaptic dopamine transporter (DAT) (Fowler et al., 1989). Malison et al. used SPECT with the radiolabeled cocaine congener [123I]P-CIT, which has high DAT binding potency, and SPECT to provide evidence that euphorigenic doses of cocaine bind in a fairly selective fashion to DAT sites (Malison et al., 1995). Logan and colleagues subsequently measured the concentration, and effective occupancy by cocaine, of striatal DAT sites in cocaine abusers with [nC]cocaine and PET, but found the estimates of DAT concentration to be fairly unstable (Logan et al., 1997). Schlaepfer et al. (1997) used PET with [11C]raclopride, a selective postsynaptic dopamine D2 receptor ligand, to assess the effect of cocaine on D2 binding. Following a dose of 48 mg cocaine hydrochloride, which produced euphoric effects in the iv drug users studied, striatal [11C]raclopride binding was reduced (displaced), supporting the contention that cocaine administration increases synaptic dopamine concentration (Schlaepfer et al., 1997). Volkow and colleagues further demonstrated the importance of DAT blockade in producing the euphoric effects of cocaine. Using euphorigenic (0.3-0.6 mg/kg) doses of [11C]cocaine as a DAT ligand in cocaine-dependent subjects, they estimated that at least half the DAT sites must be occupied to produce behavioral effects (Volkow et al., 1997a).

The interaction between cocaine and alcohol has received increasing attention. It has been suggested that increased behavioral and toxic effects associated with coabuse of cocaine and alcohol may result from the formation of cocaethylene (Hearn et al., 1991; McCance et al., 1995). Fowler et al. used PET with [11C]cocaine to evaluate the uptake, clearance, and distribution volume of cocaine before and during alcohol ingestion. They found no significant differences with alcohol, and no detectable radiolabeled cocaethylene, suggesting that the enhanced response to the combination is not directly due to altered cocaine metabolism (Fowler et al., 1992).

Chronic Cocaine Abuse and Dependence

Cerebral Blood Flow

The chronic effects of cocaine on cerebral hemodynamics have been studied in great detail in a number of controlled studies. The first report of abnormal baseline cerebral perfusion in chronic cocaine users was published by Volkow et al. in 1988. Using [15O]H2O PET in 20 chronic cocaine-abusing men, they demonstrated multifocal, patchy regions of reduced perfusion (perfusion defects) as well as decreased rCBF in prefrontal cortex (Volkow et al., 1988a). These defects were present during detoxification and again 10 days later when patients showed no signs of withdrawal. Tumeh et al. (1990) used SPECT with [123I]IMP in a group of neurologically normal, polydrug abusing, HIV-negative men. They also found multifocal cortical perfusion defects, which were more common in the frontal and temporal lobes (Tumeh et al., 1990). Follow-up studies with high-resolution 99mTc-HMPAO annular SPECT (ASPECT) in HIV-negative, cocaine- and polydrug-dependent men, many of whom tested positive for cocaine metabolites at the time of the examination, confirmed multifocal perfusion defects (see Fig. 4), generally in inferoparietal, temporal and anterofrontal cortex and basal ganglia (Holman et al., 1991). Subsequent work comparing cocaine-dependent subjects and patients with the AIDS dementia complex (ADC) demonstrated the non-specificity and similarity of perfusion defects in the two groups (Holman et al., 1992). Weber et al., using [123I]IMP SPECT, found similar focal perfusion defects and "patchy" tracer uptake in a large percentage of crack abusers with no history of intravenous drug use or dependence on any other drugs (Weber et al., 1993). Similar perfusion abnormalities have been noted by others (Miller et al., 1992; Strickland et al., 1993).

Fig. 4. Single photon emission computed tomography (SPECT) perfusion scans of a chronic cocaine-dependent subject on the right and an age-matched normal volunteer the left. Both subjects were men. Each was injected with the radiotracer 99mTc-HMPAO and imaged several minutes later in the resting state with eyes open. In the normal subject, cerebral perfusion is uniform and robust, as represented by hues of white and orange. By contrast, in the cocaine-dependent subject, in addition to an overall picture of less robust cerebral perfusion, there are focal reductions in numerous brain regions, as seen by replacement of white and orange hues with blue and black. (See color plate 8 appearing after p. 134.)

Fig. 4. Single photon emission computed tomography (SPECT) perfusion scans of a chronic cocaine-dependent subject on the right and an age-matched normal volunteer the left. Both subjects were men. Each was injected with the radiotracer 99mTc-HMPAO and imaged several minutes later in the resting state with eyes open. In the normal subject, cerebral perfusion is uniform and robust, as represented by hues of white and orange. By contrast, in the cocaine-dependent subject, in addition to an overall picture of less robust cerebral perfusion, there are focal reductions in numerous brain regions, as seen by replacement of white and orange hues with blue and black. (See color plate 8 appearing after p. 134.)

The abovementioned studies focused mainly on cocaine-dependent men. However, we subsequently demonstrated that cocaine-dependent women have far fewer perfusion abnormalities than do men with similar cocaine use histories (Levin et al., 1994). Furthermore, although cocaine-dependent women were difficult to distinguish from normal control subjects, and cocaine-dependent men had multiple abnormalities, polydrug-dependent subjects of both sexes displayed more abnormalities than did cocaine-dependent subjects. Therefore, both male gender and polydrug abuse appear to be among the greatest risk factors for the development of cerebral perfusion abnormalities in chronic cocaine dependence.

Fortunately, cocaine-associated cerebral perfusion defects appear to be limited to adults. Konkol et al. found normal cerebral perfusion in high-resolution 99mTc-HMPAO SPECT measurements of 21 neonates with a history of in utero cocaine exposure (Konkol et al., 1994). This was in contrast to their findings of behavioral or electroencephalographic abnormalities in all but four newborns, as well as microcephaly in five. Although neonates do not appear to escape significant toxic effects of in utero cocaine exposure, this study indicates that they may escape some of the cerebrovascular effects.

Cerebral Metabolism

The metabolic effects of chronic cocaine use are less clear than the hemodynamic effects. Much of this work overlaps with studies in various phases of cocaine withdrawal and will be discussed in that context below.

In studies employing [18F]FDG PET, Volkow et al. (1993a) demonstrated reduced orbitofrontal and anterior cingulate rCMRglc in abstinent cocaine-dependent men. Subsequently, in order to assess the effect of cocaine abuse on GABA-ergic systems, this group evaluated the effect of chronic cocaine abuse on the metabolic response to the benzodiazepine lorazepam. Compared to controls, cocaine abusers responded to lorazepam with greater reduction in global and regional glucose metabolism, particularly in the striatum, thalamus, and parietal cortex. These group effects were noted despite lower lorazepam plasma levels in the cocaine abusers (Volkow et al., 1998b).

Withdrawal

Using [18F]FDG PET, Baxter et al. (1988) found no abnormality in left lateral prefrontal cortical glucose metabolism in a cohort of cocaine-dependent subjects early in withdrawal, but these data are incomplete and inconclusive. Volkow and colleagues also used [18F]FDG PET in cocaine-dependent men both during and following withdrawal, and compared them to normal subjects. They found increased global CMRglc and increased rCMRglc in orbitofrontal cortex and basal ganglia, with normalization following withdrawal (Volkow et al., 1991a).

Kosten et al. (1998) evaluated cerebral perfusion with 99mTc-HMPAO SPECT in cocaine-dependent subjects in acute (1-3 d) and midterm (21 d) abstinence, with no signs of withdrawal. Frontal and parietal perfusion abnormalities were not found to change over the course of abstinence, although they seemed to be limited to subjects with a history of concomitant alcohol abuse (Kosten et al., 1998). This finding of greater perfusion abnormalities in polydrug abusing patients than in those abusing cocaine alone is consistent with previous work in our laboratory (Levin et al., 1994).

Cocaine Craving

In order to determine the functional correlates of craving, Grant et al. (1996) exposed cocaine-abusing subjects to cocaine-related cues while undergoing [18F]FDG PET (see Fig. 5). They demonstrated increases in rCMRglc in the dorsolateral prefrontal cortex, amygdala, and cerebellum that correlated with the subjects' reports of cocaine craving (Grant et al., 1996). Liu et al. (1998) evaluated both glucose metabolism and EEG in cocaine abusers and controls presented with cocaine-related cues. Cocaine abusers, but not controls, demonstrated reduced alpha power on EEG, correlating with increased glucose metabolism. However, these measures did not correlate with the time course or magnitude of cocaine craving, suggesting that cue-elicited craving is not directly related to these electrophysiological and metabolic measures (Liu et al., 1998).

Most recently, using [15O]H2O PET, Childress and colleagues measured brain activation (relative increase in rCBF) in response to cue-induced cocaine craving in limbic and control regions in detoxified cocaine users. Despite having lower baseline rCBF in limbic regions, cocaine users, but not controls, showed increased limbic activation in response to cocaine-related cues, particularly in the left amygdala and anterior cingulate cortex. The two groups did not differ in terms of activation in control regions (dorsolateral prefrontal cortex, cerebellum, thalamus, and visual cortex),

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