Neural correlates of high and craving during cocaine self-administration using BOLD fMRI
Introduction
Understanding why humans compulsively seek and self-administer certain drugs remains central to developing adequate treatments for drug abuse. It has long been postulated that the positive affective property of cocaine is responsible for at least the initiation and perhaps the maintenance of drug taking (Wise and Bozarth, 1981). It has also been suggested that an addict's hedonic set-point changes over time such that drug-taking behavior reflects an attempt to alleviate a newfound negative state (Koob and Le Moal, 1997, Kreek and Koob, 1998). Another theory is that the desire to use drugs becomes, with experience, independent from the reinforcing outcome (Robinson and Berridge, 1993). These theories are predominately based on animal models of drug dependence. To contribute to the understanding of addiction, we present a naturalistic human model of self-administration (SA) behavior demonstrating the correlation of real-time subjective state reports with neural activation.
Previous human brain imaging studies have identified subcortical and cortical effects of acute cocaine administration, generally implicating limbic, orbitofrontal and striatal regions (Breiter et al., 1997), dopamine (DA) transporter binding (Logan et al., 1997), blood flow (Pearlson et al., 1993, Wallace et al., 1996), and D2 receptor availability in abusers (Volkow et al., 1997a, Volkow et al., 1997b). A generalized decrease in global metabolism has also been reported after an acute cocaine injection in polydrug abusers (London et al., 1990). One must, however, extrapolate these findings to the operant behavioral condition when abusers take drug. To do so, one must assume that a single, blinded, passive delivery of cocaine is significantly similar to an addict's repeated drug use on the street.
However, the preclinical literature suggests that neural activity within the mesocorticolimbic (MCL) DA system and related regions depends not only on the direct pharmacological actions of the drug but also the behavioral and motivational state of the animal during drug administration. For example, using a yoked three-animal paradigm, one rat passively receives i.v. cocaine dependent upon its yoked peer's SA schedule. In this instance, the animal actively self-administering cocaine demonstrates a significantly greater increase in NAc DA levels than either the saline or passive drug yoked animal (Hemby et al., 1997). Similar results have been reported for amygdala DA and serotonin levels (Wilson et al., 1994). Such active/passive distinctions are especially significant since the MCL DA system is implicated during reinforcing stimulus processing (Wise and Rompre, 1989). As in the animal models, such differences are also likely in the human response to drugs, where a complex motivational context intertwines with addiction behavior.
A remaining question, one that is unanswerable from the animal literature, is the relationship between cocaine-induced neural activity and the subjective effects of cocaine. Previous human SA experiments (Fischman and Schuster, 1982, Foltin and Fischman, 1992, Foltin and Fischman, 1996, Ward et al., 1997) have used the ability of humans to report their subjective states, but have opted for self-report instruments that take several minutes to complete. These are, unfortunately, impractical for assessing moment-to-moment fluctuations in subjective state within a cocaine paradigm. Understanding this limitation and complementing the temporal resolution of blood oxygenation level-dependent (BOLD) fMRI, we developed a system of once per minute subjective state self-rating throughout a 1-h i.v. cocaine SA session.
To directly test the hypothesis that MCL regional neural activity correlates with self-reports of the subjective effects of cocaine and is distinct from that previously seen following single, passive cocaine administration, experienced cocaine users were allowed to self-administer intravenously delivered cocaine during fMRI. Throughout the SA scanning session, volunteers were asked to rate their behavioral responses along four axes: HIGH, CRAVING, RUSH, and ANXIOUS. In this design, we elucidate the minute by minute relationship between the subjective effects of self-administered cocaine and changes in neural activity. The utility of this study is that grounded in the current knowledge of the regional neurobiology of identified brain sites, better pharmacological and/or behavioral therapeutic strategies for drug dependence may be developed.
Section snippets
Subject selection
Eight right-handed (Oldfield, 1971) males meeting DSM-IV criteria for cocaine dependence were recruited from the general population via local advertisements [mean ± SD (range) age: 36 ± 6.8 (23–41) years; 13 ± 1.1 (12–14) years education, and 11.2 ± 3.5 (6–15) years experience smoking crack cocaine]. All were exclusively crack cocaine users, 1-pack/day cigarette smokers, and none met criterion for any other Axis I or II psychiatric disorder. Subjects underwent a thorough medical and psychiatric
Results
All subjects tolerated the SA protocol without any untoward effects or complications and rapidly learned the SA procedure. As expected, the greatest change in cardiovascular parameters occurred following the first cocaine injection. Although rapid tolerance to the cocaine-induced tachycardia and hypertension was seen with successive cocaine injections (Fig. 1), HR and BP levels remained elevated over baseline values throughout the session (mean increases of 10.5 ± 12 mm Hg SBP, 6.6 ± 8.2 mm Hg
Discussion
Using a more naturalistic laboratory model of human drug abuse than previously available, this study provides the first direct evidence that the same MCL regions implicated in preclinical models of cocaine reinforcement (Wise and Rompre, 1989) are also engaged during human drug-taking behavior. When behavioral ratings were used as reference waveforms in a correlational analysis, cocaine SA-induced HIGH correlated with neural activity in a number of limbic, paralimbic, and mesocortical regions.
Acknowledgments
This research was supported in part by NIDA grants DA09465 (RCR), K23 DA00486 (RCR), RO1 DA 11326 (ASB) and NCRR GCRC grant 5M01RR00058. The assistance of Mrs. Stacy Claesges is gratefully acknowledged.
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Current address: Department of Psychology, Trinity College Dublin, Dublin 2, Ireland.