Elsevier

NeuroImage

Volume 26, Issue 4, 15 July 2005, Pages 1097-1108
NeuroImage

Neural correlates of high and craving during cocaine self-administration using BOLD fMRI

https://doi.org/10.1016/j.neuroimage.2005.03.030Get rights and content

Abstract

Modern theories of drug dependence hold the hedonic effects of drug-taking central to understanding the motivation for compulsive drug use. Previous neuroimaging studies have begun to identify brain regions associated with acute drug effects after passive delivery. In this study, a more naturalistic model of cocaine self-administration (SA) was employed in order to identify those sites associated with drug-induced high and craving as measures of reward and motivation. Non-treatment seeking cocaine-dependent subjects chose both when and how often i.v. cocaine administration occurred within a medically supervised SA procedure. Both functional magnetic resonance imaging (fMRI) data and real-time behavioral ratings were acquired during the 1-h SA period. Drug-induced HIGH was found to correlate negatively with activity in limbic, paralimbic, and mesocortical regions including the nucleus accumbens (NAc), inferior frontal/orbitofrontal gyrus (OFC), and anterior cingulate (AC), while CRAVING correlated positively with activity in these regions. This study provides the first evidence in humans that changes in subjective state surrounding cocaine self-administration reflect neural activity of the endogenous reward system.

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.

References (57)

  • P.A. Bandettini et al.

    Processing strategies for time-course data sets in functional MRI of the human brain

    Magn. Reson. Med.

    (1993)
  • A. Bechara et al.

    Emotion, decision making and the orbitofrontal cortex

    Cereb. Cortex

    (2000)
  • R.M. Carelli et al.

    A comparison of nucleus accumbens neuronal firing patterns during cocaine self-administration and water reinforcement in rats

    J. Neurosci.

    (1994)
  • A.R. Childress et al.

    Limbic activation during cue-induced cocaine craving

    Am. J. Psychiatry

    (1999)
  • S.G. Dirckx et al.

    Comparing IV Methylphenidate and Cocaine in the Human Brain Using fMRI

  • S.A. Dudish et al.

    Smoked cocaine self-administration in females

    Psychopharmacology (Berlin)

    (1996)
  • M.W. Fischman et al.

    Effects of desipramine maintenance on cocaine self-administration by humans

    J. Pharmacol. Exp. Ther.

    (1990)
  • M.W. Fischman et al.

    Cocaine self-administration in humans

    Fed. Proc.

    (1982)
  • M.W. Fischman et al.

    Acute tolerance development to the cardiovascular and subjective effects of cocaine

    J. Pharmacol. Exp. Ther.

    (1985)
  • R.W. Foltin et al.

    Effects of methadone or buprenorphine maintenance on the subjective and reinforcing effects of intravenous cocaine in humans

    J. Pharmacol. Exp. Ther.

    (1996)
  • R.W. Foltin et al.

    Self-administration of cocaine by humans: choice between smoked and intravenous cocaine

    J. Pharmacol. Exp. Ther.

    (1992)
  • R.W. Foltin et al.

    Effects of single and multiple intravenous cocaine injections in humans maintained on methadone

    J. Pharmacol. Exp. Ther.

    (1995)
  • S.D. Forman et al.

    Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold

    Magn. Reson. Med.

    (1995)
  • H. Garavan et al.

    Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli

    Am. J. Psychiatry

    (2000)
  • R.L. Gollub et al.

    Cocaine decreases cortical cerebral blood flow but does not obscure regional activation in functional magnetic resonance imaging in human subjects

    J. Cereb. Blood Flow Metab.

    (1998)
  • S. Grant et al.

    Activation of memory circuits during cue-elicited cocaine craving

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • S.E. Hemby et al.

    Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat

    Psychopharmacology

    (1997)
  • R.I. Herning et al.

    The regulation of cerebral blood flow during intravenous cocaine administration in cocaine abusers

    Ann. N. Y. Acad. Sci.

    (1999)
  • Cited by (174)

    • Prefrontal Cortical (PFC) circuits

      2022, Neurocircuitry of Addiction
    View all citing articles on Scopus
    1

    Current address: Department of Psychology, Trinity College Dublin, Dublin 2, Ireland.

    View full text