Neuropsychopharmacology (2016) 41, 2872–2881 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org The Effects of Pharmacological Opioid Blockade on Neural Measures of Drug Cue-Reactivity in Humans 1 2 ,1,2 Kelly E Courtney , Dara G Ghahremani and Lara A Ray* 1 2 Department of Psychology, University of California, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA Interactions between dopaminergic and opioidergic systems have been implicated in the reinforcing properties of drugs of abuse. The present study investigated the effects of opioid blockade, via naltrexone, on functional magnetic resonance imaging (fMRI) measures during methamphetamine cue-reactivity to elucidate the role of endogenous opioids in the neural systems underlying drug craving. To investigate = = = this question, non-treatment seeking individuals with methamphetamine use disorder (N 23; 74% male, mean age 34.70 (SD 8.95)) were recruited for a randomized, placebo controlled, within-subject design and underwent a visual methamphetamine cue-reactivity task during two blood-oxygen-level dependent (BOLD) fMRI sessions following 3 days of naltrexone (50 mg) and matched time for placebo. fMRI analyses tested naltrexone-induced differences in BOLD activation and functional connectivity during cue processing. The results showed that naltrexone administration reduced cue-reactivity in sensorimotor regions and related to altered functional connectivity of dorsal striatum, ventral tegmental area, and precuneus with frontal, visual, sensory, and motor-related regions. Naltrexone also weakened the associations between subjective craving and precuneus functional connectivity with sensorimotor regions and strengthened the associations between subjective craving and dorsal striatum and precuneus connectivity with frontal regions. In conclusion, this study provides the first evidence that opioidergic blockade alters neural responses to drug cues in humans with methamphetamine addiction and suggests that naltrexone may be reducing drug cue salience by decreasing the involvement of sensorimotor regions and by engaging greater frontal regulation over salience attribution. Neuropsychopharmacology (2016) 41, 2872–2881; doi:10.1038/npp.2016.99; published online 13 July 2016 INTRODUCTION the endogenous opioid and dopaminergic systems have been implicated in the development of sensitization to various The incentive salience model posits that addiction is largely drugs of abuse, including stimulants. For example, increased caused by progressive neuroadaptation that results in μ-opioid receptor binding in the frontal, temporal, anterior sensitization that follows repeated drug use. This sensitiza- cingulate, and amygdalar cortices, as evidenced by positron tion process is implicated to occur within the dopaminergic emission tomography, is associated with increased subjec- pathways that subserve attribution of motivational salience tive cocaine craving in cocaine-dependent men during to mental representations of stimuli and actions (eg, drug early withdrawal (Zubieta et al, 1996). Further, increases ingestion), thus rendering these stimuli highly salient and in preproenkephalin mRNA expression and decreases in ultimately ‘wanted’ or craved (Berridge and Robinson, 2003; μ-opioid receptor levels in the dorsal and ventral striatum Robinson and Berridge, 2001). Following sensitization of were observed in sensitized wild-type mice following 7 days these pathways, the expression of incentive salience (ie, of daily intraperitoneal injections (i.p.) of methamphet- craving) can be activated by the release of dopamine that is amine, while no changes were observed in μ-opioid receptor initiated in response to drug cues or priming doses of the knockout mice. These latter opioidergic changes were drug itself (de Wit, 1996). associated with altered dopaminergic function in the same Dopaminergic function within the striatum, particularly striatal regions (Tien et al, 2007) and highlight potential the dorsal striatum (Everitt and Robbins, 2005), is thought to mechanisms by which the two systems interact to result in be critically important for the development of incentive the experience of drug craving. salience or craving for drugs (Volkow et al, 2006; Vollstadt- Given the role of endogenous opioids in the neurobiology Klein et al, 2010); however, functional interactions between of addiction, it is crucial to establish how manipulation of the opioid system through opioidergic blockade may *Correspondence: Dr LA Ray, Department of Psychology, University of California, 1285 Franz Hall, Box 951563, Los Angeles, CA disrupt addiction-maintaining processes such as cue-induced 90095-1563, USA, Tel: +1 310 794 5383, Fax: +1 310 206 5895, craving. In order to provide an efficient blockade of opioid E-mail: [email protected] receptors, the present study used naltrexone, a clinically Received 20 December 2015; revised 15 May 2016; accepted 8 June relevant opioid receptor antagonist with greatest affinity for 2016; accepted article preview online 17 June 2016 the μ- and κ-opioid receptors in humans (Emmerson et al, Opioid blockade and cue-reactivity KE Courtney et al 2873 1994; Toll et al, 1998). The efficacy of naltrexone for response to methamphetamine administration (Ray et al, substance use disorders (eg, Miranda et al, 2014; Monti et al, 2015a) and the remaining eight participants were adminis- 1999; Ray et al, 2008; Syed and Keating, 2013), including tered the medication daily on an intensive outpatient basis. amphetamine (Itzhak and Ali, 2002; Jayaram-Lindstrom Abstinence from alcohol and substances (including metham- et al, 2008) and methamphetamine (Anggadiredja et al, 2004; phetamine) during the two, 3-day study periods was required Ray et al, 2015a) may be subserved by its attenuation of drug and verified daily by a Breathalyzer test (Dräger Medical craving. Naltrexone is thought to modulate reinforcement- Inc., Telford, PA) and urine toxicology screen. A washout driven behavior via blocking dopamine release in the meso- period of at least 7 days between medication conditions was limbic dopamine system, primarily acting on the pathway required for both inpatients and outpatients to reduce from the ventral tegmental area (VTA) to the ventral medication carry-over effects. There were no differences in striatum (ie, nucleus accumbens (NAcc)) (Benjamin et al, demographic variables across the inpatient and outpatient 1993; Lee et al, 2005); however, this theoretical pathway of subsamples used in the final analysis (independent t-tests or naltrexone’s effects on behavior has not been directly tested Fisher’s Exact Tests ps 40.05; see Supplementary Table S1) in human models of cue-induced craving. and all recruitment procedures and eligibility criteria were This study employed a novel methamphetamine cue- identical across the inpatient and outpatient subsamples. exposure paradigm for functional magnetic resonance imaging (fMRI) and functional connectivity analyses as tools Neuroimaging Procedures for probing naltrexone-induced modulation of the incentive salience system in a sample of individuals with metham- Neuroimaging data were acquired using a 3 Tesla Siemens phetamine use disorder. The primary aims of the present Trio MRI scanner at the UCLA Staglin Center for Cognitive study were to determine: (1) Whether naltrexone (50 mg) vs Neuroscience. The protocol began with initial structural placebo moderates blood-oxygen-level dependent (BOLD) scans: T2-weighted, high resolution, matched-bandwidth measures of methamphetamine cue processing (ie, cue- (MBW; TR, 5 s; TE, 34 ms; FOV, 192 mm; matrix, 128 × reactivity) and (2) whether naltrexone’s effect on metham- 128; sagittal plane; slice thickness, 4 mm; 34 slices) and a phetamine cue-reactivity is associated with differential magnetization-prepared rapid-acquisition gradient echo scan functional connectivity from the striatum and VTA (regions (MPRAGE; TR, 1.9 s; TE, 2.26 ms; FOV, 250 mm; matrix, subserving reinforcement-driven behavior) and the precu- 256 × 256; sagittal plane; slice thickness, 1 mm; 176 slices). neus (a region reliably shown to respond to drug cues; These were followed by two runs of the Methamphetamine Courtney et al, 2014a; Engelmann et al, 2012; Schacht et al, Cues Task (slice thickness, 4 mm; 34 slices; TR, 2 s; TE, 2013a) to other brain regions, primarily in the cortex, during 30 ms; flip angle, 90°; matrix, 64 × 64; FOV, 192 mm; voxel methamphetamine cue processing, as compared to placebo. size, 3 × 3 × 4mm3, 150 functional T2*-weighted EPIs) and a Exploratory aims were to test: (1) The effect of naltrexone pseudo-continuous arterial spin labeling scan (ASL; slice (50 mg) on cerebral blood flow (CBF) in this sample with thickness, 5 mm; TR, 4 s; TE, 22.62 ms; FOV, 220 mm; methamphetamine use disorder, as naltrexone-induced CBF matrix, 64 × 64, 30 slices). alterations have been observed in alcohol-dependent popu- The Methamphetamine Cues Task included four blocks of lations (Catafau et al, 1999) and represent a potential methamphetamine cue pictures and four blocks of control confound for the analyses of the BOLD fMRI signal, and (2) cue pictures, pseudo-randomly presented. Each block con- whether subjective reports of cue-induced methamphet- sisted of four pictures, presented for 5 s each, for a total of amine craving are related to neural markers of methamphet- 32 pictures from each condition.