Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine
Abstract
OBJECTIVE: Dopamine is an important mediator of the reinforcing effects of cocaine, and alterations in dopamine function might be involved in cocaine dependence. The goals of the present study were to characterize pre- and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Specifically, dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). Furthermore, the relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated. METHOD: Twenty-four cocaine-dependent participants and 24 matched healthy subjects underwent [(11)C]raclopride scans under a baseline condition and following intravenous amphetamine administration (0.3 mg/kg). Cocaine-dependent participants also completed cocaine self-administration sessions in which a priming dose of cocaine was followed by the choice to either self-administer subsequent cocaine doses or receive a monetary reward. RESULTS: Cocaine dependence was associated with a marked reduction in amphetamine-induced dopamine release in each of the functional subregions of the striatum (limbic striatum: -1.2% in cocaine-dependent participants versus -12.4% in healthy subjects; associative striatum: -2.6% versus -6.7%, respectively; sensorimotor striatum: -4.3% versus -14.1%). Blunted dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for cocaine over money. CONCLUSIONS: Cocaine dependence is associated with impairment of dopamine function, and this impairment appears to play a critical role in relapse.
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Withdrawal involves decreased dopaminergic and serotonergic transmission in the nucleus accumbens, with striatal dopamine responses 50% lower in detoxified abusers and 80% lower in active abusers, and lower self-reported drug reward versus controls.
“Such changes include decreases in dopaminergic and serotonergic transmission in the nucleus accumbens during drug withdrawal as measured by in-vivo microdialysis in rats69 and brain imaging studies in humans, in which amphetamine-induced or methylphenidate-induced striatal dopamine responses are 50% lower in detoxified abusers and 80% lower in active abusers, and accompanied by lower self-reports”
From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [25]
In a cocaine choice study, low dopamine release in the ventral striatum predicted choosing cocaine over money despite the money being weighted favorably.
“The results showed that low dopamine release in the ventral striatum was predictive of the choice for cocaine over money, despite the weighting towards the money.”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as Martinez et al., 2007
In cocaine abuse, low presynaptic dopamine release in the ventral striatum is associated with the choice to self-administer cocaine.
“In cocaine abuse, low pre-synaptic dopamine release in the ventral striatum is associated with the choice to self-administer cocaine (Martinez et al., 2007).”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as Martinez et al., 2007
Cocaine-abusing subjects with blunted dopamine release chose an immediate smaller reward over a larger delayed reward when offered money or self-administered cocaine.
“when presented with the choice to obtain money or self-administer cocaine, cocaine-abusing subjects with blunted dopamine release chose the immediate, but smaller reward over the larger but delayed reward (Martinez et al., 2007).”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as Martinez et al., 2007
Brain imaging studies comparing DA increases induced by methylphenidate or amphetamine between cocaine addicted subjects and controls showed a marked attenuation of MP- or AMP-induced DA increases in striatum, 50% lower in detoxified abusers and 80% in active abusers, and lower self-reports of the drug's rewarding effects relative to non-drug-abusing controls.
“Brain imaging studies that compare the DA increases induced by the stimulant drug methylphenidate (MP) or of amphetamine (AMP) between cocaine addicted subjects and controls showed a marked attenuation of MP or AMP induced DA increases in striatum (50% lower in detoxified abusers and 80% in active abusers) and lower self-reports of the drug's rewarding effects relative to non-drug-abusing controls”
From Food and Drug Reward: Overlapping Circuits in Human Obesity and Addiction (2011) · cites this paper as Martinez et al 2007
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References 36 · Cited by 351
- Authors
- Martinez, D., Narendran, R., Foltin, R. W., Slifstein, M., Hwang, D.-R., Broft, A., Huang, Y., Cooper, T. B., Fischman, M. W., Kleber, H. D., & Laruelle, M.
- Venue
- American Journal of Psychiatry
- Published
- 2007-04
- Volume
- 164
- Issue
- 4
- Pages
- 622-629
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2122284725
- Cited by
- 351
- References
- 36
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 9 · 2023: 17 · 2022: 10 · 2021: 12 · 2020: 12 · 2019: 10 · 2018: 12 · 2017: 18 · 2016: 19 · 2015: 18 · 2014: 37 · 2013: 44 · 2012: 32
- FWCI
- 8.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01da010219-06)
- National Institute of Mental Health (1K02 MH01603-01, K02MH001603, T32MH015144)
- National Institute on Drug Abuse (K23DA000483, 2-R01-DA10219, K23 DA00483)
- National Center for Research Resources (M01RR000645, M01 RR00645)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- cocaine dependence, dopamine release, amphetamine challenge, striatum, ventral striatum, caudate nucleus, cocaine self-administration, relapse, drug reward, cocaine detoxification, [11C]raclopride PET
- MeSH terms
- Adult, Amphetamine, Basal Ganglia, Carbon Radioisotopes, Choice Behavior, Cocaine, Dopamine, Female, Humans, Limbic System, Male, Reinforcement, Psychology, Self Administration, Cocaine-Related Disorders, Raclopride, Positron-Emission Tomography
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