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Volume 17, Number 21,
Issue of November 1, 1997
pp. 8225-8233
Copyright ©1997 Society for Neuroscience
 2 Opioid Receptors in Limbic Areas of the Human
Brain Are Upregulated by Cocaine in Fatal Overdose Victims
Received April 1, 1997; revised Aug. 5, 1997; accepted Aug. 11, 1997.
Julie K. Staley1,
Richard B. Rothman2,
Kenner
C. Rice3,
John Partilla2, and
Deborah C. Mash1
1 Department of Neurology and Molecular and Cellular
Pharmacology and The Comprehensive Drug Research Center, University of
Miami School of Medicine, Miami, Florida 33101, 2 Clinical
Psychopharmacology Section, Division of Intramural Research, National
Institute on Drug Abuse, National Institutes of Health, Addiction
Research Center, Baltimore, Maryland 21224, and
3 Laboratory of Medicinal Chemistry, National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, Maryland 20892
Cocaine is thought to be addictive because chronic use leads
to molecular adaptations within the mesolimbic dopamine (DA) circuitry
that affect motivated behavior and emotion. Although the reinforcing
effects of cocaine are mediated primarily by blocking DA reuptake into
the presynaptic nerve terminal, reciprocal signaling between DA and
endogenous opioids has important implications for cocaine dependence.
The present study used the opioid antagonist 6  -[125iodo]-3,14-dihydroxy-17-cyclopropylmethyl-4,5
 -epoxymorphinan ([125I]IOXY) after pretreatment
with the site-directed acylating agents 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimidiazole-HCl (µ-selective) and
N-phenyl-N-[1-(2-(4-isothiocyanato)-phenethyl)-4-piperidinyl]-propanamide-HCl ( -selective) to examine the effect of cocaine exposure on the distribution and density of  2 receptors in autopsy
studies of human cocaine fatalities. The selective labeling of the
2 receptor subtype was demonstrated by competition
binding studies, which gave a pharmacological signature (IOXY  (+)-bremazocine  U50,488 U69,593) distinct from either the
1 or 3 receptor subtypes. Visualization
of [125I]IOXY labeling revealed that
2 receptors localize to mesocortical and subcortical
limbic areas, including the cingulate, entorhinal, insular, and
orbitofrontal cortices and the nucleus accumbens and amygdala. The
number of 2 receptors in the nucleus accumbens and other
limbic brain regions from cocaine fatalities was increased twofold as
compared with age-matched and drug-free control subjects. Cocaine
overdose victims, who experienced paranoia and marked agitation before
death, also had elevated densities of 2 receptors in the
amygdala. These findings demonstrate for the first time that
2 receptor numbers are upregulated by cocaine exposure. The molecular adaptation of 2 receptor numbers may play
a role in the motivational incentive associated with episodes of binge cocaine use and in the dysphoria that follows abrupt cocaine
withdrawal.
Key words:
cocaine;
human brain;
opioid receptor;
IOXY;
delirium;
dopamine
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