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The Journal of Neuroscience, December 15, 2000, 20(24):9333-9340
 -Opioid Receptor Activation Modifies Dopamine Uptake in the
Nucleus Accumbens and Opposes the Effects of Cocaine
Alexis C.
Thompson1,
Agustin
Zapata1,
Joseph B.
Justice Jr2,
Roxanne A.
Vaughan3,
Lawrence G.
Sharpe1, and
Toni S.
Shippenberg1
1 Behavioral Neuroscience Branch, National Institute on
Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, 2 Department of Chemistry, Emory University, Atlanta,
Georgia 30322, and 3 Department of Biochemistry and
Molecular Biology, University of North Dakota, School of Medicine and
Health Sciences, Grand Forks, North Dakota 58202
Coadministration of  -opioid receptor agonists (-agonists)
with cocaine prevents alterations in dialysate dopamine (DA)
concentration in the nucleus accumbens (Acb) that occur during
abstinence from repeated cocaine treatment. Quantitative microdialysis
was used to determine the mechanism producing these effects. Rats were injected with cocaine (20 mg/kg, i.p.), or saline, and the selective -agonist U-69593 (0.32 mg/kg, s.c.), or vehicle, once daily for 5 d. Extracellular DA concentration
(DAext) and extraction fraction (Ed), an indirect measure of DA
uptake, were determined 3 d later. Repeated cocaine treatment
increased Ed, whereas repeated
U-69593 treatment decreased Ed,
relative to controls. Coadministration of both drugs yielded
intermediate Ed values not different from controls. In vitro DA uptake assays confirmed that
repeated U-69593 treatment produces a dose-related, region-specific
decrease in DA uptake and showed that acute U-69593 administration
increases DA uptake in a nor-binaltorphimine reversible manner.
Repeated U-69593 also led to a decrease in
[125I]RTI-55 binding to the DA transporter (DAT),
but did not decrease total DAT protein. These results demonstrate that
-opioid receptor activation modulates DA uptake in the Acb in a
manner opposite to that of cocaine: repeated U-69593 administration
decreases the basal rate of DA uptake, and acute U-69593 administration transiently increases DA uptake. -agonist treatment also
alters DAT function. The action of -agonists on DA uptake or DAT
binding, or both, may be the mechanism(s) mediating the previously
reported "cocaine-antagonist" effect of -opioid receptor agonists.
Key words:
-opioid receptors; dopamine; dopamine uptake; cocaine; nucleus accumbens; striatum; quantitative microdialysis; rotating disk
electrode voltammetry; autoradiography; Western blot; rats
Copyright © 2000 Society for Neuroscience 0270-6474/00/20249333-08$05.00/0
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