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Journal of Neuroscience, Vol 14, 2966-2979, Copyright © 1994 by Society for Neuroscience
Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self- administration
JM Wilson, JN Nobrega, ME Carroll, HB Niznik, K Shannak, ST Lac, ZB Pristupa, LM Dixon and SJ Kish
Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, Toronto, Canada.
We examined the influence of chronic cocaine exposure, in an unlimited
access self-administration paradigm, on density of the dopamine transporter
(3H-WIN 35,428 and 3H-GBR 12,935 binding) and concentration of monoamine
(dopamine, serotonin, noradrenaline and metabolites) neurotransmitters in
rat brain. In normal rodent striatum 3H-WIN 35,428 and 3H-GBR 12,935
binding to the dopamine transporter, although generally similar, showed
different subregional rostrocaudal and mediolateral gradients, suggesting
that the two ligands might bind to different subtypes or states of the
dopamine transporter. Following chronic, unlimited access cocaine
self-administration, binding of 3H- WIN 35,428 was significantly elevated
in whole nucleus accumbens (+69%, p < 0.001) and striatum (+65%, p <
0.001) on the last day of cocaine exposure ("on-cocaine group"); whereas in
the 3 week withdrawn animals ("cocaine-withdrawn group"), levels were
either normal (striatum) or reduced (-30%, p < 0.05, nucleus accumbens).
Although similar changes in 3H-GBR 12,935 binding were observed, this
dopamine transporter ligand showed a smaller and highly subregionally
dependent increase in binding in striatal subdivision of the on-cocaine
group, but a more marked binding reduction in the cocaine-withdrawn
animals. As compared with the controls, mean dopamine levels were reduced
in striatum (-15%, p < 0.05) of the on-cocaine group and in nucleus
accumbens (-40%, p < 0.05) of the cocaine-withdrawn group. These data
provide additional support to the hypothesis that some of the long-term
effects of cocaine exposure (drug craving, depression) could be consequent
to reduced nucleus accumbens dopamine function. Our data also suggest that
dopamine transporter concentration, and perhaps function, might undergo up-
or downregulation, either as a direct effect of cocaine, or indirectly as
part of a homeostatic response to altered synaptic dopamine levels, and
therefore might participate in the neuronal events underlying
cocaine-induced behavioral changes.
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