Background
Psychostimulants and opiates trigger similar enduring neuroadaptations within the
reward circuitry thought to underlie addiction. Transcription factors are key to mediating
these enduring behavioral alterations. The facilitation of these maladaptive changes
by glucocorticoid hormones suggests that the glucocorticoid receptor (GR), a transcription
factor involved in the stress response, could be a common mediator of responses to
pharmacologically distinct classes of abused drugs.
Methods
We employed mouse models carrying GR gene inactivation in either dopamine or dopaminoceptive neurons to determine the
involvement of this transcription factor in behavioral responses to cocaine and morphine.
We then combined microarray analysis, drug-elicited immediate early gene induction,
and in vivo microdialysis to elucidate the molecular underpinnings of these responses.
Results
Inactivating GR within dopaminoceptive neurons markedly reduces cocaine-induced conditioned place
preference and the expression of locomotor sensitization. In striking contrast, GR
had no effect on behavioral morphine responses in either dopaminoceptive or dopamine
neurons. The dopaminoceptive mutation engenders alterations in the expression of striatal
genes that are implicated in glutamatergic transmission and plasticity. Within the
nucleus accumbens, impaired cellular responses to cocaine are conspicuous; a pronounced
deficit in cocaine-elicited extracellular dopamine release, expression of the key
IEGs c-Fos and Zif268, and phosphorylation of extracellular signal-regulated kinases 1/2 in mutants were
observed. In contrast, these molecular and neurochemical changes were not observed
in response to morphine, mirroring the lack of effect on behavioral responses to morphine.
Conclusion
Combined behavioral and molecular approaches have identified a subset of neurons in
which GR differentially influences cocaine- and morphine-induced responses.
Key Words
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Article info
Publication history
Published online: June 16, 2010
Accepted:
March 31,
2010
Received in revised form:
March 29,
2010
Received:
December 17,
2009
Footnotes
Authors JB and SP contributed equally to this work.
Identification
Copyright
© 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
