Background
Alcoholism is a complex behavioral disorder in which interactions between stressful
life events and heritable susceptibility factors contribute to the initiation and
progression of disease. Neural substrates of these interactions remain largely unknown.
Here, we examined the role of the nociceptin/orphanin FQ (N/OFQ) system, with an animal
model in which genetic selection for high alcohol preference has led to co-segregation
of elevated behavioral sensitivity to stress (Marchigian Sardinian alcohol-preferring
[msP]).
Methods
The msP and Wistar rats trained to self-administer alcohol received central injections
of N/OFQ. In situ hybridization and receptor binding assays were also performed to
evaluate N/OFQ receptor (NOP) function in naïve msP and Wistar rats.
Results
Intracerebroventricular (ICV) injection of N/OFQ significantly inhibited alcohol self-administration
in msP but not in nonselected Wistar rats. The NOP receptor messenger RNA expression
and binding was upregulated across most brain regions in msP compared with Wistar
rats. However, in msP rats [35S]GTPγS binding revealed a selective impairment of NOP receptor signaling in the central
amygdala (CeA). Ethanol self-administration in msP rats was suppressed after N/OFQ
microinjection into the CeA but not into the bed nucleus of the stria terminalis or
the basolateral amygdala.
Conclusions
These findings indicate that dysregulation of N/OFQ-NOP receptor signaling in the
CeA contributes to excessive alcohol intake in msP rats and that this phenotype can
be rescued by local administration of pharmacological doses of exogenous N/OFQ. Data
are interpreted on the basis of the anti–corticotropin releasing factor (CRF) actions
of N/OFQ and the significance of the CRF system in promoting excessive alcohol drinking
in msP rats.
Key Words
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Article info
Publication history
Published online: March 27, 2008
Accepted:
February 5,
2008
Received in revised form:
February 4,
2008
Received:
October 23,
2007
Footnotes
The authors RC and MH contributed equally.
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
