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The Journal of Neuroscience, July 2, 2003, 23(13):5674-5683
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Opioid Receptor Antagonism and Prodynorphin Gene Disruption Block Stress-Induced Behavioral Responses
Jay P. McLaughlin,
Monica Marton-Popovici, and
Charles Chavkin
Department of Pharmacology, University of Washington, Seattle, Washington
98195-7280
Previous studies have demonstrated that stress may increase prodynorphin
gene expression, and opioid agonists suppress drug reward. Therefore,
we tested the hypothesis that stress-induced release of endogenous dynorphin
may mediate behavioral responses to stress and oppose the rewarding effects of
cocaine. C57Bl/6 mice subjected to repeated forced swim testing (FST) using a
modified Porsolt procedure at 30°C showed a characteristic stress-induced
immobility response and a stress-induced analgesia observed with a tail
withdrawal latency assay. Pretreatment with the opioid receptor
antagonist nor-binaltorphimine (nor-BNI; 10 mg/kg, i.p.) blocked the
stress-induced analgesia and significantly reduced the stress-induced
immobility. The nor-BNI sensitivity of the behavioral responses suggests an
activation of the opioid receptor by a stress-induced release of
dynorphin peptides. Supporting this hypothesis, transgenic mice possessing a
disrupted prodynorphin gene showed no increase in immobility or stress-induced
analgesia after exposure to repeated FST. Because both stress and the
opioid system can modulate the response to drugs of abuse, we tested the
effects of forced swim stress on cocaine-conditioned place preference (CPP).
FST-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant
potentiation of place preference for the drug-paired chamber over the
responses of unstressed mice. Surprisingly, nor-BNI pretreatment blocked
stress-induced potentiation of cocaine CPP. Consistent with this result, mice
lacking the prodynorphin gene did not show a stress-induced potentiation of
cocaine CPP, whereas wild-type littermates did. The findings suggest that
chronic swim stress may activate the opioid system to produce
analgesia, immobility, and potentiation of the acute rewarding properties of
cocaine in C57Bl/6 mice.
Key words: ; opioid; dynorphin; stress; depression; cocaine; conditioned place preference
Received Jan. 27, 2003;
revised May. 5, 2003;
accepted May. 5, 2003.
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