Conditioned increases in anxiogenic-like behavior following exposure to contextual stimuli associated with cocaine are mediated by corticotropin-releasing factor.
Although cocaine is a powerful reinforcer, it has been reported to produce anxiety in humans and anxiogenic-like behavior in animals. The goal of this study was three-fold: (1) to determine the doses of cocaine that induce anxiogenic-like behavior in the elevated plus-maze in rats, (2) to determine if cocaine-associated contextual cues are capable of eliciting anxiogenic-like behavior in the absence of the drug, and (3) to identify possible mechanisms through which cocaine-associated cues affect behavior in the elevated plus-maze. Measurement of the amount of time that the animals spend exploring the open arms of the maze provides a sensitive index of anxiogenic-like behavior in rats. In experiment 1, rats were injected with 10 mg/kg, 20 mg/kg, or 30 mg/kg cocaine HCl or saline for 6 days. On day 6, the rats were tested in the elevated plus-maze 25 min after injection with cocaine or saline. The animals chronically treated with the three doses of cocaine exhibited a dose-dependent increase in anxiogenic-like behavior in the elevated plus-maze, compared to the saline-treated group. In experiment 2, cocaine-induced (30 mg/kg) conditioning was achieved using a simple contextual design. On the final day of the experiment (day 6), after 5 days of conditioning, the rats were exposed for 25 min to the cocaine-associated contextual cues, then placed in the elevated plus-maze. Animals that had been exposed to cocaine-associated contextual cues prior to being placed in the elevated plus-maze exhibited a significant increase in anxiogenic-like behavior compared to the control groups. However, pretreatment of the rats with the CRF antagonist, alpha-helical CRF9-41 (1 microg, i.c.v.), on the test day, prior to exposure to cocaine-associated contextual cues, attenuated the subsequent anxiogenic-like behavioral response in the elevated plus-maze (experiment 3). The results suggest that contextual cues associated with repeated treatment with 30 mg/kg cocaine are capable of eliciting anxiogenic-like behavior in the absence of the drug and that CRF mediates the expression of anxiogenic-like behaviors in the elevated plus-maze following exposure to cocaine-associated cues. The conditioned anxiogenic action elicited by cocaine-associated cues may have relevance for understanding the complex addictive nature of this drug and some of the clinical phenomena related to its use.
DeVries
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Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.
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D000818:Animals; D001007:Anxiety / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009294:Narcotics; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine