The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats.
OBJECTIVE
Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF1) receptor antagonist antalarmin.


METHODS
In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin's effect on yohimbine-induced reinstatement of alcohol seeking.


RESULTS
Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats.


CONCLUSIONS
These results suggest that extrahypothalamic CRF1 receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF1 receptor antagonists should be considered in alcohol addiction treatment.
Marinelli
Peter W
PW
Department of Neuroscience, Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada. peter_marinelli@camh.net
Funk
Douglas
D
Juzytsch
Walter
W
Harding
Stephen
S
Rice
Kenner C
KC
Shaham
Yavin
Y
Lê
A D
AD
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000437:Alcoholism / Q000517:prevention & control* / Q000523:psychology; D000818:Animals; D016739:Behavior, Addictive / Q000517:prevention & control*; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012646:Self Administration; D015016:Yohimbine / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
D000317:Adrenergic alpha-Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D015016:Yohimbine; D000431:Ethanol; D000099052:CRF Receptor, Type 1
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