Increased Consumption but Not Operant Self-administration of Ethanol in Mice Lacking the RIIβ Subunit of Protein Kinase A

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Accumulating evidence indicates that adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) is involved in the neurobiological responses to ethanol. Previous reports indicate that mice lacking the RIIβ subunit of PKA (RIIβ−/−) voluntarily consume more ethanol than wild-type controls (RIIβ+/+) using 2-bottle testing procedures. Although such procedures primarily measure consummatory behavior, operant self-administration procedures allow analysis of consummatory as well as appetitive or “ethanol-seeking” behavior (i.e., lever pressing is required to gain access to the ethanol solution). Therefore, we determined whether the high ethanol consumption characteristic of RIIβ−/− mice would be complemented by increased appetitive ethanol-seeking behavior in an operant paradigm.


RIIβ−/− (n=8) and RIIβ+/+ (n=8) mice were initially sucrose-faded until they were lever responding for nonsweetened ethanol (10, 14, and 18%). Following the self-administration testing, RIIβ+/+ and RIIβ−/− mice were given access to 2 bottles, one containing water and the other ethanol to replicate the voluntary ethanol drinking data previously from our laboratory. Finally, immediately after voluntary consumption all mice were again tested for self-administration of 10% ethanol. Alterations in the reinforcement schedule were also explored as RIIβ+/+ and RIIβ−/− mice were tested for self-administration of 10% ethanol at FR-3 and FR-5 schedules.


The RIIβ−/− mice displayed lower operant responding for ethanol and food reinforcement compared with RIIβ+/+ controls. However, this effect was driven by a significant increase in lever responses made by female RIIβ+/+ mice. When the excessive lever responses of the female RIIβ+/+ mice are accounted for, the RIIβ−/− mice show ethanol lever responses comparable to controls. Following operant self-administration testing, RIIβ−/− mice of both sexes consumed more ethanol solution compared with RIIβ+/+ mice during 2-bottle testing.


Increased ingestion of ethanol by RIIβ−/− mice is likely the result of altered PKA activity within neuronal pathways that control ethanol-consummatory behaviors. Conversely, the RIIβ subunit of PKA appears not to play a critical role in neuronal pathways that regulate appetitive behaviors directed at obtaining ethanol. Finally, increased operant self-administration of food and ethanol by female wild-type mice was absent in female RIIβ−/− mice, suggesting that normal PKA signaling may be part of a general, and sex-dependent, mechanism involved with reinforcement-seeking behavior.

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