Background:  The purpose of the present investigation was to more clearly define blood‐alcohol parameters associated with alcohol dependence produced by alcohol vapor inhalation and alcohol‐containing liquid diet.

Methods:  Alcohol levels in blood and brain were compared during and after 4 hours of acute alcohol vapor exposure; also, brain‐alcohol levels were assessed in alcohol‐exposed (14‐day alcohol vapor) and alcohol‐naïve rats during and after 4 hours of acute alcohol vapor exposure. A separate group of rats were implanted with i.v. catheters, made dependent on alcohol via vapor inhalation, and tested for operant alcohol responding; blood‐alcohol levels (BALs) were measured throughout operant alcohol drinking sessions during alcohol withdrawal. A final group of rats consumed an alcohol‐liquid diet until they were dependent, and those rats were then tested for operant behavior at various withdrawal time points; BALs were measured at different withdrawal time points and after operant sessions.

Results:  Blood‐ and brain‐alcohol levels responded similarly to vapor, but brain‐alcohol levels peaked at a higher point and more slowly returned to zero in alcohol‐naïve rats relative to alcohol‐exposed rats. Alcohol vapor exposure also produced an upward shift in subsequent operant alcohol responding and resultant BALs. Rats consumed large quantities of alcohol‐liquid diet, most of it during the dark cycle, sufficient to produce high blood‐alcohol levels and elevated operant alcohol responding when tested during withdrawal from liquid diet.

Conclusions:  These results emphasize that the key determinants of excessive alcohol drinking behavior are the BAL range and pattern of chronic high‐dose alcohol exposure.