Rationale Individuals learn associations between alcohol's sensory properties and intoxication, with such conditioned stimuli (CS) becoming involved in craving and relapse. However, these CS also carry idiosyncratic associations. Objectives This study aimed to test brain responses to novel CS conditioned with alcohol intoxication. Methods Fourteen heavy drinkers (age 24.9±3.2) performed a reaction time task with embedded novel geometric CS and were told only that the task was to measure alcohol's effect on speed. Rapid intravenous alcohol infusion (the unconditioned stimulus; UCS) began with the appearance of a CS+, using pharmacokinetic modeling to increment breath alcohol by ∼18 mg% in 200 s per each of six CS-UCS pairings. Placebo-saline infusion with CS-used the same infusion parameters in same-day randomized/counterbalanced sessions. The next morning subjects, connected to inactive intravenous pumps, underwent functional magnetic resonance imaging (fMRI) of the same task with mixed brief presentations of CS+, CS-, and irrelevant CS and were told that alcohol could be infused at any time during imaging. Results CS-responses were significantly greater than those of CS+ in medial frontal cortex. Notably, CS+ responses were negative, suggesting reduced neural activity. Negative activity was most pronounced in early scans, extinguishing with time. As subjects were told that alcohol could be administered in fMRI, a CS+ without alcohol is similar to a negative prediction error, with associated reduced frontal activity during withheld reward. Conclusions Novel stimuli relatively free of demand characteristics can be classically conditioned to intermittent brain exposure of even low alcohol concentrations, permitting imaging studies of conditioned alcohol expectancies.
- Classical conditioning
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