Haloperidol modifies instrumental aspects of slot machine gambling in pathological gamblers and healthy controls.

Instrumental conditioning has been implicated in persistence at slot machine gambling, but its specific role remains unclear. Dopamine (DA) mediates aspects of instrumental responding, and D2 antagonists reliably alter this process. This study investigated the effects of the preferential D2 antagonist, haloperidol (3 mg) on reward-related betting behavior in 20 subjects with pathological gambling (PG) and 18 healthy controls. Hierarchical regression assessed the prospective relationship between Payoff and Bet Size on consecutive trials, along with potential moderating effects of Cumulative Winnings and Phase of game (early/late) under drug and placebo. Payoff predicted Bet Size on the next trial regardless of other factors, consistent with an instrumental view of slot machine gambling. Under placebo, this correlation varied as a function of Winnings and Phase in PG subjects but was strong and invariant in Controls. Under haloperidol, the Payoff-Bet Size correlation in PG subjects resembled the invariant pattern of Controls under placebo. In contrast, the Payoff-Bet Size correlation rose then fell sharply over trials under haloperidol in controls. The correlation of Payoff with Bet Size is remarkable given that there is no actual contingency between winning and betting, and suggests that reward expectancies largely drive slot machine gambling. By blocking inhibitory D2 receptors, haloperidol may have reversed 'tolerance' to monetary reward mediated by increased tonic DA in PG subjects. Disturbance of the Payoff-Bet Size correlation in controls may reflect indiscriminate reward signaling under haloperidol in subjects with normal DA function. Indirect enhancement of DA transmission may reduce undue reward-related responding in PG subjects.