Drug and behavioral addictions have overlapping features, e.g., both manifest preference for larger, albeit costlier, reinforcement options in cost/benefit decision-making tasks. Our prior work revealed that the mixed-function serotonergic compound, mirtazapine, attenuates behaviors by rats motivated by abused drugs. To extend this work to behavioral addictions, here we determined if mirtazapine and/or ketanserin, another mixed-function serotonin-acting compound, can alter decision-making in rats that is independent of drug (or food)-motivated reward. Accordingly, we developed a novel variable-ratio task in rats wherein intracranial self-stimulation was used as the positive reinforcer. Using lever pressing for various levels of brain stimulation, the operant task provided choices between a small brain stimulation current delivered on a fixed-ratio schedule (i.e., a predictable reward) and a large brain stimulation delivered following an unpredictable number of responses (i.e., a variable-ratio schedule). This task allowed for demonstration of individualized preference and detection of shifts in motivational influences during a pharmacological treatment. Once baseline preference was established, we determined that pretreatment with mirtazapine or ketanserin significantly decreased preference for the large reinforcer presented after gambling-like schedules of reinforcement. When the rats were tested the next day without drug, preference for the unpredictable large reinforcer option was restored. These data demonstrate that mirtazapine and ketanserin can reduce preference for larger, costlier reinforcement options, and illustrate the potential for these drugs to alter behavior.