This study was carried out to test the hypothesis that neuroleptic-induced within-session response decrements reflect a fatigue process, resulting from dopamine depletion, that is present before the session begins but is masked briefly by activational cues present at the start of the session. Response decrementing effects of pimozide were examined in rats lever pressing on random interval schedules of food reinforcement. An initial experiment was carried out to rule out a pharmacokinetic explanation of the response decrement. In a second experiment, the response decrement was not exacerbated by an immediately preceding period of intense forced motor activity (wheel running). Experiments 3 and 4 tested two further predictions: that the pimozide-induced response decrement should be overcome by removing the animal to its home cage and then replacing it in the apparatus (thereby reinstating the activational cues present at the start of the session); and that response impairments should be present from the outset if the animal is confined in the apparatus prior to the start of the session (thereby allowing activational cues to dissipate). Neither prediction was confirmed. Overall, the results provide no support for the dopamine depletion hypothesis.