Microinjections of the irreversible dopamine antagonist EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), into nucleus accumbens but not into dorsal striatum, markedly decreased response rates on a fixed interval schedule of reinforcement. These preferential effects in nucleus accumbens could be prevented by selectively activating either D1 or D2 receptors. These data demonstrate a critical role for mesolimbic dopamine systems in the mediation of fixed interval schedule-controlled operant behavior.