The control of fundamental cognitive operations of working memory has been suggested to require the regulation of dopamine (DA) in the prefrontal cortex (PFC) (Tanaka 2002: Neural Netw). The internal loop between the PFC and the midbrain DA nuclei (the cortico-mesocortical loop) can work as a regulator of DA release in the PFC with peculiar characteristics (Tanaka 2003: SFN Abstr; Yamashita and Tanaka 2003: Neurocomput). We studied how this DA regulator works during the processing of multi-target spatial working memory via computer simulation of our biological model and theoretical analysis of a simplified model. The simulation shows that the time course of the extracellular DA level in the PFC goes up and down during the processing, such as loading and maintenance, of multi-target spatial working memory. It suggests, however, that there is a window of the DA level in which multiple targets are successfully processed. Within this window, the optimum DA level is different for different tasks. The theoretica...