Prepulse inhibition (PPI) refers to the attenuation of the amplitude of the startle reflex in response to sudden intense stimuli (pulse) if preceded by a weaker sensory stimulus (prepulse). PPI reflects sensorimotor gating i.e. the ability to filter out irrelevant information in the early stages of processing so that attention can be directed to more salient environmental features. Recent neuropsychological studies show greater PPI in healthy individuals with superior performance on tasks that rely on the integrity and efficiency of prefrontal cortical (PFC) function. The PFC is an important node in the cortico-striato-pallido-thalamic circuitry, which modulates PPI. PFC function has been examined in relation to the COMT Val158Met polymorphism, which determines basal PFC dopamine (DA) neurotransmission levels and consequently, performance on PFC DA-dependent cognitive tasks. Met/Met individuals have the best PFC performance or greater “efficiency” and the highest PPI, Val/Val the worst performance and the lowest PPI, and Val/Met intermediate performance and PPI. Consistent with the increasingly accepted model of an inverted U-shape relationship between PFC DA levels and PFC function, the COMT inhibitor tolcapone as well as attention-to-prepulse, increase PPI in Val/Val individuals, while Met/Met individuals are unaffected or get worse. These findings strongly suggest that inhibition at the early stage of information processing is modulated by the PFC DA activity in a “top-down” fashion and this may account for the normal inter-individual variability in PPI and in cognitive performance.