Methamphetamine, a psychostimulant drug, acts on dopaminergic neuron terminals projecting from the ventral tegmental area to the nucleus accumbens, which constitutes the reward system in the brain. In addition to dependence triggered by excessive excitation of the reward system, methamphetamine induces various effects, including hallucinations, delusions, and cognitive dysfunction. This means that molecules responsive to methamphetamine are importantly involved in the brain function. This report reviews the functions of Shati/Nat8l and Piccolo, identified as methamphetamine-responsive molecules in the murine nucleus accumbens, in cognitive and psychiatric functions clarified by rodent studies. Shati/Nat8l is related to drug addiction and depression and participates in the synaptic function of the hippocampus to maintain cognitive function. Its upregulation suppresses cognitive disturbance in Alzheimer's disease pathology. In the nucleus accumbens, Piccolo contributes to the behavioral alteration caused by methamphetamine. Piccolo downregulation in the prefrontal cortex induced schizophrenia-like behavioral and neuronal changes in mice. These findings indicate that Shati/Nat8l and Piccolo exert important functions on the brain and are potential targets for brain disorder studies. It is anticipated that understanding of brain function will be achieved through the analysis of methamphetamine-responsive molecules.