Habituation and sensitization of acoustic startle: Opposite influences of dopamine D1 and D2-family receptors

The startle response evoked by repeated presentation of a loud acoustic stimulus is regulated by the independent processes of sensitization and habituation. While schizophrenia is associated with information processing impairments, there is conflicting evidence regarding the existence of habituation deficits in schizophrenic patients. Recent clinical evidence, however, indicates that patients with schizophrenia display exaggerated startle sensitization and diminished habituation. Given the linkage between dopaminergic abnormalities and schizophrenia, the goal of the present investigation was to examine the effect of deleting D1 and D2-like dopamine receptors on sensitization and habituation of the acoustic startle reflex in mice. For these experiments, the acoustic startle reflex was assessed in dopamine D1, D2, and D3 receptor wild-type (WT) and knockout (KO) mice on a C57BL/6J background, using a methodology that can measure both sensitization and habituation. Mice lacking the D1 receptor gene displayed enhanced sensitization, along with a decrease in the amount of habituation that occurs in response to repetitive presentations of a startling stimulus. Conversely, the loss of the dopamine D2 or D3 receptor gene produced a sensitization deficit and a significant increase in habituation. The behavioral phenotype exhibited by D1 receptor KO mice is clearly distinct from that of the D2 and D3 receptor KO mice. The findings in D1 receptor KO mice are reminiscent of the abnormalities observed in schizophrenic patients tested in comparable startle paradigms, and indicate that D1 agonists may possess therapeutic efficacy against the information processing deficits associated with schizophrenia.