Several lines of evidence have pointed to a role of the dopamine system in the pathophysiology of schizophrenia. A recent postmortem study demonstrated a selective decrease of tyrosine hydroxylase fibers on pyramidal neurons in sector CA2 in the hippocampus of schizophrenics. Although both brain imaging and postmortem studies have examined the distribution of the D1 receptor in the prefrontal and cingulate cortex, no study to date has examined its expression of mRNA using a high-resolution autoradiographic approach. In order to further assess whether the regulation of the dopamine D1 receptor is altered in hippocampal neurons in this disorder, we used in situ hybridization (ISH) to measure the expression of messenger RNA for this receptor in the dentate gyrus and sectors CA1-4. Both the number of cells expressing D1 mRNA and the amount of expression per cell were measured in 15 schizophrenic, 15 bipolar disorder, and 15 normal control subjects. The results show a significant (21%) and selective decrease in D1 mRNA expression in sector CA3 of schizophrenic subjects. First-degree relatives of schizophrenics did not show any differences in either the expression of D1 mRNA per cell or the number of cells expressing this mRNA when compared to a separate group of normal controls matched for age and PMI. Subjects with bipolar disorder also showed a significant (25%) and selective increase of D1 mRNA expression in sector CA2. Other hippocampal sectors did not show significant changes. These findings in schizophrenics and bipolars were also associated with inverse changes in the overall number of neurons expressing D1 mRNA in sectors CA3 and CA2, respectively. This study shows diagnosis-specific changes in D1 mRNA expression in the hippocampus of schizophrenic versus bipolar subjects and suggests that this neuromodulatory system may show distinct changes in the pathophysiology of the two disorders.