Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects

Objective: Abnormalities in dopamine neurotransmission in the prefrontal co rtex have been implicated in the pathophysiology of schizophrenia. However, the integrity of the dopamine projections to the prefrontal cortex in this disorder has not been directly examined. Method: The authors employed immu nocytochemical methods and antibodies against tyrosine hydroxylase, the rat e-limiting enzyme in dopamine biosynthesis, and the dopamine membrane trans porter to examine dopamine axons in the dorsomedial prefrontal cortex (area 9) from 16 pairs of schizophrenic and matched control subjects. Results: C ompared to the control subjects, the total length of tyrosine hydroxylase-i mmunoreactive axons was unchanged in the superficial and middle layers of t he schizophrenic subjects but was reduced by an average of 33.6% in layer 6 . The total length of tyrosine hydroxylase-positive axons in layer 6 was de creased in 13 of the schizophrenic subjects compared to their control subje cts. Axons immunoreactive for the dopamine membrane transporter showed a si milar pattern of change. In contrast, axons labeled for the serotonin trans porter did not differ between schizophrenic and control subjects in any lay er examined. In addition, the density of tyrosine hydroxylase-containing ax ons did not differ between monkeys chronically treated with haloperidol and matched control animals. Conclusions: These findings reveal that schizophr enia is associated with an altered dopamine innervation of prefrontal corte x area 9 that is lamina- and neurotransmitter-specific and that does not ap pear to be a consequence of pharmacological treatment. Together, these data provide direct evidence for a disturbance in dopamine neurotransmission in the prefrontal cortex of schizophrenic subjects.