Haloperidol treatment downregulates DCC expression in the ventral tegmental area

A core feature in the pathophysiology of schizophrenia is abnormal development and function of mesocorticolimbic dopamine (DA) circuitry. We have previously shown that variations in the function of the netrin-1 receptor, deleted in colorectal cancer (DCC), result in changes to the development, organization and ongoing plasticity of DA circuitry. In rodents, repeated exposure to the indirect DA-agonist, amphetamine upregulates DCC expression in the ventral tegmental area (VTA), but not in DA terminal regions. This elevation in DCC expression is associated with increased vulnerability to developing and maintaining sensitized mesolimbic DA function. Antipsychotic medications remain the best treatment option for managing the symptoms in schizophrenia. The peak effects of these medications are gradual, suggesting that a therapeutic component of antipsychotic treatment involves structural reorganization. Here we assessed whether repeated exposure to typical and atypical antipsychotics could also regulate DCC. Adult mice were orally administered haloperidol, clozapine, or risperidone via their drinking water for 4 weeks. Levels of DCC were measured by Western blot analysis of tissue punches of the VTA, medial prefrontal cortex, nucleus accumbens, and dorsal striatum. Haloperidol decreased DCC levels by approximately 50% in the VTA, but not in DA targets. Furthermore, haloperidol did not alter UNC-5 homologue levels, another family of netrin-1 receptors, confirming that its effects target DCC-mediated netrin-1 signaling specifically. The atypical antipsychotics did not alter DCC expression. These results suggest that typical antipsychotics induce selective functional reorganization in the VTA via DCC-mediated netrin-1 signaling.