The effects of haloperidol on dopamine receptor gene expression

Haloperidol is a widely prescribed antipsychotic that acts as a dopamine D2 receptor antagonist. Chronic administration of haloperidol leads to an increase in striatal D2 receptor binding; however, studies examining striatal D2 receptor mRNA after haloperidol treatment report inconsistent results. This study examines the effects of haloperidol on dopaminoceptive striatal neurons, as well as dopamine D2 containing striatal inputs. Rats were injected subcutaneously with 2 mg/kg haloperidol twice daily for 7 days. A significant (36%) increase in D2 mRNA was observed in the anterior cingulate cortex. However, no changes were observed in the amounts of D1, D2, D3 mRNA, or D2 heteronuclear RNA (hnRNA) in the striatum or in the levels of D2 mRNA and hnRNA in the substantia nigra and ventral tegmental area. Thus, increased striatal D2 binding after haloperidol treatment may not be the result of altered D2 gene activity in the striatum or midbrain, but could result from an increase in D2 mRNA in cingulate corticostriatal neurons and/or a longer half-life for the D2 receptor protein in striatal neurons. Striatal proenkephalin mRNA increased significantly in the caudate-putamen (45%), nucleus accumbens (36%), and the olfactory tubercle (27%) while prodynorphin mRNA remained unaltered after haloperidol treatment. Since D2 receptor mRNA is generally colocalized with proenkephalin mRNA in striatal neurons, these results demonstrate what is likely a selective cellular increase in proenkephalin mRNA without a parallel increase in D2 mRNA.