Striatal neurons express increased level of dopamine D2 receptor mRNA in response to haloperidol treatment: a quantitative in situ hybridization study.

In the present study, quantitative in situ hybridization was used to analyse the effect of haloperidol treatment on D2 dopamine receptor gene expression in the rat caudate-putamen nucleus. Variations of D2 receptor mRNA level were studied and measured at the macroscopic level of densitometric analysis of X-ray film and at the microscopic level by counting of autoradiographic silver grains in striatal cells. Macroscopic analysis demonstrated that haloperidol treatment two times 1 mg/kg per day during seven, 14 and 21 days increased D2 receptor mRNA level in the caudate-putamen. Detailed microscopic analysis demonstrated a significant increase in D2 receptor mRNA in the two neuronal populations known to express the D2 receptor gene: medium-sized neurons previously identified as enkephalinergic neurons, and large-sized neurons previously identified as cholinergic neurons. The increase was more important in cholinergic neurons (+119%) than in enkephalinergic neurons (+54%). Haloperidol treatment did not modify the number of medium-sized enkephalinergic neurons expressing the D2 receptor mRNA. In contrast, it significantly increased the percentage of large-sized neurons containing D2 receptor mRNA (from 80 to 94%). These results demonstrate that haloperidol treatment acts at the gene level to modulate D2 receptor content in striatal dopaminoceptive neurons, and that the D2 receptor mRNA increase in postsynaptic neurons contributes to dopamine supersensitivity induced by neuroleptics in the rat. This suggests that dopamine acts trans-synaptically to control D2 receptor gene expression in target striatal neurons. These results suggest that modifications of D2 receptor gene expression may be part of the biological events that lead to the movement disorders induced by neuroleptic drugs or Parkinson's disease.