Haloperidol induces persistent down-regulation of tyrosine hydroxylase immunoreactivity in substantia nigra but not ventral tegmental area in the rat

The dopamine antagonist haloperidol can cause tardive side-effects that may persist after the drug is withdrawn. We studied the time course of changes in dopaminergic neurons of the substantia nigra and ventral tegmental area following withdrawal of haloperidol. Rats received daily intraperitoneal injections of saline or haloperidol for eight weeks and were killed at two, four or 12 weeks after the final injection. Sections of substantia nigra and ventral tegmental area were processed for tyrosine hydroxylase immunohistochemistry. Quantitative morphometric analysis was carried out blinded in order to determine the number, cell body size and topography of tyrosine hydroxylase-positive cells, and the immunoreactive area of the substantia nigra and ventral tegmental area. In haloperidol-treated rats, tyrosine hydroxylase-positive cell counts were normal in ventral tegmental area but were decreased in substantia nigra by 34% at two weeks withdrawal and by 52% at four weeks withdrawal; cell counts were almost fully recovered by 12 weeks withdrawal. Cross-sectional area of tyrosine hydroxylase immunoreactivity within the substantia nigra demonstrated a similar pattern of reduction, with full recovery by 12 weeks withdrawal. Mean cell size, by contrast, was essentially unchanged at two and four weeks withdrawal, but was significantly decreased in sub-regions of substantia nigra at 12 weeks withdrawal. These results indicate that haloperidol can produce selective changes in midbrain dopamine neurons that persist long after discontinuation of the drug. This decrease in tyrosine hydroxylase-immunoreactive cell counts may play a role in the neurobiology of the persistent tardive syndromes associated with the use of neuroleptics.