LONG-TERM TREATMENT WITH THE TETRAHYDROPYRIDINE ANALOG (HPTP) OF HALOPERIDOL INFLUENCES DOPAMINE LIGAND-BINDING IN BABOON BRAIN - AN [I-123] IODOBENZAMIDE (IBZM) SPECT STUDY

Haloperidol (HP) and its tetrahydropyridine dehydration product yl)-[4 -(fluorophenyl)-4-oxobutyl]-1,2,3,6-tetraly- dropyridine (HPTP) are bo th metabolized in vivo to several pyridinium metabolites with potentia l neurotoxic properties similar to the neurotoxin 1-methyl-4-phenylpyr idinium (MPP(+)), a metabolite of the parkinsonian-inducing agent 1-me thyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The effect of long-te rm HPTP treatment on the central nervous system of baboons (Papio ursi nus) was studied using [I-123]iodobenzamide (IBZM) and single photon e mission computed tomography (SPECT) at 1-14 weeks after termination of HPTP treatment. Striatal dopamine receptor binding was measured semiq uantitatively by calculating the IBZM count rate ratios of the basal g anglia to frontal cortex and basal ganglia to cerebellum. Relative str iatal perfusion was assessed by similar Tc-99m-HMPAO (hexamethylpropyl ene amine oxime) ratios. Time activity curves of IBZM from the brain s tructures suggest that HPTP treatment results in a marked reduction in central dopamine ligand binding, and in particular D2-like receptor b inding. Increased washout of the ligand from all the brain structures investigated was seen in the HPTP-treated animals, also consistent wit h reduced binding. Cerebral blood flow in the control and HPTP-treated groups was similar, indicating that this did not account for the redu ced dopamine receptor binding of the IBZM ligand. These data suggest t hat treatment with HPTP induces significant effects on dopamine recept or binding that may contribute to some of the neurological disorders o bserved in humans undergoing chronic HP treatment.