Clinical and neuropathological abnormalities in baboons treated with HPTP,the tetrahydropyridine analog of haloperidol

Tardive dyskinesia (TD) is relatively common among psychiatric patients on maintenance therapy with typical neuroleptics and persists in more than 20% even after withdrawal of the medication. Such persistence suggests an unde rlying pathology due to neurotoxicity. We present evidence for such a neuro toxic mechanism in a baboon model of TD. Four baboons were treated chronica lly with the dehydration product of haloperidol, 4-(4 chlorophenyl)-1-[4-(4 -fluorophenyl)oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP), which is metabol ized, similarly to haloperidol, to two neurotoxic pyridinium species. The a nimals developed orofacial dyskinesia which persisted after HPTP was ceased . Serial sections of the entire brain from the four treated animals and fou r vehicle-treated controls revealed volume loss in the basal forebrain and hypothalamus. Histological evaluation demonstrated a reduction in the densi ty of magnocellular neurons in the anterior region of the nucleus basalis o f Meynert (NbM). We speculate that the loss of these NbM neurons may be ass ociated with the persistent orofacial dyskinesia observed in the HPTP-treat ed animals. These findings may contribute to a better understanding of neur oleptic-induced TD. (C) 1999 Academic Press.