Tardive dyskinesi a (TD) is a major mental health problem complicating or limiting therapy in perhaps 20% of patients treated chronically with antischizophrenic neuroleptic drugs. Dopamine receptor suprasensitivity has been invoked to explain TD, but these receptor changes develop in neuroleptic-treated patients with and without TD, weakening this explanation. We have recently found neuroleptic-induced alterations in receptors for the peptide neurotensin in the substantia nigra. In both rat and human brains subject to long-term neuroleptics, neurotensin receptor densities almost double. In the rat, these changes are 6-8 times as large as neuroleptic-induced changes in dopamine receptors. Autoradiographic studies in rats and humans after dopamine- specific lesions suggest that most of these receptors are localized to dopaminergic nigral neurons. Could this increased density of peptide receptors contribute to motor symptoms of dopamine excess and to the clinical expression of TD? We will test these receptor changes to establish parallels with TD. These characteristics include: delayed onset after initiation of neuroleptic treatment; persistence following cessation of chronic neroleptic treatment; and development with different chemical classes of neuroleptics. Testing neuroleptic influences on other nigral receptor populations and on neurotensin receptors in other brain regions will define the specificity of the effect and possibly implicate other neurotransmitter systems in the process. In human brain, we will compare neurotensin receptors in specimens from neuroleptic-treated patients with and without TD. Recent electron microscopic observations in rats suggest the presynaptic substantia nigra systems are altered by chronic neuroleptics. Immunohistochemical studies of neurotensin-immunoreactive elements in neuroleptic-treated rats will explore the possibility that some of these altered systems contain neurotensin. Definition of neuroleptic-induced changes in peptide receptor populations should allow better understanding, and possibly even improved therapy, for TD and other motor side effects of chronic neuroleptic use.
NIH ExPorter
NIH ExPorter