Subject(s)
Antiparkinson Agents/therapeutic use , Parkinson Disease/drug therapy , Parkinson Disease/surgery , Adrenal Medulla/transplantation , Combined Modality Therapy , Dopamine Agonists/therapeutic use , Humans , Levodopa/therapeutic use , Stereotaxic Techniques , Thalamus/surgery , Transplantation, AutologousABSTRACT
Tardive dyskinesia (TD) affects between 10 and 50 percent of all patients on long-term antipsychotic therapy, depending on the population studied. Various risk factors for TD have been reported; a correlation between TD and substance abuse has been suggested in some reports and not found in others. This study analyzes the association of substance abuse with the incidence of tardive dyskinesia in a schizophrenic population. All patients at the West Side Veterans Affairs Medical Center are evaluated prior to the initiation of neuroleptic therapy with the Dyskinesia identification System: Condensed User Scale (DISCUS); those with a diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder during the years 1986 through 1993 were included in this analysis. History of substance abuse was considered positive if there was clinician report or diagnosis of substance abuse. These data were collected and analyzed using ANOVA. In a sample of 1,027 subjects (97% male), 83.2 percent had a neuroleptic exposure of 10 or more years, and slightly more than half (50.8 percent) had a positive history of substance abuse. Using research diagnostic criteria, 28.9 percent of the sample had tardive dyskinesia. Analysis of variance showed history of substance abuse (p < .000) and years on neuroleptics (p < .000) to be strongly correlated to a diagnosis of TD. Age was less strongly correlated to the DISCUS score (p < .01), and there was no association of TD with diagnosis (p = .237). This study therefore demonstrates a robust correlation between TD and substance abuse. A mechanism of action involving N-methyl-D-aspartate (NMDA)-mediated excitotoxicity is proposed.
Subject(s)
Dyskinesia, Drug-Induced/epidemiology , Substance-Related Disorders/complications , Adult , Antipsychotic Agents/adverse effects , Delayed-Action Preparations , Female , Humans , Male , Middle Aged , Retrospective Studies , Risk Factors , Schizophrenia/complications , Schizophrenia/drug therapyABSTRACT
The present investigation used an antibody directed against the extracellular domain of the signal transducing nerve growth factor receptor, trkA, to reveal immunoreactive perikarya or fibers within the olfactory bulb and tubercle, cingulate cortex, nucleus accumbens, striatum, endopiriform nucleus, septal/diagonal band complex, nucleus basalis, hippocampal complex, thalamic paraventricular and reuniens nuclei, periventricular hypothalamus, interpeduncular nucleus, mesencephalic nucleus of the fifth nerve, dorsal nucleus of the lateral lemniscus, prepositus hypoglossal nucleus, ventral cochlear nucleus, ventral lateral tegmentum, medial vestibular nucleus, spinal trigeminal nucleus oralis, nucleus of the solitary tract, raphe nuclei, and spinal cord. Colocalization experiments revealed that virtually all striatal trkA-immunoreactive neurons (> 99%) coexpressed choline acetyltransferase (ChAT) but not p75 nerve growth factor receptor (NGFR). Within the septal/diagonal band complex virtually all trkA neurons (> 95%) coexpressed both ChAT and p75 NGFR. More caudally, dual stained sections revealed numerous trkA/ChAT (> 80%) and trkA/p75 NGFR (> 95%) immunoreactive neurons within the nucleus basalis. In the brainstem, raphe serotonergic neurons (45%) coexpressed trkA. Sections stained with a pan-trk antibody that recognizes primarily trkA, as well as trkB and trkC, labeled neurons within all of these regions as well as within the hypothalamic arcuate, supramammilary, and supraoptic nuclei, hippocampus, inferior and superior colliculus, substantia nigra, ventral tegmental area of T'sai, and cerebellular Purkinje cells. Virtually all of these other regions with the exception of the cerebellum also expressed pan-trk immunoreactivity in the monkey. The widespread expression of trkA throughout the central neural axis suggests that this receptor may play a role in signal transduction mechanisms linked to NGF-related substances in cholinergic basal forebrain and noncholinergic systems. These findings suggest that pharmacological use of ligands for trkA could have beneficial effects on the multiple neuronal systems that are affected in such disorders as Alzheimer's disease.
Subject(s)
Central Nervous System/enzymology , Choline O-Acetyltransferase/metabolism , Neurons/enzymology , Protein-Tyrosine Kinases/metabolism , Receptors, Nerve Growth Factor/metabolism , Serotonin/metabolism , Animals , Central Nervous System/cytology , Immunohistochemistry , Male , Nerve Fibers/enzymology , Neurons/metabolism , Prosencephalon/enzymology , Prosencephalon/physiology , Raphe Nuclei/enzymology , Raphe Nuclei/physiology , Rats , Rats, Sprague-Dawley , Signal Transduction/physiologyABSTRACT
The free radical neuromodulator, nitric oxide (NO) has been implicated as a neurotoxin. Neurons containing NO synthase (NOS) also contain NADPH-diaphorase (NADPH-d) and are resistant to NO toxicity. We report that NADPH-d-containing neurons within the striatum are spared in patients with Parkinson's (PD) and Alzheimer's disease (AD). However, a number of these neurons in both diseases appeared shrunken or bulbous with foreshortened dendritic processes. Quantitative analysis of cell areas revealed a significant difference only in the size of putamenal AD neurons which were decreased compared to normal controls. The possible involvement of NO in the neuropathogenesis of striatal derangement is discussed.
