PHENCYCLIDINE AND CORTICOSTEROIDS INDUCE APOPTOSIS OF A SUBPOPULATIONOF STRIATAL NEURONS - A NEURAL SUBSTRATE FOR PSYCHOSIS

Phencyclidine, a non-competitive N-methyl-D-aspartate receptor antagon ist and indirect dopamine agonist, has neuroprotective properties. Phe ncyclidine, however, can also exert toxic effects and causes degenerat ion of neurons in the retrosplenial cortex. In this paper we demonstra te that acute administration of a high dose of phencyclidine to rats, (80 mg/kg), also causes death of a subpopulation of striatal neurons. The dying cells exhibited many of the morphological and biochemical fe atures of cells undergoing apoptosis as revealed by a silver methenami ne stain, propidium, iodide fluorescence histochemistry and a TUNEL pr ocedure. The majority of the dying cells tended to be clustered within the dorsomedial aspect of the striatum. The type of striatal cell und ergoing apoptosis was determined by stereotaxically injecting a colloi dal gold retrograde anatomical tracer into the major areas of striatal termination prior to the administration of phencyclidine. This proced ure demonstrated that phencyclidine induced striatal apoptosis is almo st exclusively limited to striatopallidal neurons. A similar series of experiments was conducted to determine whether the synthetic corticos teroid, dexamethasone, also induces apoptosis of striatal neurons. Cor ticosteroids are known to be toxic to hippocampal neurons and interact with striatal dopamine transmission. Acute administration of dexameth asone, (20 mg/kg), induced apoptosis of a subpopulation of striatal ce lls. As was the case with phencyclidine, most of the dexamethasone-ind uced apoptotic striatal cells were striatopallidal neurons located wit hin the dorsomedial striatum. The pathology during the early stages of Huntington's disease is restricted to an equivalent subpopulation of striatal neurons. Many Huntington's patients are extremely psychotic d uring this stage in the progression of the disease. Psychosis is also associated with the acute administration of both phencyclidine and dex amethasone to humans. We accordingly speculate that the selective loss of striatopallidal neurons in the dorsomedial striatum may represent the neural substrate of many forms of psychosis. (C) 1998 IBRO. Publis hed by Elsevier Science Ltd.