Pharmacological mechanisms mediating phencyclidine-induced apoptosis of striatopallidal neurons: the roles of glutamate, dopamine, acetylcholine and corticosteroids

Phencyclidine (PCP) has recently been shown to induce apoptosis of a subpop ulation of striatopallidal neurons which lie in the dorsomedial caudate-put amen. The pharmacological mechanisms underlying this PCP-induced striatal d eath were investigated in a series of small experiments. Striatal silver-me thenamine-stained sections from rats injected acutely with dizocilpine (MK- 801; 1.5-5 mg/kg, i.p.) were analysed to determine whether other non-compet itive N-methyl-D-aspartate (NMDA) receptor antagonists could induce apoptot ic-like changes in striatal cells, The effects of amphetamine (3-12 mg/kg, i.p.) were similarly investigated as PCP can elevate extracellular dopamine levels and dopamine has the potential to be neurotoxic. The potential invo lvement of dopamine transmission in PCP-induced striatal apoptosis was also tested by determining the effect of co-administering SCH23390 (D1 dopamine receptor antagonist) and quinpirole (D2 dopamine receptor agonist) on PCP (80 mg/kg, s.c.)-induced striatal apoptotic-like cell death. Equivalent exp eriments were performed using scopolamine (cholinergic antagonist) as this drug blocks PCP-induced damage of the retrosplenial cortex and RU38486 (cor ticosteroid receptor antagonist) as a similar subpopulation of striatal neu rons undergoes apoptosis following dexamethasone administration. Injection of neither MK-801 nor amphetamine induced elevations of apoptotic-like cell s in the striatum nor did co-administration of SCH23390 or scopolamine affe ct the levels of PCP-induced striatal cell death. In contrast, quinpirole e levated the levels of PCP-induced apoptotic-like striatal cell death and RU 38486 markedly reduced it. Within the retrosplenial cortex, scopolamine low ered PCP-induced apoptotic-like cell death whereas RU38486 was without effe ct. These results suggest that PCP-induced striatal apoptosis results from a corticosteroid-dependent mechanism. The results further demonstrate that different pathological mechanisms underlie PCP-induced neuronal damage in t he striatum and the retrosplenial cortex. (C) 2000 Elsevier Science B.V. Al l rights reserved.