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

• Published in: Brain research Vol. 855; no. 1; pp. 1 - 10
• Main Authors: Griffiths, M.R, Cooper, A.J, Barber, D.J, Mitchell, I.J
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 07.02.2000; Amsterdam Elsevier; New York, NY
• Subjects: Acetylcholine - physiology; Adrenal Cortex Hormones - physiology; Amphetamine; Amphetamine - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Behavior, Animal - drug effects; Benzazepines - pharmacology; Biogenic Monoamines - physiology; Biological and medical sciences; Caudate; Central Nervous System Stimulants - pharmacology; Cerebral Cortex - cytology; Corticosteroid; Dizocilpine Maleate - pharmacology; Dopamine - physiology; Dopamine Agonists - pharmacology; Dopamine Antagonists - pharmacology; Drug toxicity and drugs side effects treatment; Excitatory Amino Acid Antagonists - pharmacology; Globus Pallidus - cytology; Glutamic Acid - physiology; Hormone Antagonists - pharmacology; Male; Medical sciences; Mifepristone - pharmacology; Muscarinic Antagonists - pharmacology; Neostriatum - cytology; Neurons - cytology; Neurons - drug effects; NMDA; PCP; Pharmacology. Drug treatments; Phencyclidine - pharmacology; Quinpirole - pharmacology; Rats; Rats, Sprague-Dawley; Scopolamine - pharmacology; Stress, Physiological - physiopathology; Toxicity: nervous system and muscle; Corticosteroid; Caudate; Amphetamine; PCP, phencyclidine; NMDA; D2, D 2 dopamine receptor subtype; D1, D 1 dopamine receptor subtype; PCP; MK-801, dizocilpine; NMDA, N-methyl- d-aspartate; Apoptosis; Dopamine; Rat; Toxicity; Rodentia; Central nervous system; Corpus striatum; Glutamate; Pallidum; Vertebrata; Mammalia; Phencyclidine; Animal; Excitatory aminoacid; Neurotransmitter; Acetylcholine; Antagonist; NMDA receptor; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(99)01917-4

Phencyclidine (PCP) has recently been shown to induce apoptosis of a subpopulation of striatopallidal neurons which lie in the dorsomedial caudate–putamen. The pharmacological mechanisms underlying this PCP-induced striatal death were investigated in a series of small experiments. Striatal silver-methenamine-stained sections from rats injected acutely with dizocilpine (MK-801; 1.5–5 mg/kg, i.p.) were analysed to determine whether other non-competitive N-methyl- d-aspartate (NMDA) receptor antagonists could induce apoptotic-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 involvement 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 experiments were performed using scopolamine (cholinergic antagonist) as this drug blocks PCP-induced damage of the retrosplenial cortex and RU38486 (corticosteroid receptor antagonist) as a similar subpopulation of striatal neurons undergoes apoptosis following dexamethasone administration. Injection of neither MK-801 nor amphetamine induced elevations of apoptotic-like cells in the striatum nor did co-administration of SCH23390 or scopolamine affect the levels of PCP-induced striatal cell death. In contrast, quinpirole elevated the levels of PCP-induced apoptotic-like striatal cell death and RU38486 markedly reduced it. Within the retrosplenial cortex, scopolamine lowered PCP-induced apoptotic-like cell death whereas RU38486 was without effect. 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 the striatum and the retrosplenial cortex.