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 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.
Griffiths
M R
MR
School of Psychology, University of Birmingham, Birmingham, UK.
Cooper
A J
AJ
Barber
D J
DJ
Mitchell
I J
IJ
D000109:Acetylcholine / Q000502:physiology*; D000305:Adrenal Cortex Hormones / Q000502:physiology*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005917:Globus Pallidus / Q000166:cytology; D018698:Glutamic Acid / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D017072:Neostriatum / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000494:pharmacology; D013312:Stress, Physiological / Q000503:physiopathology
D000305:Adrenal Cortex Hormones; D001552:Benzazepines; D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D006727:Hormone Antagonists; D018727:Muscarinic Antagonists; D019257:Quinpirole; D015735:Mifepristone; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D000661:Amphetamine; D012601:Scopolamine; D010622:Phencyclidine; D000109:Acetylcholine; D004298:Dopamine