Characterization of interactions between phencyclidine and amphetamine in rodent prefrontal cortex and striatum: implications in NMDA/glycine-site-mediated dopaminergic dysregulation and dopamine transporter function.
N-Methyl-D-aspartate (NMDA) antagonists induced behavioral and neurochemical changes in rodents that serve as animal models of schizophrenia. Chronic phencyclidine (PCP, 15 mg/(kg day) for 3 weeks via Alzet osmotic pump) administration enhances the amphetamine (AMPH)-induced dopamine (DA) efflux in prefrontal cortex (PFC), similar to that observed in schizophrenia. NMDA/glycine-site agonists, such as glycine (GLY), administered via dietary supplementation, reverse the enhanced effect. The present study investigated mechanisms of glycine-induced reversal of PCP-induced stimulation of AMPH-induced DA release, using simultaneous measurement of DA and AMPH in brain microdialysate, as well as peripheral and tissue AMPH levels. PCP treatment, by itself, increased peripheral and central AMPH levels, presumably via interaction with hepatic enzymes (e.g. cytochrome P450 CYP2C11). GLY (16% diet) had no effect on peripheral AMPH levels in the presence of PCP. Nevertheless, GLY significantly reduced extracellular/tissue AMPH ratios in both PFC and striatum (STR), especially following PCP administration, suggesting a feedback mediated effect on the dopamine transporter. GLY also inhibited acute AMPH (5 mg/kg)-induced DA release in PFC, but not STR. These findings suggest that GLY may modulate DA release in brain by producing feedback regulation of dopamine transporter function, possibly via potentiation of NMDA-stimulated GABA release and presynaptic GABAB receptor activation. The present studies also demonstrate pharmacokinetic interaction between AMPH and PCP, which may be of both clinical and research relevance.
Sershen
Henry
H
Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY 10962, United States.
Balla
Andrea
A
Aspromonte
John M
JM
Xie
Shan
S
Cooper
Thomas B
TB
Javitt
Daniel C
DC
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D016202:N-Methylaspartate / Q000378:metabolism*; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D050483:Dopamine Plasma Membrane Transport Proteins; D016202:N-Methylaspartate; D000661:Amphetamine; D010622:Phencyclidine; D005998:Glycine; D004298:Dopamine