Characterization of the phencyclidine-induced increase in prefrontal cortical dopamine metabolism in the rat.
1. We have investigated the effects of a schizophrenomimetic drug phencyclidine (PCP) and N-methyl-D-aspartate (NMDA)-related agents alone or in combination on dopamine metabolism in the medial prefrontal cortex and striatum of the rats by measuring the tissue concentrations of dopamine and its metabolite, 3,4-dihyroxyphenylacetic acid (DOPAC), and the rate of dopamine disappearance (dopamine utilization) after its synthesis inhibition. 2. Systemic injection of PCP and selective, non-competitive, NMDA antagonists caused an increase of both tissue concentrations of DOPAC and dopamine utilization in the prefrontal cortex but not in the striatum. The PCP-induced augmentation of cortical dopamine metabolism was not influenced by selective lesion of ascending noradrenergic neurones. 3. Intra-prefrontal cortical infusion of PCP or selective competitive or non-competitive antagonists of the NMDA receptor mimicked the ability of systemic PCP injection to enhance DOPAC levels and dopamine utilization in the prefrontal cortex. However, an NMDA antagonist injected into the cell body area of the mesocortical dopaminergic neurones failed to affect dopamine metabolism in the prefrontal cortex. 4. The increasing effects of PCP and selective NMDA antagonists on cortical dopamine utilization were not additive, although a dopamine receptor antagonist, haloperidol, still accelerated the disappearance of dopamine, even in the presence of PCP. 5. Intra-cortical or intra-ventricular infusion of NMDA or D-alanine but not L-alanine, attenuated the ability of systemic PCP administration to facilitate prefrontal dopamine utilization. 6. These data suggest that PCP might activate prefrontal cortical dopaminergic neurones, at least in part, by blocking the NMDA receptor in the prefrontal cortex which participates in a tonic inhibitory control of the mesoprefrontal dopaminergic projections.
Umino
A
A
Department of Mental Disorder Research, National Institute of Neuroscience, Tokyo, Japan.
Takahashi
K
K
Nishikawa
T
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000409:Alanine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006213:Hallucinogens / Q000008:administration & dosage / Q000494:pharmacology*; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D015102:3,4-Dihydroxyphenylacetic Acid; D016202:N-Methylaspartate; D010622:Phencyclidine; D006220:Haloperidol; D000409:Alanine; D004298:Dopamine