Regulation of glutamate carboxypeptidase II function in corticolimbic regions of rat brain by phencyclidine, haloperidol, and clozapine.
Mounting evidence indicates that hypofunction of NMDA glutamate receptors causes or contributes to the full symptomatology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), an endogenous neuropeptide, blocks NMDA receptors and inhibits glutamate release by activating metabotropic mGluR3 receptors. NAAG is catabolized to glutamate and N-acetyl-aspartate by the astrocytic enzyme glutamate carboxypeptidase II (GCP II). Changes in GCP II activity may be critically linked to changes in glutamatergic neurotransmission especially at NMDA receptors. We examined whether GCP II function is altered by treatment with the noncompetitive antagonist and psychotomimetic drug phencyclidine (PCP) and with the neuroleptics haloperidol (HAL) and clozapine (CLOZ), in corticolimbic brain regions of the adult rat. Chronic exposure to PCP produced significant increases in GCP II protein expression and activity in the prefrontal cortex (PFC) and hippocampus (HIPP). This effect may be explained by a compensatory response to persistent blockade of NMDA receptors. In addition, chronic treatment with neuroleptics upregulated GCP II activity, but not protein expression, in the PFC. In contrast, GCP II activity was decreased after acute exposure to HAL or CLOZ and was not changed after acute PCP treatment. These findings provide support for a role of GCP II function in the control of glutamatergic neurotransmission and suggest that some of the therapeutic actions of neuroleptic drugs may be mediated through their effects on GCP II activity. These results demonstrate that psychotomimetic and neuroleptic drugs modulate GCP II function in brain regions that are widely involved in the neuropathology of schizophrenia.
Flores
Cecilia
C
Department of Psychiatry, Harvard Medical School and McLean Hospital, Mailman Research Center, Belmont, MA, USA. cecilia.flores@mcgill.ca
Coyle
Joseph T
JT
D000818:Animals; D015153:Blotting, Western; D002268:Carboxypeptidases / Q000502:physiology*; D003024:Clozapine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II; D006220:Haloperidol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology
D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D012702:Serotonin Antagonists; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol