Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia

• Published in: Synapse (New York, N.Y.) Vol. 62; no. 11; pp. 819 - 828
• Main Authors: Seeman, Philip, Guan, Hong-Chang
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2008
• Subjects: Amino Acids - metabolism; Amino Acids - pharmacology; Animals; Binding, Competitive - physiology; Bridged Bicyclo Compounds, Heterocyclic - metabolism; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; CHO Cells; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Cricetinae; Cricetulus; D2High receptor; DA partial agonist; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists - metabolism; Excitatory Amino Acid Agonists - pharmacology; glutamate agonist; Humans; ketamine; LY 379268; phencyclidine; Phencyclidine - metabolism; Phencyclidine - pharmacology; Protein Binding - drug effects; Protein Binding - physiology; Protein Isoforms - metabolism; Rats; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - metabolism; schizophrenia; Schizophrenia - metabolism
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.20561

It has previously been reported that the glutamate ionotropic antagonist phencyclidine directly inhibits the release of prolactin in anterior pituitary cells in culture, suggesting that phencyclidine has a dopamine (DA)‐like action on prolactin‐releasing cells. It has also been reported that the glutamate metabotropic agonist LY379268 can stimulate the incorporation of [35S]GTP‐γ‐S into DA D2Long receptors. The present study was done to examine whether such glutamatergic drugs had similar actions on the DA D2Short receptor. The present results show that phencyclidine, ketamine, and LY379268 also stimulated the incorporation of [35S]GTP‐γ‐S into D2Short receptors. The proportion of D2Long and D2Short receptors existing in the high‐affinity state were both markedly reduced by NaCl. While phencyclidine and LY379268 each stimulated the incorporation of GTP‐γ‐S into D2Long and D2Short receptors, this stimulation was reduced by NaCl, with D2Short being much more sensitive than D2Long to the inhibition by NaCl. The binding of phencyclidine and LY379268 to D2High receptors in vivo was directly confirmed by the i.v. injection of phencyclidine and LY379268 in which 50% inhibited the binding of [3H]PHNO to the striatum ex vivo at 0.25 and 1.5 mg/kg, respectively. The results confirm that glutamate agonists and antagonists have a significant affinity for DA D2High receptors. The psychotogenic action of phencyclidine may stem from a combination or synergistic action of glutamate receptor antagonism and DA D2 agonism. In addition, the antipsychotic clinical action of LY379268 congeners such as LY404039 may be related to a combined or synergistic action of glutamate receptor stimulation together with a partial DA agonist action that reduces endogenous DA neurotransmission. Synapse 62:819–828, 2008. © 2008 Wiley‐Liss, Inc.