Modulation of striatal dopamine release in vitro by agonists of the glycineB site of NMDA receptors; interaction with antipsychotics.
The N-methyl-D-aspartate (NMDA) glutamate receptor possesses an obligatory co-agonist site for D-serine and glycine, named the glycineB site. Several clinical trials indicate that glycineB agonists can improve negative and cognitive symptoms of schizophrenia when co-administered with antipsychotics. In the present study we have investigated the effects of glycineB agonists on the endogenous release of dopamine from preparations of rat striatal tissue prisms in static conditions. The glycineB agonists glycine (1 mM) and D-serine (10 microM), but not D-cycloserine (10 microM), substantially increased the spontaneous release of dopamine, but significantly reduced the release of dopamine evoked by NMDA. The effect of glycine on spontaneous release was abolished by the non-competitive NMDA antagonists 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801, 10 microM) and ifenprodil (5 microM), but was only partially suppressed by the competitive antagonist 4-(3-phosphonopropyl)-piperazine-2-carboxylic acid (CPP, 10 microM). The selective inhibitor of the glial glycine transporter GlyT1 N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS, 10 microM) significantly increased the release of dopamine in an MK-801-sensitive manner. Interestingly, haloperidol (1 microM), but not clozapine (10 microM), prevented the effects of glycine. This study shows that glycineB modulators can control dopamine release by interacting with a distinctive NMDA receptor subtype with which some typical antipsychotics can interfere.
Bennett
Stephen
S
Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, United Kingdom.
Gronier
Benjamin
B
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005998:Glycine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000819:agonists* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors; D012457:Salicylamides / Q000494:pharmacology
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D010879:Piperazines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D012457:Salicylamides; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D008274:Magnesium; D003024:Clozapine; D006220:Haloperidol; C045989:eticlopride; D005998:Glycine; D004298:Dopamine